A few diabetes papers of interest

i. Impact of Parental Socioeconomic Status on Excess Mortality in a Population-Based Cohort of Subjects With Childhood-Onset Type 1 Diabetes.

“Numerous reports have shown that individuals with lower SES during childhood have increased morbidity and all-cause mortality at all ages (10–14). Although recent epidemiological studies have shown that all-cause mortality in patients with T1D increases with lower SES in the individuals themselves (15,16), the association between parental SES and mortality among patients with childhood-onset T1D has not been reported to the best of our knowledge. Our hypothesis was that low parental SES additionally increases mortality in subjects with childhood-onset T1D. In this study, we used large population-based Swedish databases to 1) explore in a population-based study how parental SES affects mortality in a patient with childhood-onset T1D, 2) describe and compare how the effect differs among various age-at-death strata, and 3) assess whether the adult patient’s own SES affects mortality independently of parental SES.”

“The Swedish Childhood Diabetes Registry (SCDR) is a dynamic population-based cohort reporting incident cases of T1D since 1 July 1977, which to date has collected >16,000 prospective cases. […] All patients recorded in the SCDR from 1 January 1978 to 31 December 2008 were followed until death or 31 December 2010. The cohort was subjected to crude analyses and stratified analyses by age-at-death groups (0–17, 18–24, and ≥25 years). Time at risk was calculated from date of birth until death or 31 December 2010. Kaplan-Meier analyses and log-rank tests were performed to compare the effect of low maternal educational level, low paternal educational level, and family income support (any/none). Cox regression analyses were performed to estimate and compare the hazard ratios (HRs) for the socioeconomic variables and to adjust for the potential confounding variables age at onset and sex.”

“The study included 14,647 patients with childhood-onset T1D. A total of 238 deaths (male 154, female 84) occurred in 349,762 person-years at risk. The majority of mortalities occurred among the oldest age-group (≥25 years of age), and most of the deceased subjects had onset of T1D at the ages of 10–14.99 years […]. Mean follow-up was 23.9 years and maximum 46.5 years. The overall standardized mortality ratio up to the age of 47 years was 2.3 (95% CI 1.35–3.63); for females, it was 2.6 (1.28–4.66) and for males, 2.1 (1.27–3.49). […] Analyses on the effect of low maternal educational level showed an increased mortality for male patients (HR 1.43 [95% CI 1.01–2.04], P = 0.048) and a nonsignificant increased mortality for female patients (1.21 [0.722–2.018], P = 0.472). Paternal educational level had no significant effect on mortality […] Having parents who ever received income support was associated with an increased risk of death in both males (HR 1.89 [95% CI 1.36–2.64], P < 0.001) and females (2.30 [1.43–3.67], P = 0.001) […] Excluding the 10% of patients with the highest accumulated income support to parents during follow-up showed that having parents who ever received income support still was a risk factor for mortality.”

“A Cox model including maternal educational level together with parental income support, adjusting for age at onset and sex, showed that having parents who received income support was associated with a doubled mortality risk (HR 1.96 [95% CI 1.49–2.58], P < 0.001) […] In a Cox model including the adult patient’s own SES, having parents who received income support was still an independent risk factor in the younger age-at-death group (18–24 years). Among those who died at age ≥25 years of age, the patient’s own SES was a stronger predictor for mortality (HR 2.46 [95% CI 1.54–3.93], P < 0.001)”

“Despite a well-developed health-care system in Sweden, overall mortality up to the age of 47 years is doubled in both males and females with childhood-onset T1D. These results are in accordance with previous Swedish studies and reports from other comparable countries […] Previous studies indicated that low SES during childhood is associated with low glycemic control and diabetes-related morbidity in patients with T1D (8,9), and the current study implies that mortality in adulthood is also affected by parental SES. […] The findings, when stratified by age-at-death group, show that adult patients’ own need of income support independently predicted mortality in those who died at ≥25 years of age, whereas among those who died in the younger age-group (18–24 years), parental requirement of income support was still a strong independent risk factor. None of the present SES measures seem to predict mortality in the ages 0–17 years perhaps due to low numbers and, thus, power.”

ii. Exercise Training Improves but Does Not Normalize Left Ventricular Systolic and Diastolic Function in Adolescents With Type 1 Diabetes.

“Adults and adolescents with type 1 diabetes have reduced exercise capacity (810), which increases their risk for cardiovascular morbidity and mortality (11). The causes for this reduced exercise capacity are unclear. However, recent studies have shown that adolescents with type 1 diabetes have lower stroke volume during exercise, which has been attributed to alterations in left ventricular function (9,10). Reduced left ventricular compliance resulting in an inability to fill the left ventricle appropriately during exercise has been shown to contribute to the lower stroke volume during exercise in both adults and adolescents with type 1 diabetes (12).

Exercise training is recommended as part of the management of type 1 diabetes. However, the effects of exercise training on left ventricular function at rest and during exercise in adolescents with type 1 diabetes have not been investigated. In particular, it is unclear whether exercise training improves cardiac hemodynamics during exercise in adolescents with diabetes. Therefore, we aimed to assess left ventricular volumes at rest and during exercise in a group of adolescents with type 1 diabetes compared with adolescents without diabetes before and after a 20-week exercise-training program. We hypothesized that exercise training would improve exercise capacity and exercise stroke volume in adolescents with diabetes.”

RESEARCH DESIGN AND METHODS Fifty-three adolescents with type 1 diabetes (aged 15.6 years) were divided into two groups: exercise training (n = 38) and nontraining (n = 15). Twenty-two healthy adolescents without diabetes (aged 16.7 years) were included and, with the 38 participants with type 1 diabetes, participated in a 20-week exercise-training intervention. Assessments included VO2max and body composition. Left ventricular parameters were obtained at rest and during acute exercise using MRI.

RESULTS Exercise training improved aerobic capacity (10%) and stroke volume (6%) in both trained groups, but the increase in the group with type 1 diabetes remained lower than trained control subjects. […]

CONCLUSIONS These data demonstrate that in adolescents, the impairment in left ventricular function seen with type 1 diabetes can be improved, although not normalized, with regular intense physical activity. Importantly, diastolic dysfunction, a common mechanism causing heart failure in older subjects with diabetes, appears to be partially reversible in this age group.”

“This study confirms that aerobic capacity is reduced in [diabetic] adolescents and that this, at least in part, can be attributed to impaired left ventricular function and a blunted cardiac response to exercise (9). Importantly, although an aerobic exercise-training program improved the aerobic capacity and cardiac function in adolescents with type 1 diabetes, it did not normalize them to the levels seen in the training group without diabetes. Both left ventricular filling and contractility improved after exercise training in adolescents with diabetes, suggesting that aerobic fitness may prevent or delay the well-described impairment in left ventricular function in diabetes (9,10).

The increase in peak aerobic capacity (∼12%) seen in this study was consistent with previous exercise interventions in adults and adolescents with diabetes (14). However, the baseline peak aerobic capacity was lower in the participants with diabetes and improved with training to a level similar to the baseline observed in the participants without diabetes; therefore, trained adolescents with diabetes remained less fit than equally trained adolescents without diabetes. This suggests there are persistent differences in the cardiovascular function in adolescents with diabetes that are not overcome by exercise training.”

“Although regular exercise potentially could improve HbA1c, the majority of studies have failed to show this (3134). Exercise training improved aerobic capacity in this study without affecting glucose control in the participants with diabetes, suggesting that the effects of glycemic status and exercise training may work independently to improve aerobic capacity.”


iii. Change in Medical Spending Attributable to Diabetes: National Data From 1987 to 2011.

“Diabetes care has changed substantially in the past 2 decades. We examined the change in medical spending and use related to diabetes between 1987 and 2011. […] Using the 1987 National Medical Expenditure Survey and the Medical Expenditure Panel Surveys in 2000–2001 and 2010–2011, we compared per person medical expenditures and uses among adults ≥18 years of age with or without diabetes at the three time points. Types of medical services included inpatient care, emergency room (ER) visits, outpatient visits, prescription drugs, and others. We also examined the changes in unit cost, defined by the expenditure per encounter for medical services.”

RESULTS The excess medical spending attributed to diabetes was $2,588 (95% CI, $2,265 to $3,104), $4,205 ($3,746 to $4,920), and $5,378 ($5,129 to $5,688) per person, respectively, in 1987, 2000–2001, and 2010–2011. Of the $2,790 increase, prescription medication accounted for 55%; inpatient visits accounted for 24%; outpatient visits accounted for 15%; and ER visits and other medical spending accounted for 6%. The growth in prescription medication spending was due to the increase in both the volume of use and unit cost, whereas the increase in outpatient expenditure was almost entirely driven by more visits. In contrast, the increase in inpatient and ER expenditures was caused by the rise of unit costs. […] The increase was observed across all components of medical spending, with the greatest absolute increase in the spending on prescription medications ($1,528 increase), followed by inpatient visits ($680 increase) and outpatient visits ($430 increase). The absolute change in the spending on ER and other medical services use was relatively small. In relative terms, the spending on ER visits grew more than five times, faster than that of prescription medication and other medical components. […] Among the total annual diabetes-attributable medical spending, the spending on inpatient and outpatient visits dropped from 40% and 23% to 31% and 19%, respectively, between 1987 and 2011, whereas spending on prescription medication increased from 27% to 41%.”

“The unit costs rose universally in all five measures of medical care in adults with and without diabetes. For each hospital admission, diabetes patients spent significantly more than persons without diabetes. The gap increased from $1,028 to $1,605 per hospital admission between 1987 and 2001, and dropped slightly to $1,360 per hospital admission in 2011. Diabetes patients also had higher spending per ER visit and per purchase of prescription medications.”

“From 1999 to 2011, national data suggest that growth in the use and price of prescription medications in the general population is 2.6% and 3.6% per year, respectively; and the growth has decelerated in recent years (22). Our analysis suggests that the growth rates in the use and prices of prescription medications for diabetes patients are considerably higher. The higher rate of growth is likely, in part, due to the growing emphasis on achieving glycemic targets, the use of newer medications, and the use of multidrug treatment strategies in modern diabetes care practice (23,24). In addition, the growth of medication spending is fueled by the rising prices per drug, particularly the drugs that are newly introduced in the market. For example, the prices for newer drug classes such as glitazones, dipeptidyl peptidase-4 inhibitors, and incretins have been 8 to 10 times those of sulfonylureas and 5 to 7 times those of metformin (9).”

“Between 1987 and 2011, medical spending increased both in persons with and in persons without diabetes; and the increase was substantially greater among persons with diabetes. As a result, the medical spending associated with diabetes nearly doubled. The growth was primarily driven by the spending in prescription medications. Further studies are needed to assess the cost-effectiveness of increased spending on drugs.”

iv. Determinants of Adherence to Diabetes Medications: Findings From a Large Pharmacy Claims Database.

“Adults with type 2 diabetes are often prescribed multiple medications to treat hyperglycemia, diabetes-associated conditions such as hypertension and dyslipidemia, and other comorbidities. Medication adherence is an important determinant of outcomes in patients with chronic diseases. For those with diabetes, adherence to medications is associated with better control of intermediate risk factors (14), lower odds of hospitalization (3,57), lower health care costs (5,79), and lower mortality (3,7). Estimates of rates of adherence to diabetes medications vary widely depending on the population studied and how adherence is defined. One review found that adherence to oral antidiabetic agents ranged from 36 to 93% across studies and that adherence to insulin was ∼63% (10).”

“Using a large pharmacy claims database, we assessed determinants of adherence to oral antidiabetic medications in >200,000 U.S. adults with type 2 diabetes. […] We selected a cohort of members treated for diabetes with noninsulin medications (oral agents or GLP-1 agonists) in the second half of 2010 who had continuous prescription benefits eligibility through 2011. Each patient was followed for 12 months from their index diabetes claim date identified during the 6-month targeting period. From each patient’s prescription history, we collected the date the prescription was filled, how many days the supply would last, the National Drug Code number, and the drug name. […] Given the difficulty in assessing insulin adherence with measures such as medication possession ratio (MPR), we excluded patients using insulin when defining the cohort.”

“We looked at a wide range of variables […] Predictor variables were defined a priori and grouped into three categories: 1) patient factors including age, sex, education, income, region, past exposure to therapy (new to diabetes therapy vs. continuing therapy), and concurrent chronic conditions; 2) prescription factors including refill channel (retail vs. mail order), total pill burden per day, and out of pocket costs; and 3) prescriber factors including age, sex, and specialty. […] Our primary outcome of interest was adherence to noninsulin antidiabetic medications. To assess adherence, we calculated an MPR for each patient. The ratio captures how often patients refill their medications and is a standard metric that is consistent with the National Quality Forum’s measure of adherence to medications for chronic conditions. MPR was defined as the proportion of days a patient had a supply of medication during a calendar year or equivalent period. We considered patients to be adherent if their MPR was 0.8 or higher, implying that they had their medication supplies for at least 80% of the days. An MPR of 0.8 or above is a well-recognized index of adherence (11,12). Studies have suggested that patients with chronic diseases need to achieve at least 80% adherence to derive the full benefits of their medications (13). […] [W]e [also] determined whether a patient was persistent, that is whether they had not discontinued or had at least a 45-day gap in their targeted therapy.”

“Previous exposure to diabetes therapy had a significant impact on adherence. Patients new to therapy were 61% less likely to be adherent to their diabetes medication. There was also a clear age effect. Patients 25–44 years of age were 49% less likely to be adherent when compared with patients 45–64 years of age. Patients aged 65–74 years were 27% more likely to be adherent, and those aged 75 years and above were 41% more likely to be adherent when compared with the 45–64 year age-group. Men were significantly more likely to be adherent than women […I dislike the use of the word ‘significant’ in such contexts; there is a difference in the level of adherence, but it is not large in absolute terms; the male vs female OR is 1.14 (CI 1.12-1.16) – US]. Education level and household income were both associated with adherence. The higher the estimated academic achievement, the more likely the patient was to be adherent. Patients completing graduate school were 41% more likely to be adherent when compared with patients with a high school equivalent education. Patients with an annual income >$60,000 were also more likely to be adherent when compared with patients with a household income <$30,000.”

“The largest effect size was observed for patients obtaining their prescription antidiabetic medications by mail. Patients using the mail channel were more than twice as likely to be adherent to their antidiabetic medications when compared with patients filling their prescriptions at retail pharmacies. Total daily pill burden was positively associated with antidiabetic medication adherence. For each additional pill a patient took per day, adherence to antidiabetic medications increased by 22%. Patient out-of-pocket costs were negatively associated with adherence. For each additional $15 in out-of-pocket costs per month, diabetes medication adherence decreased by 11%. […] We found few meaningful differences in patient adherence according to prescriber factors.”

“In our study, characteristics that suggest a “healthier” patient (being younger, new to diabetes therapy, and taking few other medications) were all associated with lower odds of adherence to antidiabetic medications. This suggests that acceptance of a chronic illness diagnosis and the potential consequences may be an important, but perhaps overlooked, determinant of medication-taking behavior. […] Our findings regarding income and costs are important reminders that prescribers should consider the impact of medication costs on patients with diabetes. Out-of-pocket costs are an important determinant of adherence to statins (26) and a self-reported cause of underuse of medications in one in seven insured patients with diabetes (27). Lower income has previously been shown to be associated with poor adherence to diabetes medications (15) and a self-reported cause of cost-related medication underuse (27).”

v. The Effect of Alcohol Consumption on Insulin Sensitivity and Glycemic Status: A Systematic Review and Meta-analysis of Intervention Studies.

“Moderate alcohol consumption, compared with abstaining and heavy drinking, is related to a reduced risk of type 2 diabetes (1,2). Although the risk is reduced with moderate alcohol consumption in both men and women, the association may differ for men and women. In a meta-analysis, consumption of 24 g alcohol/day reduced the risk of type 2 diabetes by 40% among women, whereas consumption of 22 g alcohol/day reduced the risk by 13% among men (1).

The association of alcohol consumption with type 2 diabetes may be explained by increased insulin sensitivity, anti-inflammatory effects, or effects of adiponectin (3). Several intervention studies have examined the effect of moderate alcohol consumption on these potential underlying pathways. A meta-analysis of intervention studies by Brien et al. (4) showed that alcohol consumption significantly increased adiponectin levels but did not affect inflammatory factors. Unfortunately, the effect of alcohol consumption on insulin sensitivity has not been summarized quantitatively. A review of cross-sectional studies by Hulthe and Fagerberg (5) suggested a positive association between moderate alcohol consumption and insulin sensitivity, although the three intervention studies included in their review did not show an effect (68). Several other intervention studies also reported inconsistent results (9,10). Consequently, consensus is lacking about the effect of moderate alcohol consumption on insulin sensitivity. Therefore, we aimed to conduct a systematic review and meta-analysis of intervention studies investigating the effect of alcohol consumption on insulin sensitivity and other relevant glycemic measures.”

“22 articles met criteria for inclusion in the qualitative synthesis. […] Of the 22 studies, 15 used a crossover design and 7 a parallel design. The intervention duration of the studies ranged from 2 to 12 weeks […] Of the 22 studies, 2 were excluded from the meta-analysis because they did not include an alcohol-free control group (14,19), and 4 were excluded because they did not have a randomized design […] Overall, 14 studies were included in the meta-analysis”

“A random-effects model was used because heterogeneity was present (P < 0.01, I2 = 91%). […] For HbA1c, a random-effects model was used because the I2 statistic indicated evidence for some heterogeneity (I2 = 30%).” [Cough, you’re not supposed to make these decisions that way, coughUS. This is not the first time I’ve seen this approach applied, and I don’t like it; it’s bad practice to allow the results of (frequently under-powered) heterogeneity tests to influence model selection decisions. As Bohrenstein and Hedges point out in their book, “A report should state the computational model used in the analysis and explain why this model was selected. A common mistake is to use the fixed-effect model on the basis that there is no evidence of heterogeneity. As [already] explained […], the decision to use one model or the other should depend on the nature of the studies, and not on the significance of this test”]

“This meta-analysis shows that moderate alcohol consumption did not affect estimates of insulin sensitivity or fasting glucose levels, but it decreased fasting insulin concentrations and HbA1c. Sex-stratified analysis suggested that moderate alcohol consumption may improve insulin sensitivity and decrease fasting insulin concentrations in women but not in men. The meta-regression suggested no influence of dosage and duration on the results. However, the number of studies may have been too low to detect influences by dosage and duration. […] The primary finding that alcohol consumption does not influence insulin sensitivity concords with the intervention studies included in the review of Hulthe and Fagerberg (5). This is in contrast with observational studies suggesting a significant association between moderate alcohol consumption and improved insulin sensitivity (34,35). […] We observed lower levels of HbA1c in subjects consuming moderate amounts of alcohol compared with abstainers. This has also been shown in several observational studies (39,43,44). Alcohol may decrease HbA1c by suppressing the acute rise in blood glucose after a meal and increasing the early insulin response (45). This would result in lower glucose concentrations over time and, thus, lower HbA1c concentrations. Unfortunately, the underlying mechanism of glycemic control by alcohol is not clearly understood.”

vi. Predictors of Lower-Extremity Amputation in Patients With an Infected Diabetic Foot Ulcer.

“Infection is a frequent complication of diabetic foot ulcers, with up to 58% of ulcers being infected at initial presentation at a diabetic foot clinic, increasing to 82% in patients hospitalized for a diabetic foot ulcer (1). These diabetic foot infections (DFIs) are associated with poor clinical outcomes for the patient and high costs for both the patient and the health care system (2). Patients with a DFI have a 50-fold increased risk of hospitalization and 150-fold increased risk of lower-extremity amputation compared with patients with diabetes and no foot infection (3). Among patients with a DFI, ∼5% will undergo a major amputation and 20–30% a minor amputation, with the presence of peripheral arterial disease (PAD) greatly increasing amputation risk (46).”

“As infection of a diabetic foot wound heralds a poor outcome, early diagnosis and treatment are important. Unfortunately, systemic signs of inflammation such as fever and leukocytosis are often absent even with a serious foot infection (10,11). As local signs and symptoms of infection are also often diminished, because of concomitant peripheral neuropathy and ischemia (12), diagnosing and defining resolution of infection can be difficult.”

“The system developed by the International Working Group on the Diabetic Foot (IWGDF) and the Infectious Diseases Society of America (IDSA) provides criteria for the diagnosis of infection of ulcers and classifies it into three categories: mild, moderate, or severe. The system was validated in three relatively small cohorts of patients […] The European Study Group on Diabetes and the Lower Extremity (Eurodiale) prospectively studied a large cohort of patients with a diabetic foot ulcer (17), enabling us to determine the prognostic value of the IWGDF system for clinically relevant lower-extremity amputations. […] We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. […] Among these patients, 159 (28%) underwent an amputation. […] Patients were followed monthly until healing of the foot ulcer(s), major amputation, or death — up to a maximum of 1 year.”

“One hundred and ninety-nine patients had a grade 2 (mild) infection, 338 a grade 3 (moderate), and 38 a grade 4 (severe). Amputations were performed on 159 (28%) patients (126 minor and 33 major) within the year of follow-up; 103 patients (18%) underwent amputations proximal to and including the hallux. […] The independent predictors of any amputation were as follows: periwound edema, HR 2.01 (95% CI 1.33–3.03); foul smell, HR 1.74 (1.17–2.57); purulent and nonpurulent exudate, HR 1.67 (1.17–2.37) and 1.49 (1.02–2.18), respectively; deep ulcer, HR 3.49 (1.84–6.60); positive probe-to-bone test, HR 6.78 (3.79–12.15); pretibial edema, HR 1.53 (1.02–2.31); fever, HR 2.00 (1.15–3.48); elevated CRP levels but less than three times the upper limit of normal, HR 2.74 (1.40–5.34); and elevated CRP levels more than three times the upper limit, HR 3.84 (2.07–7.12). […] In comparison with mild infection, the presence of a moderate infection increased the hazard for any amputation by a factor of 2.15 (95% CI 1.25–3.71) and 3.01 (1.51–6.01) for amputations excluding the lesser toes. For severe infection, the hazard for any amputation increased by a factor of 4.12 (1.99–8.51) and for amputations excluding the lesser toes by a factor of 5.40 (2.20–13.26). Larger ulcer size and presence of PAD were also independent predictors of both any amputation and amputations excluding the lesser toes, with HRs between 1.81 and 3 (and 95% CIs between 1.05 and 6.6).”

“Previously published studies that have aimed to identify independent risk factors for lower-extremity amputation in patients with a DFI have noted an association with older age (5,22), the presence of fever (5), elevated acute-phase reactants (5,22,23), higher HbA1c levels (24), and renal insufficiency (5,22).”

“The new risk scores we developed for any amputation, and amputations excluding the lesser toes had higher prognostic capability, based on the area under the ROC curve (0.80 and 0.78, respectively), than the IWGDF system (0.67) […] which is currently the only one in use for infected diabetic foot ulcers. […] these Eurodiale scores were developed based on the available data of our cohort, and they will need to be validated in other populations before any firm conclusions can be drawn. The advantage of these newly developed scores is that they are easier for clinicians to perform […] These newly developed risk scores can be readily used in daily clinical practice without the necessity of obtaining additional laboratory testing.”


September 12, 2017 Posted by | Cardiology, Diabetes, Economics, Epidemiology, Health Economics, Infectious disease, Medicine, Microbiology, Statistics | Leave a comment

A few diabetes papers of interest

i. Eating Disorders in Girls and Women With Type 1 Diabetes: A Longitudinal Study of Prevalence, Onset, Remission, and Recurrence.

If these results can be trusted, then the prevalence of eating disorders in young female diabetics is disturbingly high. Some quotes:

“The prevalence, clinical characteristics, and medical consequences of disturbed eating behavior (DEB) and eating disorders (EDs) in individuals with type 1 diabetes has received increasing attention since case reports of this dangerous combination were first published in the 1980s (1,2). Although the specificity of this association was initially unclear, systematic research has demonstrated that teenage girls and women with type 1 diabetes are at significantly increased risk of DEB compared with their nondiabetic peers (3). Such DEB includes dieting, fasting, binge-eating, and a range of compensatory and purging behaviors that can directly interfere with optimal diabetes management. […] Deliberately underdosing or omitting insulin to induce hyperglycemia and loss of glucose in the urine, and thereby control weight, is a unique purging behavior to control weight that is available to individuals with type 1 diabetes (4). This is an important mediator of the association of DEB and EDs with poorer metabolic control (5,6) and contributes to an increased risk of a range of short-term and long-term diabetes-related medical complications. These include abnormal lipid profiles (7), diabetic ketoacidosis (6), retinopathy (8), neuropathy (9), and nephropathy (10), as well as higher than expected mortality (11).”

“Bryden et al. (13) assessed a group of individuals with type 1 diabetes in adolescence and then again in early adulthood. […] They found EDs or other significant eating problems in 26% of participants, as well as significant associations between eating problems, insulin misuse, and microvascular complications (14). Goebel-Fabbri et al. (15) assessed 234 adult women with type 1 diabetes twice over an 11-year period. They found insulin omission for weight control to be very common (reported by 30% at baseline). Insulin omission frequently persisted over the lengthy follow-up period and was associated with higher rates of diabetes-related medical complications and tripled risk of mortality.”

“This study describes the longitudinal course of disturbed eating behavior (DEB) and EDs in a cohort with type 1 diabetes. […] A total of 126 girls with type 1 diabetes receiving care for diabetes at The Hospital for Sick Children in Toronto participated in a series of seven interview-based assessments of ED behavior and psychopathology over a 14-year period, beginning in late childhood. […] Mean age was 11.8 ± 1.5 years at time 1 and 23.7 ± 2.1 years at time 7. At time 7, 32.4% (23/71) met the criteria for a current ED, and an additional 8.5% (6/71) had a subthreshold ED. Mean age at ED onset (full syndrome or below the threshold) was 22.6 years (95% CI 21.6–23.5), and the cumulative probability of onset was 60% by age 25 years. […] The average time between remission of ED and subsequent recurrence was 6.5 years (95% CI 4.4–8.6), and the cumulative probability of recurrence was 53% by 6 years after remission.”

“In this longitudinal study, EDs were common and persistent, and new onset of ED was documented well into adulthood. […] [The] rates provide evidence that disordered eating is a common and serious concern among girls and young women with type 1 diabetes. Although adolescent and adult women in the general population also frequently report dieting, rates of more extreme weight loss behaviors and clinical eating disorders tend to be lower than those that occurred in this study (22,2830). […] The point prevalence for DEB and ED continued to increase across the study, largely because of marked increases in reported insulin omission for weight loss. Of particular concern, insulin omission as a weight control method was reported by 27% of participants at time 7. This dangerous method of purging directly compromises metabolic control and confers both short-term and long-term medical risk. Other researchers found it to be highly persistent among adult women with type 1 diabetes and associated with increased morbidity and mortality (10,15). […] In this study, both DEB and EDs tended to be persistent, with a mean time from observed onset to detected remission of 6.0 and 4.3 years, respectively, and significant estimated risk of recurrence among those whose eating disturbances initially remitted. […] The high prevalence of DEB and EDs among women with type 1 diabetes, in addition to high incidence of new ED cases continuing into the young adult years, suggests that sustained efforts at prevention, detection, and treatment of eating disturbances are needed across the adolescent and young adult years among women with type 1 diabetes.”

ii. Excess Risk of Dying From Infectious Causes in Those With Type 1 and Type 2 Diabetes.

“Individuals with type 1 and type 2 diabetes are widely considered to be more prone to infections than those without diabetes (1). […] The underlying pathology for an increased risk of infections among people with diabetes is not fully elucidated and is probably multifactorial. However, there are some data to suggest that it could, in part, relate to a compromised immune system. Short- and long-term hyperglycemia may disturb immune functions such as neutrophil bactericidal function (13), cellular immunity (14), and complement activation (15). These defects in the immune system, along with vascular insufficiency, render patients with diabetes at higher risk for a variety of severe or invasive infections compared with those without diabetes (16).”

“While there is a reasonably good understanding of the biological link between diabetes and infection, there are few data quantifying the excess risk of acquiring an infection or dying from infections associated with diabetes. […] the objective of this study was to examine the excess risk of death from several infectious causes in those with type 1 and type 2 diabetes compared with the general population and to see if this excess risk differs by age and over time. […] A total of 1,108,982 individuals with diabetes who were registered with the Australian Diabetes register between 2000 and 2010 were linked to the National Death Index. Mortality outcomes were defined as infection-relatedA-B death (ICD codes A99–B99), pneumonia (J12–J189), septicemia (A40 and A41), and osteomyelitis (M86). […] During a median follow-up of 6.7 years, there were 2,891, 2,158, 1,248, and 147 deaths from infection-relatedA-B causes, pneumonia, septicemia, or osteomyelitis, respectively. Crude mortality rates from infectionsA-B were 0.147 and 0.431 per 1,000 person-years in type 1 and type 2 diabetes, respectively. Standardized mortality ratios (SMRs) were higher in type 1 and type 2 diabetes for all outcomes after adjustment for age and sex. For infection-relatedA-B mortality, SMRs were 4.42 (95% CI 3.68–5.34) and 1.47 (1.42–1.53) for type 1 and type 2 diabetes (P < 0.001), respectively. For pneumonia in type 1 diabetes, SMRs were approximately 5 and 6 in males and females, respectively, while the excess risk was ∼20% for type 2 (both sexes). For septicemia, SMRs were approximately 10 and 2 for type 1 and type 2 diabetes, respectively, and similar by sex. For osteomyelitis in type 1 diabetes, SMRs were 16 and 58 in males and females, respectively, and ∼3 for type 2 diabetes (both sexes).”

“This prospective study of more than one million people with diabetes provides evidence that individuals with type 1 and type 2 diabetes are more likely to die of infection-related death, in particular death due to pneumonia, septicemia, and osteomyelitis, compared with the general population. These data show that infection in those with diabetes is an important cause of mortality. […] the increased risk appears to be greater for type 1 than type 2 diabetes. […] Patients with diabetes have a higher case fatality from infections than those without diabetes (17,30), which is both due to altered host immunity and due to having a higher prevalence of comorbidities, which places them at increased risk of death.”

iii. Effects of Acute Hypoglycemia on Working Memory and Language Processing in Adults With and Without Type 1 Diabetes.

“Cognitive function is impaired during acute hypoglycemia and frequently affects people with type 1 diabetes (1,2); elucidation of which cognitive domains are affected and by how much is of practical importance. Although cognitive domains do not function independently of each other, it is pertinent to design studies that investigate how everyday activities are affected by hypoglycemia as this has direct relevance to people with diabetes. Previous studies have demonstrated the effects of hypoglycemia on specific cognitive domains, including memory, attention, nonverbal intelligence, visual and auditory information processing, psychomotor function, spatial awareness, and executive functioning (314). However, the effects of hypoglycemia on language processing have seldom been explored.”

“Slurred speech and language difficulties are recognized features of hypoglycemia, but to our knowledge, the effects of hypoglycemia on linguistic processing have not been studied systematically. The current study used transient insulin-induced hypoglycemia in adults with and without type 1 diabetes to examine its effects on three aspects of language: the relationship between working memory and language (reading span), grammatical decoding (self-paced reading), and grammatical encoding (producing subject-verb agreement). Tests of these issues have been used extensively to understand the nature of language processing and its relationship to other cognitive abilities, specifically working memory (17).”

“Forty adults were studied (20 with type 1 diabetes and 20 healthy volunteers) using a hyperinsulinemic glucose clamp to lower blood glucose to 2.5 mmol/L (45 mg/dL) (hypoglycemia) for 60 min, or to maintain blood glucose at 4.5 mmol/L (81 mg/dL) (euglycemia), on separate occasions. Language tests were applied to assess the effects of hypoglycemia on the relationship between working memory and language (reading span), grammatical decoding (self-paced reading), and grammatical encoding (subject-verb agreement). […] Hypoglycemia caused a significant deterioration in reading span (P < 0.001; η2 = 0.37; Cohen d = 0.65) and a fall in correct responses (P = 0.005; η2 = 0.19; Cohen d = 0.41). On the self-paced reading test, the reading time for the first sentence fragment increased during hypoglycemia (P = 0.039; η2 = 0.11; Cohen d = 0.25). […] Hypoglycemia caused a deterioration of subject-verb agreement (correct responses: P = 0.011; η2 = 0.159; Cohen d = 0.31).”

“[We] demonstrated a significant deterioration in the accuracy of subject-verb agreement and also in reading span, a measure of working memory. This latter finding is compatible with the results of a previous study by our group (14) that used a different cognitive test battery but had an identical study design. In the current study, performance in the TMB and DST was significantly impaired during hypoglycemia, consistent with previous observations (57,1012,24) and confirming that adequate hypoglycemia had been achieved to impair cognitive function. […] Different mental functions have been shown to vary in their sensitivity to neuroglycopenia. […] higher-level skills are more vulnerable to hypoglycemia than simple cognitive tasks (1). In addition, during hypoglycemia, speed is usually killed in order to preserve accuracy (1). […] results strongly suggest that hypoglycemia induces difficulties in seemingly easy linguistic tasks such as correctly reading aloud a simple sentence fragment and its completion. Compared with other clamp studies exploring the effects of hypoglycemia on cognitive function, this was a large study that recruited both participants with and participants without diabetes. The fact that similar results were obtained in both groups suggests that these effects on language relate to acute hypoglycemia rather than to a chronic alternation of glycemic status in diabetes.” [My bold – US. These observations seem to corroborate observations I’ve made myself in the past.]

iv. Current State of Type 1 Diabetes Treatment in the U.S.: Updated Data From the T1D Exchange Clinic Registry.

Figure 1 from this paper is the sort of image which is worth a 1000 words.

Some observations from the paper:

“Data from 16,061 participants updated between 1 September 2013 and 1 December 2014 were compared with registry enrollment data collected from 1 September 2010 to 1 August 2012. […] The overall average HbA1c was 8.2% (66 mmol/mol) at enrollment and 8.4% (68 mmol/mol) at the most recent update. During childhood, mean HbA1c decreased from 8.3% (67 mmol/mol) in 2–4-year-olds to 8.1% (65 mmol/mol) at 7 years of age, followed by an increase to 9.2% (77 mmol/mol) in 19-year-olds. Subsequently, mean HbA1c values decline gradually until ∼30 years of age, plateauing at 7.5–7.8% (58–62 mmol/mol) beyond age 30 until a modest drop in HbA1c below 7.5% (58 mmol/mol) in those 65 years of age. Severe hypoglycemia (SH) and diabetic ketoacidosis (DKA) remain all too common complications of treatment, especially in older (SH) and younger patients (DKA). […] Although the T1D Exchange registry findings are not population based and could be biased, it is clear that there remains considerable room for improving outcomes of treatment of type 1 diabetes across all age-groups.”

“[M]ean HbA1c values showed a gradual decline until ∼30 years of age, plateauing at a level of 7.5–7.8% (58–62 mmol/mol) beyond age 30 until a modest drop in HbA1c below 7.5% (58 mmol/mol) after 65 years of age. The ADA HbA1c goal of <7.5% (58 mmol/mol) was achieved by only a small percentage of children and adolescents <18 years of age (17–23%), and even fewer 18–25-year-olds (14%) met the ADA goal for adults of <7.0% (53 mmol/mol); this percentage increased to ∼30% in older adults […] across all age-groups, HbA1c was highest among non-Hispanic black participants, participants with lower annual household income, and those who performed SMBG less than four times per day […] On average, participants using an insulin pump or continuous glucose monitor tended to have lower HbA1c values [….] Among the subset of 2,561 participants who completed the participant questionnaire, 6% reported having had a seizure or loss of consciousness due to hypoglycemia in the prior 3 months, with the highest occurrence being among those who were 50 years old or older.”

“The most troubling aspect of the data is that the mean HbA1c level of 9.0% (75 mmol/mol) in 13–17-year-olds in the registry is only slightly lower than the 9.5% (80 mmol/mol) seen in 13–17-year-olds at the start of the DCCT in the 1980s (15). Clearly, advances in diabetes management over the past two decades have been less successful in overcoming the special challenges in managing teenagers than adults with type 1 diabetes. Our data also indicate that the majority of “emerging adults” in their 20s do not fully emerge with regard to glycemic control until they reach 30 years of age. […] In a cross-sectional comparison, the average HbA1c at the most recent update was higher than at enrollment (8.4 vs. 8.2% [68 vs. 66 mmol/mol]), suggesting a worsening in glycemic control over time. The greatest increase in HbA1c was observed in the 13–17 (9.0 vs. 8.7% [75 vs. 72 mmol/mol]) and 18–26-year-old (8.7 vs. 8.3% [72 vs. 67 mmol/mol]) groups. Although this could reflect differences in age and type 1 diabetes duration, the results nevertheless indicate that there certainly is no indication of improving glycemic control in these age-groups.”

v. Prevention and Reversal of Type 1 Diabetes — Past Challenges and Future Opportunities.

“Over the past three decades there have been a number of clinical trials directed at interdicting the type 1 diabetes (T1D) disease process in an attempt to prevent the development of the disease in those at increased risk or to stabilize — potentially even reverse — the disease in people with T1D, usually of recent onset. Unfortunately, to date there has been no prevention trial that has resulted in delay or prevention of T1D. […] Since the completion of the early trials, particularly during the past decade, a number of additional randomized, double-masked, adequately powered, controlled clinical trials have been conducted using many different immunological strategies. For the most part, these have been disappointing, with none showing unambiguous benefit in preserving β-cell function. […] [M]ost immune intervention trials in T1D have either failed to achieve success in preserving β-cell function or have met that hurdle but have nonetheless shown only a transient effect.”

vi. Diabetic Peripheral Neuropathy Compromises Balance During Daily Activities.

“Patients with diabetic peripheral neuropathy (DPN) have an altered gait strategy (13) and a fivefold increased risk of falling (46). Falling is a major health risk in many developed countries; for example, in the general U.K. population, over a quarter of accidents that required hospital treatment were the result of a fall (7). A fall is preceded by loss of balance, which may be recoverable in some individuals, but requires rapid responses and a high level of strength from the lower-limb muscles (8,9). Nevertheless, the more likely an individual is to lose balance, the more likely they will at some point experience a fall. Therefore, quantifying balance control during every day gait activities may be considered one of the closest proxies for the risk of falling.”

“During walking activities, when an individual transfers their weight from one limb to another there are brief periods of large separation between the center of mass and the center of pressure. High levels of muscular strength are required to maintain balance during these periods. These large separations between the center of mass and center of pressure experienced during the single stance periods of dynamic gait activities may be a contributing factor toward understanding why the risk of falling during gait activities is much greater than during quiet standing. Few studies, however, have attempted to address the issue of balance during walking in patients with diabetes, and none have addressed the much more physically challenging activities of stair ascent and descent, during which the risk of falling is known to be very high (7). We therefore investigated a more “dynamic” measure of balance during stair ascent, stair descent, and level walking — three activities with the highest risk of fall-related injury (7) — with the hypothesis that individuals with peripheral neuropathy would display greater separations between their center of mass and center of pressure (i.e., poorer balance), thereby contributing to explaining why they are at high risk of falls.”

“Gait analysis during level walking and stair negotiation was performed in 22 patients with diabetic neuropathy (DPN), 39 patients with diabetes without neuropathy (D), and 28 nondiabetic control subjects (C) using a motion analysis system and embedded force plates in a staircase and level walkway. Balance was assessed by measuring the separation between the body center of mass and center of pressure during level walking, stair ascent, and stair descent. […] DPN patients demonstrated greater (P < 0.05) maximum and range of separations of their center of mass from their center of pressure in the medial-lateral plane during stair descent, stair ascent, and level walking compared with the C group, as well as increased (P < 0.05) mean separation during level walking and stair ascent. The same group also demonstrated greater (P < 0.05) maximum anterior separations (toward the staircase) during stair ascent. […] Greater separations of the center of mass from the center of pressure present a greater challenge to balance. Therefore, the higher medial-lateral separations found in patients with DPN will require greater muscular demands to control upright posture. This may contribute to explaining why patients with DPN are more likely to fall, with the higher separations placing them at a higher risk of experiencing a sideways fall than nondiabetic control subjects. […] balance is markedly impaired in patients with DPN during the gait activities of level ground walking, stair ascent, and stair descent. […] During the gait tasks, we found no significant balance impairments in patients with diabetes without DPN, clearly emphasizing that the link between diabetes and instability is a symptom of peripheral neuropathy.”

August 26, 2017 Posted by | Diabetes, Infectious disease, Language, Neurology, Studies | Leave a comment

Infectious Disease Surveillance (III)

I have added some more observations from the book below.

“Zoonotic diseases are infections transmitted between animals and humans […]. A recent survey identified more than 1,400 species of human disease–causing agents, over half (58%) of which were zoonotic [2]. Moreover, nearly three-quarters (73%) of infectious diseases considered to be emerging or reemerging were zoonotic [2]. […] In many countries there is minimal surveillance for live animal imports or imported wildlife products. Minimal surveillance prevents the identification of wildlife trade–related health risks to the public, agricultural industry, and native wildlife [36] and has led to outbreaks of zoonotic diseases […] Southeast Asia [is] a hotspot for emerging zoonotic diseases because of rapid population growth, high population density, and high biodiversity […] influenza virus in particular is of zoonotic importance as multiple human infections have resulted from animal exposure [77–79].”

“[R]abies is an important cause of death in many countries, particularly in Africa and Asia [85]. Rabies is still underreported throughout the developing world, and 100-fold underreporting of human rabies is estimated for most of Africa [44]. Reasons for underreporting include lack of public health personnel, difficulties in identifying suspect animals, and limited laboratory capacity for rabies testing. […] Brucellosis […] is transmissible to humans primarily through consumption of unpasteurized milk or dairy products […] Brucella is classified as a category B bioterrorism agent [90] because of its potential for aerosolization [I should perhaps here mention that the book coverage does overlaps a bit with that of Fong & Alibek’s book – which I covered here – but that I decided against covering those topics in much detail here – US] […] The key to preventing brucellosis in humans is to control or eliminate infections in animals [91–93]; therefore, veterinarians are crucial to the identification, prevention, and control of brucellosis [89]. […] Since 1954 [there has been] an ongoing eradication program involving surveillance testing of cattle at slaughter, testing at livestock markets, and whole-herd testing on the farm [in the US] […] Except for endemic brucellosis in wildlife in the Greater Yellowstone Area, all 50 states and territories in the United States are free of bovine brucellosis [94].”

“Because of its high mortality rate in humans in the absence of early treatment, Y. pestis is viewed as one of the most pathogenic human bacteria [101]. In the United States, plague is most often found in the Southwest where it is transmitted by fleas and maintained in rodent populations [102]. Deer mice and voles typically serve as maintenance hosts [and] these animals are often resistant to plague [102]. In contrast, in amplifying host species such as prairie dogs, ground squirrels, chipmunks, and wood rats, plague spreads rapidly and results in high mortality [103]. […] Human infections with Y. pestis can result in bubonic, pneumonic, or septicemic plague, depending on the route of exposure. Bubonic plague is most common; however, pneumonic plague poses a more serious public health risk since it can be easily transmitted person-to-person through inhalation of aerosolized bacteria […] Septicemic plague is characterized by bloodstream infection with Y. pestis and can occur secondary to pneumonic or bubonic forms of infection or as a primary infection [6,60].
Plague outbreaks are often correlated with animal die-offs in the area [104], and rodent control near human residences is important to prevent disease [103]. […] household pets can be an important route of plague transmission and flea control in dogs and cats is an important prevention measure [105]. Plague surveillance involves monitoring three populations for infection: vectors (e.g., fleas), humans, and rodents [106]. In the past 20 years, the numbers of human cases of plague reported in the United States have varied from 1 to 17 cases per year [90]. […]
Since rodent species are the main reservoirs of the bacteria, these animals can be used for sentinel surveillance to provide an early warning of the public health risk to humans [106]. […] Rodent die-offs can often be an early indicator of a plague outbreak”.

“Zoonotic disease surveillance is crucial for protection of human and animal health. An integrated, sustainable system that collects data on incidence of disease in both animals and humans is necessary to ensure prompt detection of zoonotic disease outbreaks and a timely and focused response [34]. Currently, surveillance systems for animals and humans [operate] largely independently [34]. This results in an inability to rapidly detect zoonotic diseases, particularly novel emerging diseases, that are detected in the human population only after an outbreak occurs [109]. While most industrialized countries have robust disease surveillance systems, many developing countries currently lack the resources to conduct both ongoing and real-time surveillance [34,43].”

“Acute hepatitis of any cause has similar, usually indistinguishable, signs and symptoms. Acute illness is associated with fever, fatigue, nausea, abdominal pain, followed by signs of liver dysfunction, including jaundice, light to clay-colored stool, dark urine, and easy bruising. The jaundice, dark urine, and abnormal stool are because of the diminished capacity of the inflamed liver to handle the metabolism of bilirubin, which is a breakdown product of hemoglobin released as red blood cells are normally replaced. In severe hepatitis that is associated with fulminant liver disease, the liver’s capacity to produce clotting factors and to clear potential toxic metabolic products is severely impaired, with resultant bleeding and hepatic encephalopathy. […] An effective vaccine to prevent hepatitis A has been available for more than 15 years, and incidence rates of hepatitis A are dropping wherever it is used in routine childhood immunization programs. […] Currently, hepatitis A vaccine is part of the U.S. childhood immunization schedule recommended by the Advisory Committee on Immunization Practices (ACIP) [31].”

Chronic hepatitis — persistent and ongoing inflammation that can result from chronic infection — usually has minimal to no signs or symptoms […] Hepatitis B and C viruses cause acute hepatitis as well as chronic hepatitis. The acute component is often not recognized as an episode of acute hepatitis, and the chronic infection may have little or no symptoms for many years. With hepatitis B, clearance of infection is age related, as is presentation with symptoms. Over 90% of infants exposed to HBV develop chronic infection, while <1% have symptoms; 5–10% of adults develop chronic infection, but 50% or more have symptoms associated with acute infection. Among those who acquire hepatitis C, 15–45% clear the infection; the remainder have lifelong infection unless treated specifically for hepatitis C.”

“[D]ata are only received on individuals accessing care. Asymptomatic acute infection and poor or unavailable measurements for high risk populations […] have resulted in questionable estimates of the prevalence and incidence of hepatitis B and C. Further, a lack of understanding of the different types of viral hepatitis by many medical providers [18] has led to many undiagnosed individuals living with chronic infection, who are not captured in disease surveillance systems. […] Evaluation of acute HBV and HCV surveillance has demonstrated a lack of sensitivity for identifying acute infection in injection drug users; it is likely that most cases in this population go undetected, even if they receive medical care [36]. […] Best practices for conducting surveillance for chronic hepatitis B and C are not well established. […] The role of health departments in responding to infectious diseases is typically responding to acute disease. Response to chronic HBV infection is targeted to prevention of transmission to contacts of those infected, especially in high risk situations. Because of the high risk of vertical transmission and likely development of chronic disease in exposed newborns, identification and case management of HBV-infected pregnant women and their infants is a high priority. […] For a number of reasons, states do not conduct uniform surveillance for chronic hepatitis C. There is not agreement as to the utility of surveillance for chronic HCV infection, as it is a measurement of prevalent rather than incident cases.”

“Among all nationally notifiable diseases, three STDs (chlamydia, gonorrhea, and syphilis) are consistently in the top five most commonly reported diseases annually. These three STDs made up more than 86% of all reported diseases in the United States in 2010 [2]. […] The true burden of STDs is likely to be higher, as most infections are asymptomatic [4] and are never diagnosed or reported. A synthesis of a variety of data sources estimated that in 2008 there were over 100 million prevalent STDs and nearly 20 million incident STDs in the United States [5]. […] Nationally, 72% of all reported STDs are among persons aged 15–24 years [3], and it is estimated that 1 in 4 females aged 14–19 has an STD [7]. […] In 2011, the rates of chlamydia, gonorrhea, and primary and secondary syphilis among African-­Americans were, respectively, 7.5, 16.9, and 6.7 times the rates among whites [3]. Additionally, men who have sex with men (MSM) are disproportionately infected with STDs. […] several analyses have shown risk ratios above 100 for the associations between being an MSM and having syphilis or HIV [9,10]. […] Many STDs can be transmitted congenitally during pregnancy or birth. In 2008, over 400,000 neonatal deaths and stillbirths were associated with syphilis worldwide […] untreated chlamydia and gonorrhea can cause ophthalmia neonatorum in newborns, which can result in blindness [13]. The medical and societal costs for STDs are high. […] One estimate in 2008 put national costs at $15.6 billion [15].”

“A significant challenge in STD surveillance is that the term “STD” encompasses a variety of infections. Currently, there are over 35 pathogens that can be transmitted sexually, including bacteria […] protozoa […] and ectoparasites […]. Some infections can cause clinical syndromes shortly after exposure, whereas others result in no symptoms or have a long latency period. Some STDs can be easily diagnosed using self-collected swabs, while others require a sample of blood or a physical examination by a clinician. Consequently, no one particular surveillance strategy works for all STDs. […] The asymptomatic nature of most STDs limits inferences from case­-based surveillance, since in order to be counted in this system an infection must be diagnosed and reported. Additionally, many infections never result in disease. For example, an estimated 90% of human papillomavirus (HPV) infections resolve on their own without sequelae [24]. As such, simply counting infections may not be appropriate, and sequelae must also be monitored. […] Strategies for STD surveillance include case reporting; sentinel surveillance; opportunistic surveillance, including use of administrative data and positivity in screened populations; and population-­based studies […] the choice of strategy depends on the type of STD and the population of interest.”

“Determining which diseases and conditions should be included in mandatory case reporting requires balancing the benefits to the public health system (e.g., utility of the data) with the costs and burdens of case reporting. While many epidemiologists and public health practitioners follow the mantra “the more data, the better,” the costs (in both dollars and human resources) of developing and maintaining a robust case­-based reporting system can be large. Case­-based surveillance has been mandated for chlamydia, gonorrhea, syphilis, and chancroid nationally; but expansion of state­-initiated mandatory reporting for other STDs is controversial.”

August 18, 2017 Posted by | Books, Epidemiology, Immunology, Infectious disease, Medicine | Leave a comment

Infectious Disease Surveillance (II)

Some more observation from the book below.

“There are three types of influenza viruses — A, B, and C — of which only types A and B cause widespread outbreaks in humans. Influenza A viruses are classified into subtypes based on antigenic differences between their two surface glycoproteins, hemagglutinin and neuraminidase. Seventeen hemagglutinin subtypes (H1–H17) and nine neuraminidase subtypes (N1–N9) have been identifed. […] The internationally accepted naming convention for influenza viruses contains the following elements: the type (e.g., A, B, C), geographical origin (e.g., Perth, Victoria), strain number (e.g., 361), year of isolation (e.g., 2011), for influenza A the hemagglutinin and neuraminidase antigen description (e.g., H1N1), and for nonhuman origin viruses the host of origin (e.g., swine) [4].”

“Only two antiviral drug classes are licensed for chemoprophylaxis and treatment of influenza—the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir and zanamivir). […] Antiviral resistant strains arise through selection pressure in individual patients during treatment [which can lead to treatment failure]. […] they usually do not transmit further (because of impaired virus fitness) and have limited public health implications. On the other hand, primarily resistant viruses have emerged in the past decade and in some cases have completely replaced the susceptible strains. […] Surveillance of severe influenza illness is challenging because most cases remain undiagnosed. […] In addition, most of the influenza burden on the healthcare system is because of complications such as secondary bacterial infections and exacerbations of pre-existing chronic diseases, and often influenza is not suspected as an underlying cause. Even if suspected, the virus could have been already cleared from the respiratory secretions when the testing is performed, making diagnostic confirmation impossible. […] Only a small proportion of all deaths caused by influenza are classified as influenza-related on death certificates. […] mortality surveillance based only on death certificates is not useful for the rapid assessment of an influenza epidemic or pandemic severity. Detection of excess mortality in real time can be done by establishing specific monitoring systems that overcome these delays [such as sentinel surveillance systems, US].”

“Influenza vaccination programs are extremely complex and costly. More than half a billion doses of influenza vaccines are produced annually in two separate vaccine production cycles, one for the Northern Hemisphere and one for the Southern Hemisphere [54]. Because the influenza virus evolves constantly and vaccines are reformulated yearly, both vaccine effectiveness and safety need to be monitored routinely. Vaccination campaigns are also organized annually and require continuous public health efforts to maintain an acceptable level of vaccination coverage in the targeted population. […] huge efforts are made and resources spent to produce and distribute influenza vaccines annually. Despite these efforts, vaccination coverage among those at risk in many parts of the world remains low.”

“The Active Bacterial Core surveillance (ABCs) network and its predecessor have been examples of using surveillance as information for action for over 20 years. ABCs has been used to measure disease burden, to provide data for vaccine composition and recommended-use policies, and to monitor the impact of interventions. […] sites represent wide geographic diversity and approximately reflect the race and urban-to-rural mix of the U.S. population [37]. Currently, the population under surveillance is 19–42 million and varies by pathogen and project. […] ABCs has continuously evolved to address challenging questions posed by the six pathogens (H. influenzae; GAS [Group A Streptococcus], GBS [Group B Streptococcus], S.  pneumoniae, N. meningitidis, and MRSA) and other emerging infections. […] For the six core pathogens, the objectives are (1) to determine the incidence and epidemiologic characteristics of invasive disease in geographically diverse populations in the United States through active, laboratory, and population-based surveillance; (2) to determine molecular epidemiologic patterns and microbiologic characteristics of isolates collected as part of routine surveillance in order to track antimicrobial resistance; (3) to detect the emergence of new strains with new resistance patterns and/or virulence and contribute to development and evaluation of new vaccines; and (4) to provide an infrastructure for surveillance of other emerging pathogens and for conducting studies aimed at identifying risk factors for disease and evaluating prevention policies.”

“Food may become contaminated by over 250 bacterial, viral, and parasitic pathogens. Many of these agents cause diarrhea and vomiting, but there is no single clinical syndrome common to all foodborne diseases. Most of these agents can also be transmitted by nonfoodborne routes, including contact with animals or contaminated water. Therefore, for a given illness, it is often unclear whether the source of infection is foodborne or not. […] Surveillance systems for foodborne diseases provide extremely important information for prevention and control.”

“Since 1995, the Centers for Disease Control and Prevention (CDC) has routinely used an automated statistical outbreak detection algorithm that compares current reports of each Salmonella serotype with the preceding 5-year mean number of cases for the same geographic area and week of the year to look for unusual clusters of infection [5]. The sensitivity of Salmonella serotyping to detect outbreaks is greatest for rare serotypes, because a small increase is more noticeable against a rare background. The utility of serotyping has led to its widespread adoption in surveillance for food pathogens in many countries around the world [6]. […] Today, a new generation of subtyping methods […] is increasing the specificity of laboratory-based surveillance and its power to detect outbreaks […] Molecular subtyping allows comparison of the molecular “fingerprint” of bacterial strains. In the United States, the CDC coordinates a network called PulseNet that captures data from standardized molecular subtyping by PFGE [pulsed field gel electrophoresis]. By comparing new submissions and past data, public health officials can rapidly identify geographically dispersed clusters of disease that would otherwise not be apparent and evaluate them as possible foodborne-disease outbreaks [8]. The ability to identify geographically dispersed outbreaks has become increasingly important as more foods are mass-produced and widely distributed. […] Similar networks have been developed in Canada, Europe, the Asia Pacifc region, Latin America and the Caribbean region, the Middle Eastern region and, most recently, the African region”.

“Food consumption and practices have changed during the past 20 years in the United States, resulting in a shift from readily detectable, point-source outbreaks (e.g., attendance at a wedding dinner), to widespread outbreaks that occur over many communities with only a few illnesses in each community. One of the changes has been establishment of large food-producing facilities that disseminate products throughout the country. If a food product is contaminated with a low level of pathogen, contaminated food products are distributed across many states; and only a few illnesses may occur in each community. This type of outbreak is often difficult to detect. PulseNet has been critical for the detection of widely dispersed outbreaks in the United States [17]. […] The growth of the PulseNet database […] and the use of increasingly sophisticated epidemiological approaches have led to a dramatic increase in the number of multistate outbreaks detected and investigated.”

“Each year, approximately 35 million people are hospitalized in the United States, accounting for 170 million inpatient days [1,2]. There are no recent estimates of the numbers of healthcare-associated infections (HAI). However, two decades ago, HAI were estimated to affect more than 2 million hospital patients annually […] The mortality attributed to these HAI was estimated at about 100,000 deaths annually. […] Almost 85% of HAI in the United States are associated with bacterial pathogens, and 33% are thought to be preventable [4]. […] The primary purpose of surveillance [in the context of HAI] is to alert clinicians, epidemiologists, and laboratories of the need for targeted prevention activities required to reduce HAI rates. HAI surveillance data help to establish baseline rates that may be used to determine the potential need to change public health policy, to act and intervene in clinical settings, and to assess the effectiveness of microbiology methods, appropriateness of tests, and allocation of resources. […] As less than 10% of HAI in the United States occur as recognized epidemics [18], HAI surveillance should not be embarked on merely for the detection of outbreaks.”

“There are two types of rate comparisons — intrahospital and interhospital. The primary goals of intrahospital comparison are to identify areas within the hospital where HAI are more likely to occur and to measure the efficacy of interventional efforts. […] Without external comparisons, hospital infection control departments may [however] not know if the endemic rates in their respective facilities are relatively high or where to focus the limited fnancial and human resources of the infection control program. […] The CDC has been the central aggregating institution for active HAI surveillance in the United States since the 1960s.”

“Low sensitivity (i.e., missed infections) in a surveillance system is usually more common than low specificity (i.e., patients reported to have infections who did not actually have infections).”

“Among the numerous analyses of CDC hospital data carried out over the years, characteristics consistently found to be associated with higher HAI rates include affiliation with a medical school (i.e., teaching vs. nonteaching), size of the hospital and ICU categorized by the number of beds (large hospitals and larger ICUs generally had higher infection rates), type of control or ownership of the hospital (municipal, nonprofit, investor owned), and region of the country [43,44]. […] Various analyses of SENIC and NNIS/NHSN data have shown that differences in patient risk factors are largely responsible for interhospital differences in HAI rates. After controlling for patients’ risk factors, average lengths of stay, and measures of the completeness of diagnostic workups for infection (e.g., culturing rates), the differences in the average HAI rates of the various hospital groups virtually disappeared. […] For all of these reasons, an overall HAI rate, per se, gives little insight into whether the facility’s infection control efforts are effective.”

“Although a hospital’s surveillance system might aggregate accurate data and generate appropriate risk-adjusted HAI rates for both internal and external comparison, comparison may be misleading for several reasons. First, the rates may not adjust for patients’ unmeasured intrinsic risks for infection, which vary from hospital to hospital. […] Second, if surveillance techniques are not uniform among hospitals or are used inconsistently over time, variations will occur in sensitivity and specificity for HAI case finding. Third, the sample size […] must be sufficient. This issue is of concern for hospitals with fewer than 200 beds, which represent about 10% of hospital admissions in the United States. In most CDC analyses, rates from hospitals with very small denominators tend to be excluded [37,46,49]. […] Although many healthcare facilities around the country aggregate HAI surveillance data for baseline establishment and interhospital comparison, the comparison of HAI rates is complex, and the value of the aggregated data must be balanced against the burden of their collection. […] If a hospital does not devote sufficient resources to data collection, the data will be of limited value, because they will be replete with inaccuracies. No national database has successfully dealt with all the problems in collecting HAI data and each varies in its ability to address these problems. […] While comparative data can be useful as a tool for the prevention of HAI, in some instances no data might be better than bad data.”

August 10, 2017 Posted by | Books, Data, Epidemiology, Infectious disease, Medicine, Statistics | Leave a comment

Infectious Disease Surveillance (I)

Concepts and Methods in Infectious Disease Surveillance […] familiarizes the reader with basic surveillance concepts; the legal basis for surveillance in the United States and abroad; and the purposes, structures, and intended uses of surveillance at the local, state, national, and international level. […] A desire for a readily accessible, concise resource that detailed current methods and challenges in disease surveillance inspired the collaborations that resulted in this volume. […] The book covers major topics at an introductory-to-intermediate level and was designed to serve as a resource or class text for instructors. It can be used in graduate level courses in public health, human and veterinary medicine, as well as in undergraduate programs in public health–oriented disciplines. We hope that the book will be a useful primer for frontline public health practitioners, hospital epidemiologists, infection-control practitioners, laboratorians in public health settings, infectious disease researchers, and medical informatics specialists interested in a concise overview of infectious disease surveillance.”

I thought the book was sort of okay, but not really all that great. I assume part of the reason I didn’t like it as much as I might have is that someone like me don’t really need to know all the details about, say, the issues encountered in Florida while they were trying to implement electronic patient records, or whether or not the mandated reporting requirements for brucellosis in, say, Texas are different from those of, say, Florida – but the book has a lot of that kind of information. Useful knowledge if you work with this stuff, but if you don’t and you’re just curious about the topic ‘in a general way’ those kinds of details can subtract a bit from the experience. A lot of chapters cover similar topics and don’t seem all that well coordinated, in the sense that details which could easily have been left out of specific chapters without any significant information loss (because those details were covered elsewhere in the publication) are included anyway; we are probably told at least ten times what is the difference between active and passive surveillance. It probably means that the various chapters can be read more or less independently (you don’t need to read chapter 5 to understand the coverage in chapter 11), but if you’re reading the book from cover to cover the way I was that sort of approach is not ideal. However in terms of the coverage included in the individual chapters and the content in general, I feel reasonably confident that if you’re actually working in public health or related fields and so a lot of this stuff might be ‘work-relevant’ (especially if you’re from the US), it’s probably a very useful book to keep around/know about. I didn’t need to know how many ‘NBS-states’ there are, and whether or not South Carolina is such a state, but some people might.

As I’ve pointed out before, a two star goodreads rating on my part (which is the rating I gave this publication) is not an indication that I think a book is terrible, it’s an indication that the book is ‘okay’.

Below I’ve added some quotes and observations from the book. The book is an academic publication but it is not a ‘classic textbook’ with key items in bold etc.; I decided to use bold to highlight key concepts and observations below, to make the post easier to navigate later on (none of the bolded words below were in bold in the original text), but aside from that I have made no changes to the quotes included in this post. I would note that given that many of the chapters included in the book are not covered by copyright (many chapters include this observation: “Materials appearing in this chapter are prepared by individuals as part of their official duties as United States government employees and are not covered by the copyright of the book, and any views expressed herein do not necessarily represent the views of the United States government.”) I may decide to cover the book in a bit more detail than I otherwise would have.

“The methods used for infectious disease surveillance depend on the type of disease. Part of the rationale for this is that there are fundamental differences in etiology, mode of transmission, and control measures between different types of infections. […] Despite the fact that much of surveillance is practiced on a disease-specific basis, it is worth remembering that surveillance is a general tool used across all types of infectious and, noninfectious conditions, and, as such, all surveillance methods share certain core elements. We advocate the view that surveillance should not be regarded as a public health “specialty,” but rather that all public health practitioners should understand the general principles underlying surveillance.”

“Control of disease spread is achieved through public health actions. Public health actions resulting from information gained during the investigation usually go beyond what an individual physician can provide to his or her patients presenting in a clinical setting. Examples of public health actions include identifying the source of infection […] identifying persons who were in contact with the index case or any infected person who may need vaccines or antiinfectives to prevent them from developing the infection; closure of facilities implicated in disease spread; or isolation of sick individuals or, in rare circumstances, quarantining those exposed to an infected person. […] Monitoring surveillance data enables public health authorities to detect sudden changes in disease occurrence and distribution, identify changes in agents or host factors, and detect changes in healthcare practices […] The primary use of surveillance data at the local and state public health level is to identify cases or outbreaks in order to implement immediate disease control and prevention activities. […] Surveillance data are also used by states and CDC to monitor disease trends, demonstrate the need for public health interventions such as vaccines and vaccine policy, evaluate public health activities, and identify future research priorities. […] The final and most-important link in the surveillance chain is the application of […] data to disease prevention and control. A surveillance system includes a functional capacity for data collection, analysis, and dissemination linked to public health programs [6].

“The majority of reportable disease surveillance is conducted through passive surveillance methods. Passive surveillance means that public health agencies inform healthcare providers and other entities of their reporting requirements, but they do not usually conduct intensive efforts to solicit all cases; instead, the public health agency waits for the healthcare entities to submit case reports. Because passive surveillance is often incomplete, public health agencies may use hospital discharge data, laboratory testing records, mortality data, or other sources of information as checks on completeness of reporting and to identify additional cases. This is called active surveillance. Active surveillance usually includes intensive activities on the part of the public health agency to identify all cases of a specific reportable disease or group of diseases. […] Because it can be very labor intensive, active surveillance is usually conducted for a subset of reportable conditions, in a defined geographic locale and for a defined period of time.”

“Active surveillance may be conducted on a routine basis or in response to an outbreak […]. When an outbreak is suspected or identified, another type of surveillance known as enhanced passive surveillance may also be initiated. In enhanced passive surveillance methods, public health may improve communication with the healthcare community, schools, daycare centers, and other facilities and request that all suspected cases be reported to public health. […] Case-based surveillance is supplemented through laboratory-based surveillance activities. As opposed to case-based surveillance, the focus is on laboratory results themselves, independent of whether or not an individual’s result is associated with a “case” of illness meeting the surveillance case definition. Laboratory-based surveillance is conducted by state public health laboratories as well as the healthcare community (e.g., hospital, private medical office, and commercial laboratories). […] State and local public health entities participate in sentinel surveillance activities. With sentinel methods, surveillance is conducted in a sample of reporting entities, such as healthcare providers or hospitals, or in a specific population known to be an early indicator of disease activity (e.g., pediatric). However, because the goal of sentinel surveillance is not to identify every case, it is not necessarily representative of the underlying population of interest; and results should be interpreted accordingly.”

Syndromic surveillance identifies unexpected changes in prediagnostic information from a variety of sources to detect potential outbreaks [56]. Sources include work- or school-absenteeism records, pharmacy sales for over-the-counter pharmaceuticals, or emergency room admission data [51]. During the 2009 H1N1 pandemic, syndromic surveillance of emergency room visits for influenza-like illness correlated well with laboratory diagnosed cases of influenza [57]. […] According to a 2008 survey of U.S. health departments, 88% of respondents reported that they employ syndromic-based approaches as part of routine surveillance [21].

“Public health operated for many decades (and still does to some extent) using stand-alone, case-based information systems for collection of surveillance data that do not allow information sharing between systems and do not permit the ability to track the occurrences of different diseases in a specific person over time. One of the primary objectives of NEDSS [National Electronic Disease Surveillance System] is to promote person-based surveillance and integrated and interoperable surveillance systems. In an integrated person-based system, information is collected to create a public health record for a given person for different diseases over time. This enables public health to track public health conditions associated with a person over time, allowing analyses of public health events and comorbidities, as well as more robust public health interventions. An interoperable system can exchange information with other systems. For example, data are shared between surveillance systems or between other public health or clinical systems, such as an electronic health record or outbreak management system. Achieving the goal of establishing a public health record for an individual over time does not require one monolithic system that supports all needs; this can, instead, be achieved through integration and/or interoperability of systems.

“For over a decade, public health has focused on automation of reporting of laboratory results to public health from clinical laboratories and healthcare providers. Paper-based submission of laboratory results to public health for reportable conditions results in delays in receipt of information, incomplete ascertainment of possible cases, and missing information on individual reports. All of these aspects are improved through automation of the process [39–43].”

“During the pre-vaccine era, rotavirus infected nearly every unvaccinated child before their fifth birthday. In the absence of vaccine, multiple rotavirus infections may occur during infancy and childhood. Rotavirus causes severe diarrhea and vomiting (acute gastroenteritis [AGE]), which can lead to dehydration, electrolyte depletion, complications of viremia, shock, and death. Nearly one-half million children around the world die of rotavirus infections each year […] [In the US] this virus was responsible for 40–50% of hospitalizations because of acute gastroenteritis during the winter months in the era before vaccines were introduced. […] Because first infections have been shown to induce strong immunity against severe rotavirus reinfections [3] and because vaccination mimics such first infections without causing illness, vaccination was identified as the optimal strategy for decreasing the burden associated with severe and fatal rotavirus diarrhea. Any changes that may be later attributed to vaccination effects require knowledge of the pre-licensure (i.e., baseline) rates and trends in the target disease as a reference […] Efforts to obtain baseline data are necessary before a vaccine is licensed and introduced [13]. […] After the first year of widespread rotavirus vaccination coverage in 2008, very large and consistent decreases in rotavirus hospitalizations were noted around the country. Many of the decreases in childhood hospitalizations resulting from rotavirus were 90% or more, compared with the pre-licensure, baseline period.”

There is no single perfect data source for assessing any VPD [Vaccine-Preventable Disease, US]. Meaningful surveillance is achieved by the much broader approach of employing diverse datasets. The true impact of a vaccine or the accurate assessment of disease trends in a population is more likely the result of evaluating many datasets having different strengths and weaknesses. Only by understanding these strengths and weaknesses can a public health practitioner give the appropriate consideration to the findings derived from these data. […] In a Phase III clinical trial, the vaccine is typically administered to large numbers of people who have met certain inclusionary and exclusionary criteria and are then randomly selected to receive either the vaccine or a placebo. […] Phase III trials represent the “best case scenario” of vaccine protection […] Once the Phase III trials show adequate protection and safety, the vaccine may be licensed by the FDA […] When the vaccine is used in routine clinical practice, Phase IV trials (called post-licensure studies or post-marketing studies) are initiated. These are the evaluations conducted during the course of VPD surveillance that delineate additional performance information in settings where strict controls on who receives the vaccine are not present. […] Often, measuring vaccine performance in the broader population yields slightly lower protective results compared to Phase III clinical trials […] During these post-licensure Phase IV studies, it is not the vaccine’s efficacy but its effectiveness that is assessed. […] Administrative datasets may be created by research institutions, managed-care organizations, or national healthcare utilization repositories. They are not specifically created for VPD surveillance and may contain coded data […] on health events. They often do not provide laboratory confirmation of specific diseases, unlike passive and active VPD surveillance. […] administrative datasets offer huge sample sizes, which allow for powerful inferences within the confines of any data limitations.”

August 6, 2017 Posted by | Books, Epidemiology, Infectious disease, Medicine, Pharmacology | Leave a comment

Random stuff

It’s been a long time since I last posted one of these posts, so a great number of links of interest has accumulated in my bookmarks. I intended to include a large number of these in this post and this of course means that I surely won’t cover each specific link included in this post in anywhere near the amount of detail it deserves, but that can’t be helped.

i. Autism Spectrum Disorder Grown Up: A Chart Review of Adult Functioning.

“For those diagnosed with ASD in childhood, most will become adults with a significant degree of disability […] Seltzer et al […] concluded that, despite considerable heterogeneity in social outcomes, “few adults with autism live independently, marry, go to college, work in competitive jobs or develop a large network of friends”. However, the trend within individuals is for some functional improvement over time, as well as a decrease in autistic symptoms […]. Some authors suggest that a sub-group of 15–30% of adults with autism will show more positive outcomes […]. Howlin et al. (2004), and Cederlund et al. (2008) assigned global ratings of social functioning based on achieving independence, friendships/a steady relationship, and education and/or a job. These two papers described respectively 22% and 27% of groups of higher functioning (IQ above 70) ASD adults as attaining “Very Good” or “Good” outcomes.”

“[W]e evaluated the adult outcomes for 45 individuals diagnosed with ASD prior to age 18, and compared this with the functioning of 35 patients whose ASD was identified after 18 years. Concurrent mental illnesses were noted for both groups. […] Comparison of adult outcome within the group of subjects diagnosed with ASD prior to 18 years of age showed significantly poorer functioning for those with co-morbid Intellectual Disability, except in the domain of establishing intimate relationships [my emphasis. To make this point completely clear, one way to look at these results is that apparently in the domain of partner-search autistics diagnosed during childhood are doing so badly in general that being intellectually disabled on top of being autistic is apparently conferring no additional disadvantage]. Even in the normal IQ group, the mean total score, i.e. the sum of the 5 domains, was relatively low at 12.1 out of a possible 25. […] Those diagnosed as adults had achieved significantly more in the domains of education and independence […] Some authors have described a subgroup of 15–27% of adult ASD patients who attained more positive outcomes […]. Defining an arbitrary adaptive score of 20/25 as “Good” for our normal IQ patients, 8 of thirty four (25%) of those diagnosed as adults achieved this level. Only 5 of the thirty three (15%) diagnosed in childhood made the cutoff. (The cut off was consistent with a well, but not superlatively, functioning member of society […]). None of the Intellectually Disabled ASD subjects scored above 10. […] All three groups had a high rate of co-morbid psychiatric illnesses. Depression was particularly frequent in those diagnosed as adults, consistent with other reports […]. Anxiety disorders were also prevalent in the higher functioning participants, 25–27%. […] Most of the higher functioning ASD individuals, whether diagnosed before or after 18 years of age, were functioning well below the potential implied by their normal range intellect.”

Related papers: Social Outcomes in Mid- to Later Adulthood Among Individuals Diagnosed With Autism and Average Nonverbal IQ as Children, Adults With Autism Spectrum Disorders.

ii. Premature mortality in autism spectrum disorder. This is a Swedish matched case cohort study. Some observations from the paper:

“The aim of the current study was to analyse all-cause and cause-specific mortality in ASD using nationwide Swedish population-based registers. A further aim was to address the role of intellectual disability and gender as possible moderators of mortality and causes of death in ASD. […] Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27 122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2 672 185). […] During the observed period, 24 358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38–2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability. […] Premature mortality was markedly increased in ASD owing to a multitude of medical conditions. […] Mortality was significantly elevated in both genders relative to the general population (males: OR = 2.87; females OR = 2.24)”.

“Individuals in the control group died at a mean age of 70.20 years (s.d. = 24.16, median = 80), whereas the corresponding figure for the entire ASD group was 53.87 years (s.d. = 24.78, median = 55), for low-functioning ASD 39.50 years (s.d. = 21.55, median = 40) and high-functioning ASD 58.39 years (s.d. = 24.01, median = 63) respectively. […] Significantly elevated mortality was noted among individuals with ASD in all analysed categories of specific causes of death except for infections […] ORs were highest in cases of mortality because of diseases of the nervous system (OR = 7.49) and because of suicide (OR = 7.55), in comparison with matched general population controls.”

iii. Adhesive capsulitis of shoulder. This one is related to a health scare I had a few months ago. A few quotes:

Adhesive capsulitis (also known as frozen shoulder) is a painful and disabling disorder of unclear cause in which the shoulder capsule, the connective tissue surrounding the glenohumeral joint of the shoulder, becomes inflamed and stiff, greatly restricting motion and causing chronic pain. Pain is usually constant, worse at night, and with cold weather. Certain movements or bumps can provoke episodes of tremendous pain and cramping. […] People who suffer from adhesive capsulitis usually experience severe pain and sleep deprivation for prolonged periods due to pain that gets worse when lying still and restricted movement/positions. The condition can lead to depression, problems in the neck and back, and severe weight loss due to long-term lack of deep sleep. People who suffer from adhesive capsulitis may have extreme difficulty concentrating, working, or performing daily life activities for extended periods of time.”

Some other related links below:

The prevalence of a diabetic condition and adhesive capsulitis of the shoulder.
“Adhesive capsulitis is characterized by a progressive and painful loss of shoulder motion of unknown etiology. Previous studies have found the prevalence of adhesive capsulitis to be slightly greater than 2% in the general population. However, the relationship between adhesive capsulitis and diabetes mellitus (DM) is well documented, with the incidence of adhesive capsulitis being two to four times higher in diabetics than in the general population. It affects about 20% of people with diabetes and has been described as the most disabling of the common musculoskeletal manifestations of diabetes.”

Adhesive Capsulitis (review article).
“Patients with type I diabetes have a 40% chance of developing a frozen shoulder in their lifetimes […] Dominant arm involvement has been shown to have a good prognosis; associated intrinsic pathology or insulin-dependent diabetes of more than 10 years are poor prognostic indicators.15 Three stages of adhesive capsulitis have been described, with each phase lasting for about 6 months. The first stage is the freezing stage in which there is an insidious onset of pain. At the end of this period, shoulder ROM [range of motion] becomes limited. The second stage is the frozen stage, in which there might be a reduction in pain; however, there is still restricted ROM. The third stage is the thawing stage, in which ROM improves, but can take between 12 and 42 months to do so. Most patients regain a full ROM; however, 10% to 15% of patients suffer from continued pain and limited ROM.”

Musculoskeletal Complications in Type 1 Diabetes.
“The development of periarticular thickening of skin on the hands and limited joint mobility (cheiroarthropathy) is associated with diabetes and can lead to significant disability. The objective of this study was to describe the prevalence of cheiroarthropathy in the well-characterized Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort and examine associated risk factors […] This cross-sectional analysis was performed in 1,217 participants (95% of the active cohort) in EDIC years 18/19 after an average of 24 years of follow-up. Cheiroarthropathy — defined as the presence of any one of the following: adhesive capsulitis, carpal tunnel syndrome, flexor tenosynovitis, Dupuytren’s contracture, or a positive prayer sign [related link] — was assessed using a targeted medical history and standardized physical examination. […] Cheiroarthropathy was present in 66% of subjects […] Cheiroarthropathy is common in people with type 1 diabetes of long duration (∼30 years) and is related to longer duration and higher levels of glycemia. Clinicians should include cheiroarthropathy in their routine history and physical examination of patients with type 1 diabetes because it causes clinically significant functional disability.”

Musculoskeletal disorders in diabetes mellitus: an update.
“Diabetes mellitus (DM) is associated with several musculoskeletal disorders. […] The exact pathophysiology of most of these musculoskeletal disorders remains obscure. Connective tissue disorders, neuropathy, vasculopathy or combinations of these problems, may underlie the increased incidence of musculoskeletal disorders in DM. The development of musculoskeletal disorders is dependent on age and on the duration of DM; however, it has been difficult to show a direct correlation with the metabolic control of DM.”

Rheumatic Manifestations of Diabetes Mellitus.

Prevalence of symptoms and signs of shoulder problems in people with diabetes mellitus.

Musculoskeletal Disorders of the Hand and Shoulder in Patients with Diabetes.
“In addition to micro- and macroangiopathic complications, diabetes mellitus is also associated with several musculoskeletal disorders of the hand and shoulder that can be debilitating (1,2). Limited joint mobility, also termed diabetic hand syndrome or cheiropathy (3), is characterized by skin thickening over the dorsum of the hands and restricted mobility of multiple joints. While this syndrome is painless and usually not disabling (2,4), other musculoskeletal problems occur with increased frequency in diabetic patients, including Dupuytren’s disease [“Dupuytren’s disease […] may be observed in up to 42% of adults with diabetes mellitus, typically in patients with long-standing T1D” – link], carpal tunnel syndrome [“The prevalence of [carpal tunnel syndrome, CTS] in patients with diabetes has been estimated at 11–30 % […], and is dependent on the duration of diabetes. […] Type I DM patients have a high prevalence of CTS with increasing duration of disease, up to 85 % after 54 years of DM” – link], palmar flexor tenosynovitis or trigger finger [“The incidence of trigger finger [/stenosing tenosynovitis] is 7–20 % of patients with diabetes comparing to only about 1–2 % in nondiabetic patients” – link], and adhesive capsulitis of the shoulder (5–10). The association of adhesive capsulitis with pain, swelling, dystrophic skin, and vasomotor instability of the hand constitutes the “shoulder-hand syndrome,” a rare but potentially disabling manifestation of diabetes (1,2).”

“The prevalence of musculoskeletal disorders was greater in diabetic patients than in control patients (36% vs. 9%, P < 0.01). Adhesive capsulitis was present in 12% of the diabetic patients and none of the control patients (P < 0.01), Dupuytren’s disease in 16% of diabetic and 3% of control patients (P < 0.01), and flexor tenosynovitis in 12% of diabetic and 2% of control patients (P < 0.04), while carpal tunnel syndrome occurred in 12% of diabetic patients and 8% of control patients (P = 0.29). Musculoskeletal disorders were more common in patients with type 1 diabetes than in those with type 2 diabetes […]. Forty-three patients [out of 100] with type 1 diabetes had either hand or shoulder disorders (37 with hand disorders, 6 with adhesive capsulitis of the shoulder, and 10 with both syndromes), compared with 28 patients [again out of 100] with type 2 diabetes (24 with hand disorders, 4 with adhesive capsulitis of the shoulder, and 3 with both syndromes, P = 0.03).”

Association of Diabetes Mellitus With the Risk of Developing Adhesive Capsulitis of the Shoulder: A Longitudinal Population-Based Followup Study.
“A total of 78,827 subjects with at least 2 ambulatory care visits with a principal diagnosis of DM in 2001 were recruited for the DM group. The non-DM group comprised 236,481 age- and sex-matched randomly sampled subjects without DM. […] During a 3-year followup period, 946 subjects (1.20%) in the DM group and 2,254 subjects (0.95%) in the non-DM group developed ACS. The crude HR of developing ACS for the DM group compared to the non-DM group was 1.333 […] the association between DM and ACS may be explained at least in part by a DM-related chronic inflammatory process with increased growth factor expression, which in turn leads to joint synovitis and subsequent capsular fibrosis.”

It is important to note when interpreting the results of the above paper that these results are based on Taiwanese population-level data, and type 1 diabetes – which is obviously the high-risk diabetes subgroup in this particular context – is rare in East Asian populations (as observed in Sperling et al., “A child in Helsinki, Finland is almost 400 times more likely to develop diabetes than a child in Sichuan, China”. Taiwanese incidence of type 1 DM in children is estimated at ~5 in 100.000).

iv. Parents who let diabetic son starve to death found guilty of first-degree murder. It’s been a while since I last saw one of these ‘boost-your-faith-in-humanity’-cases, but they in my impression do pop up every now and then. I should probably keep at hand one of these articles in case my parents ever express worry to me that they weren’t good parents; they could have done a lot worse…

v. Freedom of medicine. One quote from the conclusion of Cochran’s post:

“[I]t is surely possible to materially improve the efficacy of drug development, of medical research as a whole. We’re doing better than we did 500 years ago – although probably worse than we did 50 years ago. But I would approach it by learning as much as possible about medical history, demographics, epidemiology, evolutionary medicine, theory of senescence, genetics, etc. Read Koch, not Hayek. There is no royal road to medical progress.”

I agree, and I was considering including some related comments and observations about health economics in this post – however I ultimately decided against doing that in part because the post was growing unwieldy; I might include those observations in another post later on. Here’s another somewhat older Westhunt post I at some point decided to bookmark – I in particular like the following neat quote from the comments, which expresses a view I have of course expressed myself in the past here on this blog:

“When you think about it, falsehoods, stupid crap, make the best group identifiers, because anyone might agree with you when you’re obviously right. Signing up to clear nonsense is a better test of group loyalty. A true friend is with you when you’re wrong. Ideally, not just wrong, but barking mad, rolling around in your own vomit wrong.”

vi. Economic Costs of Diabetes in the U.S. in 2012.

“Approximately 59% of all health care expenditures attributed to diabetes are for health resources used by the population aged 65 years and older, much of which is borne by the Medicare program […]. The population 45–64 years of age incurs 33% of diabetes-attributed costs, with the remaining 8% incurred by the population under 45 years of age. The annual attributed health care cost per person with diabetes […] increases with age, primarily as a result of increased use of hospital inpatient and nursing facility resources, physician office visits, and prescription medications. Dividing the total attributed health care expenditures by the number of people with diabetes, we estimate the average annual excess expenditures for the population aged under 45 years, 45–64 years, and 65 years and above, respectively, at $4,394, $5,611, and $11,825.”

“Our logistic regression analysis with NHIS data suggests that diabetes is associated with a 2.4 percentage point increase in the likelihood of leaving the workforce for disability. This equates to approximately 541,000 working-age adults leaving the workforce prematurely and 130 million lost workdays in 2012. For the population that leaves the workforce early because of diabetes-associated disability, we estimate that their average daily earnings would have been $166 per person (with the amount varying by demographic). Presenteeism accounted for 30% of the indirect cost of diabetes. The estimate of a 6.6% annual decline in productivity attributed to diabetes (in excess of the estimated decline in the absence of diabetes) equates to 113 million lost workdays per year.”

vii. Total red meat intake of ≥0.5 servings/d does not negatively influence cardiovascular disease risk factors: a systemically searched meta-analysis of randomized controlled trials.

viii. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. Did I blog this paper at some point in the past? I could not find any coverage of it on the blog when I searched for it so I decided to include it here, even if I have a nagging suspicion I may have talked about these findings before. What did they find? The short version is this:

“A modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, important falls in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations. These results support a reduction in population salt intake, which will lower population blood pressure and thereby reduce cardiovascular disease.”

ix. Some wikipedia links:

Heroic Age of Antarctic Exploration (featured).

Wien’s displacement law.

Kuiper belt (featured).

Treason (one quote worth including here: “Currently, the consensus among major Islamic schools is that apostasy (leaving Islam) is considered treason and that the penalty is death; this is supported not in the Quran but in the Hadith.[42][43][44][45][46][47]“).

Lymphatic filariasis.

File:World map of countries by number of cigarettes smoked per adult per year.

Australian gold rushes.

Savant syndrome (“It is estimated that 10% of those with autism have some form of savant abilities”). A small sidenote of interest to Danish readers: The Danish Broadcasting Corporation recently featured a series about autistics with ‘special abilities’ – the show was called ‘The hidden talents’ (De skjulte talenter), and after multiple people had nagged me to watch it I ended up deciding to do so. Most of the people in that show presumably had some degree of ‘savantism’ combined with autism at the milder end of the spectrum, i.e. Asperger’s. I was somewhat conflicted about what to think about the show and did consider blogging it in detail (in Danish?), but I decided against it. However I do want to add here to Danish readers reading along who’ve seen the show that they would do well to repeatedly keep in mind that a) the great majority of autistics do not have abilities like these, b) many autistics with abilities like these presumably do quite poorly, and c) that many autistics have even greater social impairments than do people like e.g. (the very likeable, I have to add…) Louise Wille from the show).

Quark–gluon plasma.

Simo Häyhä.

Chernobyl liquidators.

Black Death (“Over 60% of Norway’s population died in 1348–1350”).

Renault FT (“among the most revolutionary and influential tank designs in history”).

Weierstrass function (“an example of a pathological real-valued function on the real line. The function has the property of being continuous everywhere but differentiable nowhere”).

W Ursae Majoris variable.

Void coefficient. (“a number that can be used to estimate how much the reactivity of a nuclear reactor changes as voids (typically steam bubbles) form in the reactor moderator or coolant. […] Reactivity is directly related to the tendency of the reactor core to change power level: if reactivity is positive, the core power tends to increase; if it is negative, the core power tends to decrease; if it is zero, the core power tends to remain stable. […] A positive void coefficient means that the reactivity increases as the void content inside the reactor increases due to increased boiling or loss of coolant; for example, if the coolant acts as a neutron absorber. If the void coefficient is large enough and control systems do not respond quickly enough, this can form a positive feedback loop which can quickly boil all the coolant in the reactor. This happened in the RBMK reactor that was destroyed in the Chernobyl disaster.”).

Gregor MacGregor (featured) (“a Scottish soldier, adventurer, and confidence trickster […] MacGregor’s Poyais scheme has been called one of the most brazen confidence tricks in history.”).


Irish Civil War.

March 10, 2017 Posted by | Astronomy, autism, Cardiology, Diabetes, Economics, Epidemiology, Health Economics, History, Infectious disease, Mathematics, Medicine, Papers, Physics, Psychology, Random stuff, Wikipedia | Leave a comment

The Ageing Immune System and Health (I)

as we age, we observe a greater heterogeneity of ability and health. The variation in, say, walking speed is far greater in a group of 70 year olds, than in a group on 20 year olds. This makes the study of ageing and the factors driving that heterogeneity of health and functional ability in old age vital. […] The study of the immune system across the lifespan has demonstrated that as we age the immune system undergoes a decline in function, termed immunosenescence. […] the decline in function is not universal across all aspects of the immune system, and neither is the magnitude of functional loss similar between individuals. The theory of inflammageing, which represents a chronic low grade inflammatory state in older people, has been described as a major consequence of immunosenescence, though lifestyle factors such as reduced physical activity and increased adiposity also play a major role […] In poor health, older people accumulate disease, described as multimorbidity. This in turn means traditional single system based health care becomes less valid as each system affected by disease impacts on other systems. This leads some older people to be at greater risk of adverse events such as disability and death. The syndrome of this increased vulnerability is described as frailty, and increasing fundamental evidence is emerging that suggests immunosenescence and inflammageing may underpin frailty […] Thus frailty is seen as one clinical manifestation of immunosenescence.”

The above quotes are from the book‘s preface. I gave it 3 stars on goodreads. I should probably, considering that this topic is mentioned in the preface, mention explicitly that the book doesn’t actually go into a lot of details about the downsides of ‘traditional single system based health care’; the book is mainly about immunology and related topics, and although it provides coverage of intervention studies etc., it doesn’t really provide detailed coverage about issues like the optimization of organizational structures/systems analysis etc.. The book I was currently reading while I started out writing this post – Integrated Diabetes Care – A Multidisciplinary Approach (blog coverage here) – is incidentally pretty much exclusively devoted to providing coverage of these sorts of topics (and it did a fine job).

If you have never read any sort of immunology text before the book will probably be unreadable to you – “It is aimed at fundamental scientists and clinicians with an interest in ageing or the immune system.” In my coverage below I have not made any efforts towards picking out quotes which would be particularly easy for the average reader to read and understand; this is another way of saying that the post is mainly written for my own benefit, perhaps even more so than is usually the case, not for the benefit of potential readers reading along here.

“Physiological ageing is associated with significant re-modelling of the immune system. Termed immunosenescence, age-related changes have been described in the composition, phenotype and function of both the innate and adaptive arms of the immune system. […] Neutrophils are the most abundant leukocyte in circulation […] The first step in neutrophil anti-microbial defence is their extravasation from the bloodstream and migration to the site of infection. Whilst age appears to have no effect upon the speed at which neutrophils migrate towards chemotactic signals in vitro [15], the directional accuracy of neutrophil migration to inflammatory agonists […] as well as bacterial peptides […] is significantly reduced [15]. […] neutrophils from older adults clearly exhibit defects in several key defensive mechanisms, namely chemotaxis […], phagocytosis of opsonised pathogens […] and NET formation […]. Given this near global impairment in neutrophil function, alterations to a generic signalling element rather than defects in molecules specific to each anti-microbial defence strategy is likely to explain the aberrations in neutrophil function that occur with age. In support of this idea, ageing in rodents is associated with a significant increase in neutrophil membrane fluidity, which coincides with a marked reduction in neutrophil function […] ageing results in a reduction in NK cell production and proliferation […] Numerous studies have examined the impact of age […], with the general consensus that at the single cell level, NK cell cytotoxicity (NKCC) is reduced with age […] retrospective and prospective studies have reported relationships between low NK cell activity in older adults and (1) a past history of severe infection, (2) an increased risk of future infection, (3) a reduced probability of surviving infectious episodes and (4) infectious morbidity [49–51]. Related to this increased risk of infection, reduced NKCC prior to and following influenza vaccination in older adults has been shown to be associated with reduced protective anti-hemagglutinin titres, worsened health status and an increased incidence of respiratory tract infection […] Whilst age has no effect upon the frequency or absolute number of monocytes [54, 55], the composition of the monocyte pool is markedly different in older adults, who present with an increased frequency of non-classical and intermediate monocytes, and fewer classical monocytes when compared to their younger counterparts”.

“Via their secretion of growth factors, pro-inflammatory cytokines, and proteases, senescent cells compromise tissue homeostasis and function, and their presence has been causally implicated in the development of such age-associated conditions as sarcopenia and cataracts [92]. Several studies have demonstrated a role for innate immune cells in the recognition and clearance of senescent cells […] ageing is associated with a low-grade systemic up-regulation of circulating inflammatory mediators […] Results from longitudinal-based studies suggest inflammageing is deleterious to human health with studies in older cohorts demonstrating that low-grade increases in the circulating levels of TNF-α [103], IL-6 […] and CRP [105] are associated with both all-cause […] and cause-specific […] mortality. Furthermore, inflammageing is a predictor of frailty [106] and is considered a major factor in the development of several age-related pathologies, such as atherosclerosis [107], Alzheimer’s disease [100] and sarcopenia [108].”

“Persistent viral infections, reduced vaccination responses, increased autoimmunity, and a rise in inflammatory syndromes all typify immune ageing. […] These changes can be in part attributed to the accumulation of highly differentiated senescent T cells, characterised by their decreased proliferative capacity and the activation of senescence signaling pathways, together with alterations in the functional competence of regulatory cells, allowing inflammation to go unchecked. […] Immune senescence results from defects in different leukocyte populations, however the dysfunction is most profound in T cells [6, 7]. The responses of T cells from aged individuals are typically slower and of a lower magnitude than those of young individuals […] while not all equally affected by age, the overall T cell number does decline dramatically as a result of thymic atrophy […] T cell differentiation is a highly complex process controlled not only by costimulation but also by the strength and duration of T cell receptor (TCR) signalling [34]. Nearly all TCR signalling pathways have been found altered during ageing […] two phenotypically distinct subsets of B cells […] have been demonstrated to exert immunosuppressive functions. The frequency and function of both these Breg subsets declines with age”.

“The immune impairments in patients with chronic hyperglycemia resemble those seen during ageing, namely poor control of infections and reduced vaccination response [99].” [This is hardly surprising. ‘Hyperglycemia -> accelerated ageing’ seems generally to be a good (over-)simplified model in many contexts. To give another illustrative example from Czernik & Fowlkes text, “approximately 4–6 years of diabetes exposure in some children may be sufficient to increase skin AGEs to levels that would naturally accumulate only after ~25 years of chronological aging”].

“The term “immunosenescence” is commonly taken to mean age-associated changes in immune parameters hypothesized to contribute to increased susceptibility and severity of the older adult to infectious disease, autoimmunity and cancer. In humans, it is characterized by lower numbers and frequencies of naïve T and B cells and higher numbers and frequencies of late-differentiated T cells, especially CD8+ T cells, in the peripheral blood. […] Low numbers of naïve cells render the aged highly susceptible to pathogens to which they have not been previously exposed, but are not otherwise associated with an “immune risk profile” predicting earlier mortality. […] many of the changes, or most often, differences, in immune parameters of the older adult relative to the young have not actually been shown to be detrimental. The realization that compensatory changes may be developing over time is gaining ground […] Several studies have now shown that lower percentages and absolute numbers of naïve CD8+ T cells are seen in all older subjects whereas the accumulation of very large numbers of CD8+ late-stage differentiated memory cells is seen in a majority but not in all older adults [2]. The major difference between this majority of subjects with such accumulations of memory cells and those without is that the former are infected with human herpesvirus 5 (Cytomegalovirus, CMV). Nevertheless, the question of whether CMV is associated with immunosenescence remains so far uncertain as no causal relationship has been unequivocally established [5]. Because changes are seen rapidly after primary infection in transplant patients [6] and infants [7], it is highly likely that CMV does drive the accumulation of CD8+ late-stage memory cells, but the relationship of this to senescence remains unclear. […] In CMV-seropositive people, especially older people, a remarkably high fraction of circulating CD8+ T lymphocytes is often found to be specific for CMV. However, although the proportion of naïve CD8+ T cells is lower in the old than the young whether or not they are CMV-infected, the gross accumulation of late-stage differentiated CD8+ T cells only occurs in CMV-seropositive individuals […] It is not clear whether this is adaptive or pathological […] The total CMV-specific T-cell response in seropositive subjects constitutes on average approximately 10 % of both the CD4+ and CD8+ memory compartments, and can be far greater in older people. […] there are some published data suggesting that that in young humans or young mice, CMV may improve immune responses to some antigens and to influenza virus, probably by way of increased pro-inflammatory responses […] observations suggest that the effect of CMV on the immune system may be highly dependent also on an individuals’ age and circumstances, and that what is viewed as ageing is in fact later collateral damage from immune reactivity that was beneficial in earlier life [47, 48]. This is saying nothing more than that the same immune pathology that always accompanies immune responses to acute viruses is also caused by CMV, but over a chronic time scale and usually subclinical. […] data suggest that the remodeling of the T-cell compartment in the presence of a latent infection with CMV represents a crucial adaptation of the immune system towards the chronic challenge of lifelong CMV.”

The authors take issue with using the term ‘senescence’ to describe some of the changes discussed above, because this term by definition should be employed only in the context of changes that are demonstrably deleterious to health. It should be kept in mind in this context that insufficient immunological protection against CMV in old age could easily be much worse than the secondary inflammatory effects, harmful though these may well be; CMV in the context of AIDS, organ transplantation (“CMV is the most common and single most important viral infection in solid organ transplant recipients” – medscape) and other disease states involving compromised immune systems can be really bad news (“Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression.” Holmes et al.)

“The role of CMV in the etiology of […] age-associated diseases is currently under intensive investigation […] in one powerful study, the impact of CMV infection on mortality was investigated in a cohort of 511 individuals aged at least 65 years at entry, who were then followed up for 18 years. Infection with CMV was associated with an increased mortality rate in healthy older individuals due to an excess of vascular deaths. It was estimated that those elderly who were CMV- seropositive at the beginning of the study had a near 4-year reduction in lifespan compared to those who were CMV-seronegative, a striking result with major implications for public health [59]. Other data, such as those from the large US NHANES-III survey, have shown that CMV seropositivity together with higher than median levels of the inflammatory marker CRP correlate with a significantly lower 10-year survival rate of individuals who were mostly middle-aged at the start of the study [63]. Further evidence comes from a recently published Newcastle 85+ study of the immune parameters of 751 octogenarians investigated for their power to predict survival during a 65-month follow-up. It was documented that CMV-seropositivity was associated with increased 6-year cardiovascular mortality or death from stroke and myocardial infarction. It was therefore concluded that CMV-seropositivity is linked to a higher incidence of coronary heart disease in octogenarians and that senescence in both the CD4+ and CD8+ T-cell compartments is a predictor of overall cardiovascular mortality”.

“The incidence and severity of many infections are increased in older adults. Influenza causes approximately 36,000 deaths and more than 100,000 hospitalizations in the USA every year […] Vaccine uptake differs tremendously between European countries with more than 70 % of the older population being vaccinated against influenza in The Netherlands and the United Kingdom, but below 10 % in Poland, Latvia and Estonia during the 2012–2013 season […] several systematic reviews and meta-analyses have estimated the clinical efficacy and/or effectiveness of a given influenza vaccine, taking into consideration not only randomized trials, but also cohort and case-control studies. It can be concluded that protection is lower in the old than in young adults […] [in one study including “[m]ore than 84,000 pneumococcal vaccine-naïve persons above 65 years of age”] the effect of age on vaccine efficacy was studied and the statistical model showed a decline of vaccine efficacy for vaccine-type CAP and IPD [Invasive Pneumococcal Disease] from 65 % (95 % CI 38–81) in 65-year old subjects, to 40 % (95 % CI 17–56) in 75-year old subjects […] The most effective measure to prevent infectious disease is vaccination. […] Over the last 20–30 years tremendous progress has been achieved in developing novel/improved vaccines for children, but a lot of work still needs to be done to optimize vaccines for the elderly.”

December 12, 2016 Posted by | Books, Cardiology, Diabetes, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

Water Supply in Emergency Situations (I)

I didn’t think much of this book (here’s my goodreads review), but I did learn some new things from reading it. Some of the coverage in the book overlapped a little bit with stuff I’d read before, e.g. coverage provided in publications such as Rodricks and Fong and Alibek, but I read those books in 2013 and 2014 respectively (so I’ve already forgot a great deal) and most of the stuff in the book was new stuff. Below I’ve added a few observations and data from the first half of the publication.

“Mediterranean basin demands for water are high. Today, the region uses around 300 billion cubic meters per year. Two thirds of Mediterranean countries now use over 500  per year per inhabitant mainly because of heavy use of irrigation. But these per capita demands are irregular and vary across a wide range – from a little over 100 to more than 1,000 per year. Globally, demand has doubled since the beginning of the 20th century and increased by 60% over the last 25 years. […] the Middle East ecosystems […]  populate some 6% of the world population, but have only some 1% of its renewable fresh water. […] Seasonality of both supply and demand due to tourism […] aggravate water resource problems. During the summer months, water shortages become more frequent. Distribution networks left unused during the winter period face overload pressures in the summer. On the other hand, designing the system with excess capability to satisfy tourism-related summer peak demands raises construction and maintenance costs significantly.”

“There are over 30,000 km of mains within London and over 30% of these are over 150 years old, they serve 7.5 million people with 2,500 million liters of water a day.”

“A major flooding of the Seine River would have tremendous consequences and would impact very significantly the daily life of the 10 million people living in the Parisian area. A deep study of the impacts of such a catastrophic natural hazard has recently been initiated by the French authorities. […] The rise of the water level in the Seine during the last two major floods occurred slowly over several weeks which may explain their low number of fatalities: 50 deaths in 1658 and only one death in 1910. The damage and destruction to buildings and infrastructure, and the resulting effect on economic activity were, however, of major proportions […] Dams have been constructed on the rivers upstream from Paris, but their capacity to stock water is only 830 million cubic meters, which would be insufficient when compared to the volume of 4 billion cubic meters of water produced by a big flood. […] The drinkable water supply system in Paris, as well as that of the sewer network, is still constrained by the decisions and orientations taken during the second half of the 19th century during the large public works projects realized under Napoleon III. […] two of the three water plants which treat river water and supply half of Paris with drinkable water existed in 1910. Water treatment technology has radically changed, but the production sites have remained the same. New reservoirs for potable water have been added, but the principles of distribution have not changed […] The average drinking water production in Paris is 615,000 /day.”

They note in the chapter from which the above quotes are taken that a flood comparable to that which took place in 1910 would in 2005 have resulted in 20% of the surface of Paris being flooded, and 600.000 people being without electricity, among other things. The water distribution system currently in place would also be unable to deal with the load, however a plan for how to deal with this problem in an emergency setting does exist. In that context it’s perhaps worth noting that Paris is hardly unique in terms of the structure of the distribution system – elsewhere in the book it is observed that: “The water infrastructure developed in Europe during the 19th century and still applied, is almost completely based on options of centralized systems: huge supply and disposal networks with few, but large waterworks and sewage treatment plants.” Having both centralized and decentralized systems working at the same time/in the same area tends to increase costs, but may also lower risk; it’s observed in the book during the coverage of an Indonesian case-study that in that region the centralized service provider may take a long time to repair broken water pipes, which is … not very nice if you live in a tropical climate and prefer to have drinking water available to you.

“Water resources management challenges differ enormously in Romania, depending on the type of human settlement. The spectrum of settlement types stretches from the very low-density scattered single dwellings found in rural areas, through villages and small towns, to the much more dense and crowded cities. […] Water resources management will always face the challenge of balancing the needs of different water users. This is the case both in large urban or relatively small rural communities. The water needs of the agricultural production, energy and industrial sectors are often in competition. […] Romania’s water resources are relatively poor and unequally distributed in time and space […] There is a vast differential between urban and rural settlements when it comes to centralized drinking water systems; all the 263 municipalities and towns have such systems, while only 17% of rural communities benefit from this service. […] In Braila and Harghita counties, no village has a sewage network, and Giurgiu and Ialomita counties have only one a piece each. Around 47 of the largest cities which do not have wastewater treatment plants (Bucharest, Braila, Craiova, Turnu Severin Tulcea, etc.) produce ∼20 /s of wastewater, which is directly discharged untreated into surface water.”

There is a difference in quality between water from centralized and decentralized supply systems [in the Ukraine (and likely elsewhere as well)]. Water quality in decentralized systems is the worst (some 30% of samples fail to meet standards, compared to 5.7% in the centralized supply). […] The Sanitary epidemiological stations draw random samples from 1,139 municipal, 6,899 departmental, and 8,179 rural pipes, and from 158,254 points of decentralized water supply, including 152,440 wells, 996 springs, and 4,818 artesian wells. […] From the first day following the accident at Chernobyl Nuclear Power Plant (ChNPP), one of the most serious problems was to prevent general contamination of the Dnieper water system and to guarantee safe water consumption for people living in the affected zone. The water protection and development of monitoring programs for the affected water bodies were among the most important post-accident countermeasures taken by the Government Bodies in Ukraine. […] To solve the water quality problem for Kiev, an emergency water intake at the Desna River was constructed within a very short period. […] During 1986 and the early months of 1987, over 130 special filtration dams […] with sorbing screens containing zeolite (klinoptilolite) were installed for detaining radionuclides while letting the water through. […] After the spring flood of 1987, the construction of new dams was terminated and the decision was made to destroy most of the existing dams. It was found that the 90Sr concentration reduction by the dams studied was insignificant […] Although some countermeasures and cleanup activities applied to radionuclides sources on catchments proved to have positive effects, many other actions were evaluated as ineffective and even useless. […] The most effective measures to reduce radioactivity in drinking water are those, which operate at the water treatment and distribution stage.

“Diversification and redundancy are important technical features to make infrastructure systems less vulnerable to natural and social (man-made) hazards. […] risk management does not only encompass strategies to avoid the occurrence of certain events which might lead to damages or catastrophes, but also strategies of adaptation to limit damages.

The loss of potable water supply typically leads to waterborne diseases, such as typhus and cholera.”

Water velocity in a water supply system is about 1 \s. Therefore, time is a primordial factor in contamination spread along the system. In order to minimize the damage caused by contamination of water, it is essential to act with maximum speed to achieve minimum spread of the contaminant”

October 21, 2016 Posted by | Books, Engineering, Geography, Infectious disease, Microbiology | Leave a comment

Oxford Handbook of Clinical Medicine (III)

Here are my first two posts about the book, which I have now finished. I gave the book three stars on goodreads, but I’m close to a four star rating and I may change my opinion later – overall it’s a pretty good book. I’ve read about many of the topics covered before but there was also quite a bit of new stuff along the way; as a whole the book spans very widely, but despite this the level of coverage of individual topics is not bad – I actually think the structure of the book makes it more useful as a reference tool than is McPhee et al. (…in terms of reference books which one might find the need to refer to in order to make sense of medical tests and test results, I should of course add that no book can beat Newman & Kohn). I have tried to take this into account along the way in terms of the way I’ve been reading the book, in the sense that I’ve tried to make frequent references in the margin to other relevant works going into more detail about specific topics whenever this seemed like it might be useful, and I think if one does something along those lines systematically a book like this one can become a really powerful tool – you get the short version with the most important information (…or at least what the authors considered to be the most important information) here almost regardless of what topic you’re interested in – I should note in this context that the book has only very limited coverage of mental health topics, so this is one area where you definitely need to go elsewhere for semi-detailed coverage – and if you need more detail than what’s provided in the coverage you’ll also know from your notes where to go next.

In my last post I talked a bit about which topics were covered in the various chapters in the book – I figured it might make sense here to list the remaining chapter titles in this post. After the (long) surgery chapter, the rest of the chapters deal with epidemiology (I thought this was a poor chapter and the authors definitely did not consider this topic to be particularly important; they spent only 12 pages on it), clinical chemistry (lab results, plasma proteins, topics like ‘what is hypo- and hypernatremia’, …), eponymous syndromes (a random collection of diseases, many of which are quite rare), radiology (MRI vs X-ray? When to use, or not use, contrast material? Etc.), ‘reference intervals etc.‘ (the ‘etc.’ part covered drug therapeutic ranges for some commonly used drugs, as well as some important drug interactions – note to self: The effects of antidiabetic drugs are increased by alcohol, beta-blockers, bezafibrate, and MAOIs, and are decreased by contraceptive steroids, corticosteroids, diazoxide, diuretics, and possibly also lithium), practical procedures (I was considering skipping this chapter because I’m never going to be asked to e.g. insert a chest drain and knowing how to do it seems to be of limited benefit to me, but I figured I might as well read it anyway; there were some details about what can go wrong in the context of specific procedures and what should be done when this happens, and this seemed like valuable information. Also, did you know that “There is no evidence that lying flat post procedure prevents headache” in the context of lumbar punctures? I didn’t, and a lot of doctors probably also don’t. You can actually go even further than that: “Despite years of anecdotal advice to the contrary, none of the following has ever been shown to be a risk factor [for post-LP headache]: position during or after the procedure; hydration status before, during, or after; amount of CSF removed; immediate activity or rest post-LP.”), and emergencies.

In this post I won’t cover specific chapters of the book in any detail, rather I’ll talk about a few specific topics and observations I could be bothered to write some stuff about here. Let’s start with some uplifting news about the topic of liver tumours: Most of these (~90%) are secondary (i.e. metastatic) tumours with an excellent prognosis (“Often ↑3yr survival to 59% from 13%; but ~50% have recurrence by 3yrs.[3] Liver transplant gives a 5yr survival rate of 70%.” It should be noted in a disease impact context that this type of cancer is far more common in areas of the world with poorly developed health care systems like Africa and China.

Alcoholism is another one of the causes of liver tumors. In the book they include the observation that the lifetime prevalence of alcoholism is around 10% for men and 4% for women, but such numbers are of course close to being completely meaningless almost regardless of where they’re coming from. Alcoholism is dangerous; in cases with established cirrhosis roughly half (52%) of people who do not stop drinking will be dead within 5 years, whereas this is also the case for 23% of the people who do stop drinking. Excessive alcohol consumption can cause alcoholic hepatitis; “[m]ild episodes hardly affect mortality” but in severe cases half will be dead in a month, and in general 40% of people admitted to the hospital for alcoholic hepatitis will be dead within one year of admission. Alcohol can cause portal hypertension (80% of cases are caused by cirrhosis in the UK), which may lead to the development of abnormal blood vessels e.g. in the oesophagus which will have a tendency to cause bleeding, which can be fatal.  Roughly 30% of cirrhotics with varices bleed, and rebleeding is common: “After a 1st variceal bleed, 60% rebleed within 1yr” and “40% of rebleeders die of complications.” Alcoholism can kill you in a variety of different ways (acute poisonings and accidents should probably also be included here as well), and many don’t survive long enough to develop cancer.

As mentioned in the first post about the book acute kidney injury is common in a hospital setting. In the following I’ve added a few more observations about renal disease. “Renal pain is usually a dull ache, constant and in the loin.” But renal disease don’t always cause pain, and in general: “There is often a poor correlation between symptoms and severity of renal disease. Progression [in chronic disease] may be so insidious that patients attribute symptoms to age or a minor illnesses. […] Serious renal failure may cause no symptoms at all.” The authors note that odd chronic symptoms like fatigue should not be dismissed without considering a renal function test first. The book has a nice brief overview of the pathophysiology of diabetic nephropathy – this part is slightly technical, but I decided to include it here anyway before moving on to a different topic:
“Early on, glomerular and tubular hypertrophy occur, increasing GFR [glomerular filtration rate, an indicator variable used to assess kidney function] transiently, but ongoing damage from advanced glycosylation end-products (AGE—caused by non-enzymatic glycosylation of proteins from chronic hyperglycaemia) triggers more destructive disease. These AGE trigger an inflammatory response leading to deposition of type IV collagen and mesangial expansion, eventually leading to arterial hyalinization, thickening of the mesangium and glomerular basement membrane and nodular glomerulosclerosis (Kimmelstiel–Wilson lesions). Progression generally occurs in four stages:
1 GFR elevated: early in disease renal blood flow increases, increasing the GFR and leading to microalbuminuria. […]
2 Glomerular hyperfiltration: in the next 5–10yrs mesangial expansion gradually occurs and hyperfiltration at the glomerulus is seen without microalbuminuria.
3 Microalbuminuria: as soon as this is detected it indicates progression of disease, GFR may be raised or normal. This lasts another 5–10yrs.
4 Nephropathy: GFR begins to decline and proteinuria increases.
Patients with type 2 DM may present at the later stages having had undetected hyperglycaemia for many years before diagnosis.”

Vitamin B12 deficiency is quite common, the authors note that it occurs in up to 15% of older people. Severe B12 deficiency is not the sort of thing which will lead to you feeling ‘a bit under the weather’ – it can lead to permanent brain damage and damage to the spinal cord. “Vitamin B12 is found in meat, fish, and dairy products, but not in plants.” It’s important to note that “foods of non-animal origin contain no B12 unless fortified or contain bacteria.” The wiki article incidentally includes even higher prevalence estimates (“It is estimated to occur in about 6% of those under the age of 60 and 20% of those over the age of 60. Rates may be as high as 80% in parts of Africa and Asia.”) than the one included in the book – this vitamin deficiency is common, and if severe it can have devastating consequences.

On bleeding disorders: “After injury, 3 processes halt bleeding: vasoconstriction, gap-plugging by platelets, and the coagulation cascade […]. Disorders of haemostasis fall into these 3 groups. The pattern of bleeding is important — vascular and platelet disorders lead to prolonged bleeding from cuts, bleeding into the skin (eg easy bruising and purpura), and bleeding from mucous membranes (eg epistaxis [nose bleeds], bleeding from gums, menorrhagia). Coagulation disorders cause delayed bleeding into joints and muscle.” An important observation in the context of major bleeds is incidentally this: “Blood should only be given if strictly necessary and there is no alternative. Outcomes are often worse after a transfusion.” The book has some good chapters about the leukaemias, but they’re relatively rare diseases and some of them are depressing (e.g. acute myeloid leukaemia: according to the book coverage death occurs in ~2 months if untreated, and roughly four out of five treated patients are dead within 3 years) so I won’t talk a lot about them. One thing I found somewhat interesting about the blood disorders covered in the book is actually how rare they are, all things considered: “every day each of us makes 175 billion red cells, 70 billion granulocytes, and 175 billion platelets”. There are lots of opportunities for things to go wrong here…

Some ways to prevent traveller’s diarrhea: “If in doubt, boil all water. Chlorination is OK, but doesn’t kill amoebic cysts (get tablets from pharmacies). Filter water before purifying. Distinguish between simple gravity filters and water purifiers (which also attempt to sterilize chemically). […] avoid surface water and intermittent tap supplies. In Africa assume that all unbottled water is unsafe. With bottled water, ensure the rim is clean & dry. Avoid ice. […] Avoid salads and peel your own fruit. If you cannot wash your hands, discard the part of the food that you are holding […] Hot, well-cooked food is best (>70°C for 2min is no guarantee; many pathogens survive boiling for 5min, but few last 15min)”

An important observation related to this book’s coverage about how to control hospital acquired infection: “Cleaning hospitals: Routine cleaning is necessary to ensure that the hospital is visibly clean and free from dust and soiling. 90% of microorganisms are present within ‘visible dirt’, and the purpose of routine cleaning is to eliminate this dirt. Neither soap nor detergents have antimicrobial activity, and the cleaning process depends essentially on mechanical action.”

Falciparum malaria causes one million deaths/year, according to the book, and mortality is close to 100% in untreated severe malaria – treatment reduces this number to 15-20%. Malaria in returning travellers is not particularly common, but there are a couple thousand cases in the UK each year. Malaria prophylaxis does not give full protection, and “[t]here is no good protection for parts of SE Asia.” Multidrug resistance is common.

November 8, 2015 Posted by | alcohol, Books, Cancer/oncology, Epidemiology, Infectious disease, Medicine, Nephrology | Leave a comment

Random stuff

It’s been a while since I posted anything here so I figured I should at least post something…

i. A few Khan Academy videos I watched a while back:

(No comments)

(Bookmark remark: (‘Not completely devoid of slight inaccuracies as usual – e.g. in meningitis, neck stiffness is not as much as symptom as it is a clinical sign (see Chamberlain’s symptoms and signs…))’

(Bookmark remark: ‘Very simplified, but not terrible’)

(No comments)

ii. I previously read the wiki on strategic bombing during WW2, but the article did not really satisfy my curiosity and it turns out that the wiki also has a great (featured) article about Air raids on Japan (a topic not covered in a great amount of detail in the aforementioned wiki article). A few random observations from the article:

“Overall, the attacks in May destroyed 94 square miles (240 km2) of buildings, which was equivalent to one seventh of Japan’s total urban area.”

“In Tokyo, Osaka, Nagoya, Yokohama, Kobe, and Kawasaki, “over 126,762 people were killed … and a million and a half dwellings and over 105 square miles (270 km2) of urban space were destroyed.”[136] In Tokyo, Osaka and Nagoya, “the areas leveled (almost 100 square miles (260 km2)) exceeded the areas destroyed in all German cities by both the American and English air forces (approximately 79 square miles (200 km2)).”[136]

“In financial terms, the Allied air campaign and attacks on merchant ships destroyed between one third and a quarter of Japan’s wealth.[289]

“Approximately 40 percent of the urban area of the 66 cities subjected to area attacks were destroyed.[290] This included the loss of about 2.5 million housing units, which rendered 8.5 million people homeless.”

iii. A few longer lectures I’ve watched recently but did not think were particularly good: The Fortress (GM Akobian, Chess), Safety in the Nuclear Industry (Philip Thomas, Gresham College), War, Health and Medicine: The medical lessons of World War I (Mark Harrison, Gresham College – topic had potential, somehow did not like ‘the delivery’; others may find it worth watching).

iv. I play a lot of (too much) chess these days, so I guess it makes sense to post a little on this topic as well. Here’s a list of some of my recent opponents on the ICC: GM Zurab Azmaiparashvili, IM Jerzy Slaby, IM Petar Gojkovic, GM Goran Kosanovic, IM Jeroen Bosch, WGM Alla Grinfeld. I recall encountering a few titled players when I started out on the ICC and my rating was still adjusting and stabilizing, but now I’ve sort of fixed at a level around 1700-1800 in both the 1, 3 and 5 minute pools – sometimes a bit higher, sometimes a bit lower (and I’ve played relatively few 5 minute games so far)). This is a level where at least in bullet some of the semi-regular opponents I’ll meet in the rating pool are guys like these. I was quite dissatisfied with my play when I started out on the ICC because I hadn’t realized how tough it is to maintain a high rating there; having a closer look at which sort of opponents I was actually facing gradually made me realize I was probably doing quite well, all things considered. Lately I’ve been thinking that I have probably even been doing quite a bit better than I’d thought I had. See also this and this link. I’ve gradually concluded that I’m probably never ‘going back’ now that I’ve familiarized myself with the ICC server.

And yes, I do occasionally win against opposition like that, also on position – below an example from a recent game against a player not on the list above (there are quite a few anonymous title-holders as well on the server):

Click to view full size – the list to the lower left is a list of other players online on the server at that point in time, ordered by rating; as should be clear, lots of title-holders have relatively low ratings (I’m not completely sure which rating pool was displayed in the sidebar at that time, but the defaults on display for me are 5- or 3-minutes, so for example the international master ‘softrain’ thus had either a 3 or 5 minute rating of 1799 at that time. Do note that ICC requires proof for titles to display on the server; random non-titled players do not display as titleholders on the ICC (actually the formally approved titled accounts obviously do not account for all accounts held by title-holders as some titled players on the server use accounts which do not give away the fact that they have a title).

Here’s another very nice illustration of how tough the X-minute pools are (/how strong the players playing on the ICC are):

Wang Hao
Again, click to view in full size. This is Chinese Grandmaster Wang Hao‘s ICC account. Wang Hao is currently #39 on the FIDE list of active chess players in the world, with a FIDE rating above 2700. Even his 5-minute rating on the ICC, based on more than a thousand games, is below 2300, and his current 3 minute rating is barely above 2000. With numbers like those, I currently feel quite satisfied with my 1700-1800 ratings (although I know I should be spending less time on chess than I currently do).

v. A few words I’ve recently encountered on Anaphora, usufruct, mimesis, amanuensis, peculate, elide, ataraxia, myrmidon, velleity.

vi. A few other wiki links: Fritz Haber, Great Stink (featured), Edward Low (a really nice guy, it seems – “A story describes Low burning a French cook alive, saying he was a “greasy fellow who would fry well”, and another tells he once killed 53 Spanish captives with his cutlass.[6]“), 1940 Soviet ultimatum to Lithuania (‘good article’).

vii. A really cute paper from the 2013 Christmas edition of the British Medical Journal: Were James Bond’s drinks shaken because of alcohol induced tremor? Here’s the abstract:

Objective To quantify James Bond’s consumption of alcohol as detailed in the series of novels by Ian Fleming.

Design Retrospective literature review.

Setting The study authors’ homes, in a comfy chair.

Participants Commander James Bond, 007; Mr Ian Lancaster Fleming.

Main outcome measures Weekly alcohol consumption by Commander Bond.

Methods All 14 James Bond books were read by two of the authors. Contemporaneous notes were taken detailing every alcoholic drink taken. Predefined alcohol unit levels were used to calculate consumption. Days when Bond was unable to consume alcohol (such as through incarceration) were noted.

Results After exclusion of days when Bond was unable to drink, his weekly alcohol consumption was 92 units a week, over four times the recommended amount. His maximum daily consumption was 49.8 units. He had only 12.5 alcohol free days out of 87.5 days on which he was able to drink.

Conclusions James Bond’s level of alcohol intake puts him at high risk of multiple alcohol related diseases and an early death. The level of functioning as displayed in the books is inconsistent with the physical, mental, and indeed sexual functioning expected from someone drinking this much alcohol. We advise an immediate referral for further assessment and treatment, a reduction in alcohol consumption to safe levels, and suspect that the famous catchphrase “shaken, not stirred” could be because of alcohol induced tremor affecting his hands.”

viii. A couple of other non-serious links which I found hilarious:
1) The Prof(essor) or Hobo quiz (via SSC).
2) Today’s SMBC. I’ll try to remember the words in the votey in the highly unlikely case I’ll ever have use for them – in my opinion it would be a real tragedy if one were to miss an opportunity to make a statement like that, given that it was at all suitable to the situation at hand..

July 6, 2015 Posted by | Chess, Diabetes, Epidemiology, History, Immunology, Infectious disease, Khan Academy, Lectures, Medicine, Personal | Leave a comment

An Introduction to Medical Diagnosis (4)

Here’s a previous post in the series covering this book. There’s a lot of stuff in these chapters, so the stuff below’s just some of the things I thought were interesting and worth being aware of. I’ve covered three chapters in this post: One about skin, nails and hair, one about the eye, and one about infectious and tropical diseases. I may post one more post about the book later on, but I’m not sure if I’ll do that or not at this point so this may be the last post in the series.

Okay, on to the book – skin, nails and hair (my coverage mostly deals with the skin):

“The skin is a highly specialized organ that covers the entire external surface of the body. Its various roles include protecting the body from trauma, infection and ultraviolet radiation. It provides waterproofing and is important for fluid and temperature regulation. It is essential for the detection of some sensory stimuli. […] Skin problems are extremely common and are responsible for 10–15 per cent of all consultations in general practice. […] Given that there are around 2000 dermatological conditions described, only common and important conditions, including some that might be especially relevant in the examination setting, can be covered here.”

Urticaria is characterized by the development of red dermal swellings known as weals […]. Scaling is not seen and the lesions are typically very itchy. The lesions result from the release of histamine from mast cells. An important clue to the diagnosis is that individual lesions come and go within 24 hours, although new lesions may be appearing at other sites. Another associated feature is dermographism: a firm scratch of the skin with an orange stick will produce a linear weal within a few minutes. Urticaria is common, estimated to affect up to 20 per cent of the population at some point in their lives.”

“Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are thought to be two ends of a spectrum of the same condition. They are usually attributable to drug hypersensitivity, though a precipitant is not always identified. The latent period following initiation of the drug tends to be longer than seen with a classical maculopapular drug eruption. The disease is termed:
*SJS when 10 per cent or less of the body surface area epidermis detaches
*TEN when greater than 30 per cent detachment occurs.
Anything in between is designated SJS/TEN overlap. Following a prodrome of fever, an erythematous eruption develops. Macules, papules, or plaques may be seen. Some or all of the affected areas become vesicular or bullous, followed by sloughing off of the dead epidermis. This leads to potentially widespread denudation of skin. […] The affected skin is typically painful rather than itchy. […] The risk of death relates to the extent of epidermal loss and can exceed 30 per cent. […] A widespread ‘drug rash’ that is very painful should ring alarm bells.”

“Various skin problems arise in patients with diabetes mellitus. Bacterial and fungal infections are more common, due to impaired immunity. Vascular disease and neuropathy lead to ulceration on the feet, which can sometimes be very deep and there may be underlying osteomyelitis. Granuloma annulare […] and necrobiosis lipoidica have also been associated with diabetes, though many cases are seen in non-diabetic patients. The former produces smooth papules in an annular configuration, often coalescing into a ring. The latter usually occurs over the shins giving rise to yellow-brown discoloration, with marked atrophy and prominent telangiectasia. There is often an annular appearance, with a red or brown border. Acanthosis nigricans, velvety thickening of the flexural skin […], is seen with insulin resistance, with or without frank diabetes. […] Diabetic bullae are also occasionally seen and diabetic dermopathy produces hyperpigmented, atrophic plaques on the legs. The aetiology of these is unknown.”

“Malignant melanoma is one of the commonest cancers in young adults [and it] is responsible for almost three-quarters of skin cancer deaths, despite only accounting for around 4 per cent of skin cancers. Malignant melanoma can arise de novo or from a pre-existing naevus. Most are pigmented, but some are amelanotic. The most important prognostic factor for melanoma is the depth of the tumour when it is excised – Breslow’s thickness. As most malignant melanomas undergo a relatively prolonged radial (horizontal) growth phase prior to invading vertically, there is a window of opportunity for early detection and management, while the prognosis remains favourable. […] ‘Red flag’ findings […] in pigmented lesions are increasing size, darkening colour, irregular pigmentation, multiple colours within the same lesion, and itching or bleeding for no reason. […] In general, be suspicious if a lesion is rapidly changing.”

The eye:

“Most ocular surface diseases […] are bilateral, whereas most serious pathology (usually involving deeper structures) is unilateral […] Any significant reduction of vision suggests serious pathology [and] [s]udden visual loss always requires urgent investigation and referral to an ophthalmologist. […] Sudden loss of vision is commonly due to a vascular event. These may be vessel occlusions giving rise to ischaemia of vision-serving structures such as the retina, optic nerve or brain. Alternatively there may be vessel rupture and consequent bleeding which may either block transmission of light as in traumatic hyphaema (haemorrhage into the anterior chamber) and vitreous haemorrhage, or may distort the retina as in ‘wet’ age-related macular degeneration (AMD). […] Gradual loss of vision is commonly associated with degenerations or depositions. […] Transient loss of vision is commonly due to temporary or subcritical vascular insufficiency […] Persistent loss of vision suggests structural changes […] or irreversible damage”.

There are a lot of questions one might ask here, and I actually found it interesting to know how much can be learned simply by asking some questions which might help narrow things down – the above are just examples of variables to consider, and there are others as well, e.g. whether or not there is pain (“Painful blurring of vision is most commonly associated with diseases at the front of the eye”, whereas “Painless loss of vision usually arises from problems in the posterior part of the eye”), whether there’s discharge, just how the vision is affected (a blind spot, peripheral field loss, floaters, double vision, …), etc.

“Ptosis (i.e. drooping lid) and a dilated pupil suggest an ipsilateral cranial nerve III palsy. This is a neuro-ophthalmic emergency since it may represent an aneurysm of the posterior communicating artery. […] In such cases the palsy may be the only warning of impending aneurysmal rupture with subsequent subarachnoid haemorrhage. One helpful feature that warns that a cranial nerve III palsy may be compressive is pupil involvement (i.e. a dilated pupil).”

“Although some degree of cataract (loss of transparency of the lens) is almost universal in those >65 years of age, it is only a problem when it is restricting the patient’s activity. It is most commonly due to ageing, but it may be associated with ocular disease (e.g. uveitis), systemic disease (e.g. diabetes), drugs (e.g. systemic corticosteroids) or it may be inherited. It is the commonest cause of treatable blindness worldwide. […] Glaucoma describes a group of eye conditions characterized by a progressive optic neuropathy and visual field loss, in which the intraocular pressure is sufficiently raised to impair normal optic nerve function. Glaucoma may present insidiously or acutely. In the more common primary open angle glaucoma, there is an asymptomatic sustained elevation in intraocular pressure which may cause gradual unnoticed loss of visual field over years, and is a significant cause of blindness worldwide. […] Primary open angle glaucoma is asymptomatic until sufficiently advanced for field loss to be noticeable to the patient. […] Acute angle closure glaucoma is an ophthalmic emergency in which closure of the drainage angle causes a sudden symptomatic elevation of intraocular pressure which may rapidly damage the optic nerve.”

“Age-related macular degeneration is the commonest cause of blindness in the older population (>65 years) in the Western world. Since it is primarily the macula […] that is affected, patients retain their peripheral vision and with it a variable level of independence. There are two forms: ‘dry’ AMD accounts for 90 per cent of cases and the more dramatic ‘wet’ (also known as neovascular) AMD accounts for 10 per cent. […] Treatments for dry AMD do not alter the course of the disease but revolve around optimizing the patient’s remaining vision, such as using magnifiers. […] Treatments for wet AMD seek to reverse the neovascular process”.

“Diabetes is the commonest cause of blindness in the younger population (<65 years) in the Western world. Diabetic retinopathy is a microvascular disease of the retinal circulation. In both type 1 and type 2 diabetes glycaemic control and blood pressure should be optimized to reduce progression. Progression of retinopathy to the proliferative stage is most commonly seen in type 1 diabetes, whereas maculopathy is more commonly a feature of type 2 diabetes. […] Symptoms
*Bilateral. *Usually asymptomatic until either maculopathy or vitreous haemorrhage. [This is part of why screening programs for diabetic eye disease are so common – the first sign of eye disease may well be catastrophic and irreversible vision loss, despite the fact that the disease process may take years or decades to develop to that point] *Gradual loss of vision – suggests diabetic maculopathy (especially if distortion) or cataract. *Sudden loss of vision – most commonly vitreous haemorrhage secondary to proliferative diabetic retinopathy.”

Recap of some key points made in the chapter:
“*For uncomfortable/red eyes, grittiness, itchiness or a foreign body sensation usually indicate ocular surface problems such as conjunctivitis.
*Severe ‘aching’ eye pain suggests serious eye pathology such as acute angle closure glaucoma or scleritis.  *Photophobia is most commonly seen with acute anterior uveitis or corneal disease (ulcers or trauma). [it’s also common in migraine]
*Sudden loss of vision is usually due to a vascular event (e.g. retinal vessel occlusions, anterior ischaemic optic neuropathy, ‘wet’ AMD).
*Gradual loss of vision is common in the ageing population. It is frequently due to cataract […], primary open angle glaucoma (peripheral field loss) or ‘dry’ AMD (central field loss).
*Recent-onset flashes and floaters should be presumed to be retinal tear/detachment.
*Double vision may be monocular (both images from the same eye) or binocular (different images from each eye). Binocular double vision is serious, commonly arising from a cranial nerve III, IV or VI palsy. […]
the following presentations are sufficiently serious to warrant urgent referral to an ophthalmologist: sudden loss of vision, severe ‘aching’ eye pain, new-onset flashes and floaters, [and] new-onset binocular diplopia.”

Infectious and tropical diseases:

“Patients with infection (and inflammatory conditions or, less commonly, malignancy) usually report fever […] Whatever the cause, body temperature generally rises in the evening and falls during the night […] Fever is often lower or absent in the morning […]. A sensation of ‘feeling hot’ or ‘feeling cold’ is unreliable – healthy individuals often feel these sensations, as may those with menopausal flushing, thyrotoxicosis, stress, panic, or migraine. The height and duration of fever are important. Rigors (chills or shivering, often uncontrollable and lasting for 20–30 minutes) are highly significant, and so is a documented temperature over 37.5 °C taken with a reliable oral thermometer. Drenching sweats are also highly significant. Rigors generally indicate serious bacterial infections […] or malaria. An oral temperature >39 °C has the same significance as rigors. Rigors generally do not occur in mild viral infections […] malignancy, connective tissue diseases, tuberculosis and other chronic infections. […] Anyone with fever lasting longer than a week should have lost weight – if a patient reports a prolonged fever but no weight loss, the ‘fever’ usually turns out to be of no consequence. […] untouched meals indicate ongoing illness; return of appetite is a reliable sign of recovery.”

“Bacterial infections are the most common cause of sepsis, but other serious infections (e.g. falciparum malaria) or inflammatory states (e.g. pancreatitis, pre-eclamptic toxaemia, burns) can cause the same features. Below are listed the indicators of sepsis – the more abnormal the result, the more severe is the patient’s condition.
*Check if it is above 38 °C or below 36 °C.
*Simple viral infections seldom exceed 39 °C.
*Temperatures (from any cause) are generally higher in the evening than in the early morning.
*As noted above, rigors (uncontrollable shivering) are important indicators of severe bacterial infection or malaria. […] A heart rate greater than 90 beats/min is abnormal, and in severe sepsis a pulse of 140/min is not unusual. […] Peripheries (fingers, toes, nose) are often markedly cooler than central skin (trunk, forehead) with prolonged capillary refill time […] Blood pressure (BP) is low in the supine position (systolic BP <90 mmHg) and falls further when the patient is repositioned upright. In septic shock sometimes the BP is unrecordable on standing, and the patient may faint when they are helped to stand up […] The first sign [of respiratory disturbance] is a respiratory rate greater than 20 breaths/min. This is often a combination of two abnormalities: hypoxia caused by intrapulmonary shunts, and lactic acidosis. […] in hypoxia, the respiratory pattern is normal but rapid. Acidotic breathing has a deep, sighing character (also known as Kussmaul’s respiration). […] Also called toxic encephalopathy or delirium, confusion or drowsiness is often present in sepsis. […] Sepsis is always severe when it is accompanied by organ dysfunction. Septic shock is defined as severe sepsis with hypotension despite adequate fluid replacement.”

“Involuntary neck stiffness (‘nuchal rigidity’) is a characteristic sign of meningitis […] Patients with meningitis or subarachnoid haemorrhage characteristically lie still and do not move the head voluntarily. Patients who complain about a stiff neck are often worried about meningitis; patients with meningitis generally complain of a sore head, not a sore neck – thus neck stiffness is a sign, not a symptom, of meningitis.”

“General practitioners are generally correct when they say an infection is ‘a virus’, but the doctor needs to make an accurate assessment to be sure of not missing a serious bacterial infection masquerading as ‘flu’. […]
*Influenza is highly infectious, so friends, family, or colleagues should also be affected at the same time – the incubation period is short (1–3 days). If there are no other cases, question the diagnosis.
*The onset of viraemic symptoms is abrupt and often quite severe, with chills, headache, and myalgia. There may be mild rigors on the first day, but these are not sustained.
*As the next few days pass, the fever improves each day, and by day 3 the fever is settling or absent. A fever that continues for more than 3 days is not uncomplicated ’flu, and nor is an illness with rigors after the first day.
*As the viraemia subsides, so the upper respiratory symptoms become prominent […] The patient experiences a combination of: rasping sore throat, dry cough, hoarseness, coryza, red eyes, congested sinuses. These persist for a long time (10 days is not unusual) and the patient feels ‘miserable’ but the fever is no longer prominent.”

“Several infections cause a similar picture to ‘glandular fever’. The commonest is EBV [Epstein–Barr Virus], with cytomegalovirus (CMV) a close second; HIV seroconversion may look clinically identical, and acute toxoplasmosis similar (except for the lack of sore throat). Glandular fever in the USA is called ‘infectious mononucleosis’ […] The illness starts with viraemic symptoms of fever (without marked rigors), myalgia, lassitude, and anorexia. A sore throat is characteristic, and the urine often darkens (indicating liver involvement). […] Be very alert for any sign of stridor, or if the tonsils meet in the middle or are threatening to obstruct (a clue is that the patient is unable to swallow their saliva and is drooling or spitting it out). If there are any of these signs of upper airway obstruction, give steroids, intravenous fluids, and call the ENT surgeons urgently – fatal obstruction occasionally occurs in the middle of the night. […] Be very alert for a painful or tender spleen, or any signs of peritonism. In glandular fever the spleen may rupture spontaneously; it is rare, but tragic. It usually begins as a subcapsular haematoma, with pain and tenderness in the left upper quadrant. A secondary rupture through the capsule then occurs at a later date, and this is often rapidly fatal.”

April 7, 2015 Posted by | Books, Cancer/oncology, Diabetes, Infectious disease, Medicine, Neurology, Ophthalmology | Leave a comment

A Systematic Review… (II)

Yesterday I gave some of the reasons I had for disliking the book; in this post I’ll provide some of the reasons why I kept reading. The book had a lot of interesting data. I know I’ve covered some of these topics and numbers before (e.g. here), but I don’t mind repeating myself every now and then; some things are worth saying more than once, and as for the those that are not I must admit I don’t really care enough about not repeating myself here to spend time perusing the archives in order to make sure I don’t repeat myself here. Anyway, here are some number from the coverage:

“Twenty-two high-burden countries account for over 80 % of the world’s TB cases […] data referring to 2011 revealed 8.7 million new cases of TB [worldwide] (13 % coinfected with HIV) and 1.4 million people deaths due to such disease […] Around 80 % of TB cases among people living with HIV were located in Africa. In 2011, in the WHO European Region, 6 % of TB patients were coinfected with HIV […] In 2011, the global prevalence of HIV accounted for 34 million people; 69 % of them lived in Sub-Saharan Africa. Around five million people are living with HIV in South, South-East and East Asia combined. Other high-prevalence regions include the Caribbean, Eastern Europe and Central Asia [11]. Worldwide, HIV incidence is in downturn. In 2011, 2.5 million people acquired HIV infection; this number was 20 % lower than in 2001. […] Sub-Saharan Africa still accounts for 70 % of all AIDS-related deaths […] Worldwide, an estimated 499 million new cases of curable STIs (as gonorrhoea, chlamydia and syphilis) occurred in 2008; these findings suggested no improvement compared to the 448 million cases occurring in 2005. However, wide variations in the incidence of STIs are reported among different regions; the burden of STIs mainly occurs in low-income countries”.

“It is estimated that in 2010 alone, malaria caused 216 million clinical episodes and 655,000 deaths. An estimated 91 % of deaths in 2010 were in the African Region […]. A total of 3.3 billion people (half the world’s population) live in areas at risk of malaria transmission in 106 countries and territories”.

“Diarrhoeal diseases amount to an estimated 4.1 % of the total disability-adjusted life years (DALY) global burden of disease, and are responsible for 1.8 million deaths every year. An estimated 88 % of that burden is attributable to unsafe supply of water, sanitation and hygiene […] It is estimated that diarrhoeal diseases account for one in nine child deaths worldwide, making diarrhoea the second leading cause of death among children under the age of 5 after pneumonia”

“NCDs [Non-Communicable Diseases] are the leading global cause of death worldwide, being responsible for more
deaths than all other causes combined. […] more than 60 % of all deaths worldwide currently stem from NCDs [3].
In 2008, the leading causes of all NCD deaths (36 million) were:
• CVD [cardiovascular disease] (17 million, or 48 % of NCD deaths) [nearly 30 % of all deaths];
• Cancer (7.6 million, or 21 % of NCD deaths) [about 13 % of all deaths]
• Respiratory diseases (4.2 million, or 12 % of NCD deaths) [7 % of all deaths]
• Diabetes (1.3 million, 4 % of NCD deaths) [4].” [Elsewhere in the publication they report that: “In 2010, diabetes was responsible for 3.4 million deaths globally and 3.6 % of DALYs” – obviously there’s a lot of uncertainty here. How to avoid ‘double-counting’ is one of the major issues, because we have a pretty good idea what they die of: “CVD is by far the most frequent cause of death in both men and women with diabetes, accounting for about 60 % of all mortality”].

“Behavioural risk factors such as physical inactivity, tobacco use and unhealthy diet explain nearly 80 % of the CVD burden”

“nearly 80 % of NCD deaths occur in low- and middle-income countries [4], up sharply from just under 40 % in 1990 […] Low- and lower-middle-income countries have the highest proportion of deaths from NCDs under 60 years. Premature deaths under 60 years for high-income countries were 13 and 25 % for upper-middle-income countries. […] In low-income countries, the proportion of premature NCD deaths under 60 years is 41 %, three times the proportion in high-income countries [7]. […] Overall, NCDs account for more than 50 % of DALYs [disability-adjusted life years] in most counties. This percentage rises to over 80 % in Australia, Japan and the richest countries of Western Europe and North America […] In Europe, CVD causes over four million deaths per year (52 % of deaths in women and 42 % of deaths in men), and they are the main cause of death in women in all European countries.”

“Overall, age-adjusted CVD death rates are higher in most low- and middle-income countries than in developed countries […]. CHD [coronary heart disease] and stroke together are the first and third leading causes of death in developed and developing countries, respectively. […] excluding deaths from cancer, these two conditions were responsible for more deaths in 2008 than all remaining causes among the ten leading causes of death combined (including chronic diseases of the lungs, accidents, diabetes, influenza, and pneumonia)”.

“The global prevalence of diabetes was estimated to be 10 % in adults aged 25 + years […] more than half of all nontraumatic lower limb amputations are due to diabetes [and] diabetes is one of the leading causes of visual impairment and blindness in developed countries [14].”

“Almost six million people die from tobacco each year […] Smoking is estimated to cause nearly 10 % of CVD […] Approximately 2.3 million die each year from the harmful use of alcohol. […] Alcohol abuse is responsible for 3.8 % of all deaths (half of which are due to CVD, cancer, and liver cirrhosis) and 4.5 % of the global burden of disease […] Heavy alcohol consumption (i.e. ≥ 4 drinks/day) is significantly associated with an about fivefold increased risk of oral and pharyngeal cancer and oesophageal squamous cell carcinoma (SqCC), 2.5-fold for laryngeal cancer, 50 % for colorectal and breast cancers and 30 % for pancreatic cancer [37]. These estimates are based on a large number of epidemiological studies, and are generally consistent across strata of several covariates. […] The global burden of cancer attributable to alcohol drinking has been estimated at 3.6 and 3.5 % of cancer deaths [39], although this figure is higher in high-income countries (e.g. the figure of 6 % has been proposed for UK [9] and 9 % in Central and Eastern Europe).”

“At least two million cancer cases per year (18 % of the global cancer burden) are attributable to chronic infections by human papillomavirus, hepatitis B virus, hepatitis C virus and Helicobacter pylori. These infections are largely preventable or treatable […] The estimate of the attributable fraction is higher in low- and middle-income countries than in high-income countries (22.9 % of total cancer vs. 7.4 %).”

“Information on the magnitude of CVD in high-income countries is available from three large longitudinal studies that collect multidisciplinary data from a representative sample of European and American individuals aged 50 and older […] according to the Health Retirement Survey (HRS) in the USA, almost one in three adults have one or more types of CVD [11, 12]. By contrast, the data of Survey of Health, Ageing and Retirement in Europe (SHARE), obtained from 11 European countries, and English Longitudinal Study of Aging (ELSA) show that disease rates (specifically heart disease, diabetes, and stroke) across these populations are lower (almost one in five)”

“In 1990, the major fraction of morbidity worldwide was due to communicable, maternal, neonatal, and nutritional disorders (47 %), while 43 % of disability adjusted life years (DALYs) lost were attributable to NCDs. Within two decades, these estimates had undergone a drastic change, shifting to 35 % and 54 %, respectively”

“Estimates of the direct health care and nonhealth care costs attributable to CVD in many countries, especially in low- and middle-income countries, are unclear and fragmentary. In high-income countries (e.g., USA and Europe), CVD is the most costly disease both in terms of economic costs and human costs. Over half (54 %) of the total cost is due to direct health care costs, while one fourth (24 %) is attributable to productivity losses and 22 % to the informal care of people with CVD. Overall, CVD is estimated to cost the EU economy, in terms of health care, almost €196 billion per year, i.e., 9 % of the total health care expenditure across the EU”

“In the WHO European Region, the Eastern Mediterranean Region, and the Region of the Americas, over 50 % of women are overweight. The highest prevalence of overweight among infants and young children is in upper-to-middle-income populations, while the fastest rise in overweight is in the lower-to-middle-income group [19]. Globally, in 2008, 9.8 % of men and 13.8 % of women were obese compared to 4.8 % of men and 7.9 % of women in 1980 [27].”

“In low-income countries, around 25 % of adults have raised total cholesterol, while in high-income countries, over 50 % of adults have raised total cholesterol […]. Overall, one third of CHD disease is attributable to high cholesterol levels” (These numbers seem very high to me, but I’m reporting them anyway).

“interventions based on tobacco taxation have a proportionally greater effect on smokers of lower SES and younger smokers, who might otherwise be difficult to influence. Several studies suggest that the application of a 10 % rise in price could lead to as much as a 2.5–10 % decline in smoking [20, 45, 50, 56].”

“The decision to allocate resources for implementing a particular health intervention depends not only on the strength of the evidence (effectiveness of intervention) but also on the cost of achieving the expected health gain. Cost-effectiveness analysis is the primary tool for evaluating health interventions on the basis of the magnitude of their incremental net benefits in comparison with others, which allows the economic attractiveness of one program over another to be determined [More about this kind of stuff here]. If an intervention is both more effective and less costly than the existing one, there are compelling reasons to implement it. However, the majority of health interventions do not meet these criteria, being either more effective but more costly, or less costly but less effective, than the existing interventions [see also this]. Therefore, in most cases, there is no “best” or absolute level of cost-effectiveness, and this level varies mainly on the basis of health care system expenditure and needs [102].”

“The number of new cases of cancer worldwide in 2008 has been estimated at about 12,700,000 [3]. Of these, 6,600,000 occurred in men and 6,000,000 in women. About 5,600,000 cases occurred in high-resource countries […] and 7,100,000 in low- and middle-income countries. Among men, lung, stomach, colorectal, prostate and liver cancers are the most common […], while breast, colorectal, cervical, lung and stomach are the most common neoplasms among women […]. The number of deaths from cancer was estimated at about 7,600,000 in 2008 […] No global estimates of survival from cancer are available: Data from selected cancer registries suggest wide disparities between high- and low-income countries for neoplasms with effective but expensive treatment, such as leukaemia, while the gap is narrow for neoplasms without an effective therapy, such as lung cancer […]. The overall 5-year survival of cases diagnosed during 1995– 1999 in 23 European countries was 49.6 % […] Tobacco smoking is the main single cause of human cancer worldwide […] In high-income countries, tobacco smoking causes approximately 30 % of all human cancers [9].”

“Systematic reviews have concluded that nutritional factors may be responsible for about one fourth of human cancers in high-income countries, although, because of the limitations of the current understanding of the precise role of diet in human cancer, the proportion of cancers known to be avoidable in practicable ways is much smaller [9]. The only justified dietary recommendation for cancer prevention is to reduce the total caloric intake, which would contribute to a decrease in overweight and obesity, an established risk factor for human cancer. […] The magnitude of the excess risk [associated with obesity] is not very high (for most cancers, the relative risk (RR) ranges between 1.5 and 2 for body weight higher than 35 % above the ideal weight). Estimates of the proportion of cancers attributable to overweight and obesity in Europe range from 2 % [9] to 5 % [34]. However, this figure is likely to be larger in North America, where the prevalence of overweight and obesity is higher.”

“Estimates of the global burden of cancer attributable to occupation in high-income countries result in the order of 1–5 % [9, 42]. In the past, almost 50 % of these were due to asbestos alone […] The available evidence suggests, in most populations, a small role of air, water and soil pollutants. Global estimates are in the order of 1 % or less of total cancers [9, 42]. This is in striking contrast with public perception, which often identifies pollution as a major cause of human cancer.”

“Avoidance of sun exposure, in particular during the middle of the day, is the primary preventive measure to reduce the incidence of skin cancer. There is no adequate evidence of a protective effect of sunscreens, possibly because use of sunscreens is associated with increased exposure to the sun. The possible benefit in reducing skin cancer risk by reduction of sun exposure, however, should be balanced against possible favourable effects of UV radiation in promoting vitamin D metabolism.”

March 30, 2015 Posted by | alcohol, Books, Cancer/oncology, Cardiology, Data, Diabetes, Epidemiology, Infectious disease, Medicine | Leave a comment

Chlamydia and gonorrhea…

Below some observations from Holmes et al.‘s chapters about the sexually transmitted bacterial infections chlamydia and gonorrhea. A few of these chapters covered some really complicated stuff, but I’ve tried to keep the coverage reasonably readable by avoiding many of the technical details. I’ve also tried to make the excerpts easier to read by adding relevant links and by adding brief explanations of specific terms in brackets where this approach seemed like it might be helpful.

“Since the early 1970s, Chlamydia trachomatis has been recognized as a genital pathogen responsible for an increasing variety of clinical syndromes, many closely resembling infections caused by Neisseria gonorrhoeae […]. Because many practitioners have lacked access to facilities for laboratory testing for chlamydia, these infections often have been diagnosed and treated without benefit of microbiological confirmation. Newer, molecular diagnostic tests have in part now addressed this problem […] Unfortunately, many chlamydial infections, particularly in women, are difficult to diagnose clinically and elude detection because they produce few or no symptoms and because the symptoms and signs they do produce are nonspecific. […] chlamydial infections tend to follow a fairly self-limited acute course, resolving into a low-grade persistent infection which may last for years. […] The disease process and clinical manifestations of chlamydial infections probably represent the combined effects of tissue damage from chlamydial replication and inflammatory responses to chlamydiae and the necrotic material from destroyed host cells. There is an abundant immune response to chlamydial infection (in terms of circulating antibodies or cell-mediated responses), and there is evidence that chlamydial diseases are diseases of immunopathology. […] A common pathologic end point of chlamydial infection is scarring of the affected mucous membranes. This is what ultimately leads to blindness in trachoma and to infertility and ectopic pregnancy after acute salpingitis. There is epidemiologic evidence that repeated infection results in higher rates of sequelae.”

“The prevalence of chlamydial urethral infection has been assessed in populations of men attending general medical clinics, STD clinics, adolescent medicine clinics, and student health centers and ranges from 3–5% of asymptomatic men seen in general medical settings to 15–20% of all men seen in STD clinics. […] The overall incidence of C. trachomatis infection in men has not been well defined, since in most countries these infections are not officially reported, are not microbiologically
confirmed, and often may be asymptomatic, thus escaping detection. […] The prevalence of chlamydial infection has been studied in pregnant women, in women attending gynecology or family planning clinics, in women attending STD clinics, in college students, and in women attending general medicine or family practice clinics in school-based clinics and more recently in population-based studies. Prevalence of infection in these studies has ranged widely from 3% in asymptomatic women in community-based surveys to over 20% in women seen in STD clinics.[31–53] During pregnancy, 3–7% of women generally have been chlamydia positive […] Several studies in the United States indicate that approximately 5% of neonates acquire chlamydial infection perinatally, yet antibody prevalence in later childhood before onset of sexual activity may exceed 20%.”

“Clinically, chlamydia-positive and chlamydia-negative NGU [Non-Gonococcal Urethritis] cannot be differentiated on the basis of signs or symptoms.[76] Both usually present after a 7–21-day incubation period with dysuria and mild-to-moderate whitish or clear urethral discharge. Examination reveals no abnormalities other than the discharge in most cases […] Clinical recognition of chlamydial cervicitis depends on a high index of suspicion and a careful cervical examination. There are no genital symptoms that are specifically correlated with chlamydial cervical infection. […] Although urethral symptoms may develop in some women with chlamydial infection, the majority of female STD clinic patients with urethral chlamydial infection do not have dysuria or frequency. […] the majority of women with chlamydial infection cannot be distinguished from uninfected women either by clinical examination or by […] simple tests and thus require the use of specific diagnostic testing. […] Since many chlamydial infections are asymptomatic, it has become clear that effective control must involve periodic testing of individuals at risk.[168] As the cost of extensive screening may be prohibitive, various approaches to defining target populations at increased risk of infection have been evaluated. One strategy has been to designate patients attending specific high prevalence clinic populations for universal testing. Such clinics would include STD, juvenile detention, and some family planning clinics. This approach, however, fails to account for the majority of asymptomatic infections, since attendees at high prevalence clinics often attend because of symptoms or suspicion of infection. Consequently, selective screening criteria have been developed for use in various clinical settings.[204–208] Among women, young age (generally,

If you’re a woman who’s decided not to have children and so aren’t terribly worried about infertility, it should be emphasized that untreated chlamydia can cause other really unpleasant stuff as well, like chronic pelvic pain from pelvic inflammatory disease, or ectopic pregnancy, which may be life-threatening. This is the sort of infection you’ll want to get treated even if you’re not bothered by symptoms.

Neisseria gonorrhoeae (gonococci) is the etiologic agent of gonorrhea and its related clinical syndromes (urethritis, cervicitis, salpingitis, bacteremia, arthritis, and others). It is closely related to Neisseria meningitidis (meningococci), the etiologic agent of one form of bacterial meningitis, and relatively closely to Neisseria lactamica, an occasional human pathogen. The genus Neisseria includes a variety of other relatively or completely nonpathogenic organisms that are principally important because of their occasional diagnostic confusion with gonococci and meningococci. […] Many dozens of specific serovars have been defined […] By a combination of auxotyping and serotyping […] gonococci can be divided into over 70 different strains; the number may turn out to be much larger.”

“Humans are the only natural host for gonococci. Gonococci survive only a short time outside the human body. Although gonococci can be cultured from a dried environment such as a toilet seat up to 24 hours after being artificially inoculated in large numbers onto such a surface, there is virtually no evidence that natural transmission occurs from toilet seats or similar objects. Gonorrhea is a classic example of an infection spread by contact: immediate physical contact with the mucosal surfaces of an infected person, usually a sexual partner, is required for transmission. […] Infection most often remains localized to initial sites of inoculation. Ascending genital infections (salpingitis, epididymitis) and bacteremia, however, are relatively common and account for most of the serious morbidity due to gonorrhea.”

“Consideration of clinical manifestations of gonorrhea suggests many facets of the pathogenesis of the infection. Since gonococci persist in the male urethra despite hydrodynamic forces that would tend to wash the organisms from the mucosal surface, they must be able to adhere effectively to mucosal surfaces. Similarly, since gonococci survive in the urethra despite close attachment to large numbers of neutrophils, they must have mechanisms that help them to survive interactions with polymorphonuclear neutrophils. Since some gonococci are able to invade and persist in the bloodstream for many days at least, they must be able to evade killing by normal defense mechanisms of plasma […] Invasion of the bloodstream also implies that gonococci are able to invade mucosal barriers in order to gain access to the bloodstream. Repeated reinfections of the same patient by one strain strongly suggest that gonococci are able to change surface antigens frequently and/or to escape local immune mechanisms […] The considerable tissue damage of fallopian tubes consequent to gonococcal salpingitis suggests that gonococci make at least one tissue toxin or gonococci trigger an immune response that results in damage to host tissues.[127] There is evidence to support many of these inferences. […] Since the mid-1960s, knowledge of the molecular basis of gonococcal–host interactions and of gonococcal epidemiology has increased to the point where it is amongst the best described of all microbial pathogens. […] Studies of pathogenesis are [however] complicated by the absence of a suitable animal model. A variety of animal models have been developed, each of which has certain utility, but no animal model faithfully reproduces the full spectrum of naturally acquired disease of humans.”

“Gonococci are inherently quite sensitive to antimicrobial agents, compared with many other gram-negative bacteria. However, there has been a gradual selection for antibioticresistant mutants in clinical practice over the past several decades […] The consequence of these events has been to make penicillin and tetracycline therapy ineffective in most areas. Antibiotics such as spectinomycin, ciprofloxacin, and ceftriaxone generally are effective but more expensive than penicillin G and tetracycline. Resistance to ciprofloxacin emerged in SE Asia and Africa in the past decade and has spread gradually throughout much of the world […] Streptomycin (Str) is not frequently used for therapy of gonorrhea at present, but many gonococci exhibit high-level resistance to Str. […] Resistance to fluoroquinolones is increasing, and now has become a general problem in many areas of the world.”

“The efficiency of gonorrhea transmission depends on anatomic sites infected and exposed as well as the number of exposures. The risk of acquiring urethral infection for a man following a single episode of vaginal intercourse with an infected woman is estimated to be 20%, rising to an estimated 60–80% following four exposures.[16] The prevalence of infection in women named as secondary sexual contacts of men with gonococcal urethritis has been reported to be 50–90%,[16,17] but no published studies have carefully controlled for number of exposures. It is likely that the single-exposure transmission rate from male to female is higher than that from female to male […] Previous reports saying that 80% of women with gonorrhea were asymptomatic were most often based on studies of women who were examined in screening surveys or referred to STD clinics because of sexual contact with infected men.[23] Symptomatic infected women who sought medical attention were thus often excluded from such surveys. However […] more than 75% of women with gonorrhea attending acute care facilities such as hospital emergency rooms are symptomatic.[24] The true proportion of infected women who remain asymptomatic undoubtedly lies between these extremes […] Asymptomatic infections occur in men as well as women […] Asymptomatically infected males and females contribute disproportionately to gonorrhea transmission, because symptomatic individuals are more likely to cease sexual activity and seek medical care.”

“the incidence of asymptomatic urethral gonococcal infection in the general population also has been estimated at approximately 1–3%.[27] The prevalence of asymptomatic infection may be much higher, approaching 5% in some studies, because untreated asymptomatic infections may persist for considerable periods. […] The prevalence of gonorrhea within communities tends to be dynamic, fluctuating over time, and influenced by a number of interactive factors. Mathematical models for gonorrhea within communities suggest that gonorrhea prevalence is sustained not only through continued transmission by asymptomatically infected patients but also by “core group” transmitters who are more likely than members of the general population to become infected and transmit gonorrhea to their sex partners. […] At present, gonorrhea prevention and control efforts are heavily invested in the concept of vigorous pursuit and treatment of infected core-group members and asymptomatically infected individuals.”

“Relatively large numbers (>50) of gonococcal A/S [auxotype/serotype] classes usually are present in most communities simultaneously […] and new strains can be detected over time. The distribution of isolates within A/S classes tends to be uneven, with a few A/S classes contributing disproportionately to the total number of isolates. These predominant A/S classes generally persist within communities for months or years. […] Interviews of the patients infected by [a specific] strain early in [an] outbreak identified one infected female who acknowledged over 100 different sexual partners over the preceding 2 months, suggesting that she may have played an important role in the introduction and establishment of this gonococcal strain in the community. Thus the Proto/IB-3 strain may have become common in Seattle not because of specific biologic factors but because of its chance of transmission to members of a core population by a high-frequency transmitter.” [100+ partners over a 2 month period! I was completely dumbstruck when I’d read that.]

“clinical gonorrhea is manifested by a broad spectrum of clinical presentations including asymptomatic and symptomatic local infections, local complicated infections, and systemic dissemination. […] Acute anterior urethritis is the most common manifestation of gonococcal infection in men. The incubation period ranges from 1 to 14 days or even longer; however, the majority of men develop symptoms within 2–5 days […] The predominant symptoms are urethral discharge or dysuria [pain on urination]. […] Without treatment, the usual course of gonococcal urethritis is spontaneous resolution over a period of several weeks, and before the development of effective antimicrobial therapy, 95% of untreated patients became asymptomatic within 6 months.[43] […] The incubation period for urogenital gonorrhea in women is less certain and probably more variable than in men, but most who develop local symptoms apparently do so within 10 days of infection.[51,52] The most common symptoms are those of most lower genital tract infections in women […] and include increased vaginal discharge, dysuria, intermenstrual uterine bleeding, and menorrhagia [abnormally heavy and prolonged menstrual period], each of which may occur alone or in combination and may range in intensity from minimal to severe. […] The clinical assessment of women for gonorrhea is often confounded […] by the nonspecificity of these signs and symptoms and by the high prevalence of coexisting cervical or vaginal infections with Chlamydia trachomatis, Trichomonas vaginalis, Candida albicans, herpes simplex virus, and a variety of other organisms […] Among coinfecting agents for patients with gonorrhea in the United States, C. trachomatis [chlamydia] is preeminent. Up to 10–20% of men and 20–30% of women with acute urogenital gonorrhea are coinfected with C. trachomatis.[10,46,76,139–141] In addition, substantial numbers of women with acute gonococcal infection have simultaneous T. vaginalis infections.”

“Among patients with gonorrhea, pharyngeal infection occurs in 3–7% of heterosexual men, 10–20% of heterosexual women, and 10–25% of homosexually active men. […] Gonococcal infection is transmitted to the pharynx by orogenital sexual contact and is more efficiently acquired by fellatio than by cunnilingus.[63]”

“In men, the most common local complication of gonococcal urethritis is epididymitis […], a syndrome that occurred in up to 20% of infected patients prior to the availability of modern antimicrobial therapy. […] Postinflammatory urethral strictures were common complications of untreated gonorrhea in the preantibiotic era but are now rare […] In acute PID [pelvic inflammatory disease], the clinical syndrome comprised primarily of salpingitis, and frequently including endometritis, tubo-ovarian tuboovarian abscess, or pelvic peritonitis is the most common complication of gonorrhea in women, occurring in an estimated 10–20% of those with acute gonococcal infection.[75,76] PID is the most common of all complications of gonorrhea, as well as the most important in terms of public-health impact, because of both its acute manifestations and its longterm sequelae (infertility, ectopic pregnancy, and chronic pelvic pain).”

“A major impediment to use of culture for gonorrhea diagnosis in many clinical settings are the time, expense, and logistical limitations such as specimen transport to laboratories for testing, a process that may take several days and result in temperature variation or other circumstances that can jeopardize culture viability.[111] In recent years, reliable nonculture assays for gonorrhea detection have become available and are being used increasingly. […] recently, nucleic acid amplification tests (NAATs) for gonorrhea diagnosis have become widely available.[116,117] Assays based on polymerase chain reaction (PCR), transcription-mediated amplification (TMA), and other nucleic acid amplification technologies have been developed. As a group, commercially available NAATs are more sensitive than culture for gonorrhea diagnosis and specificities are nearly as high as for culture. […] Emerging data suggest that most currently available NAATs are substantially more sensitive for gonorrhea detection than conventional culture.”

“Prior to the mid-1930s, when sulfanilamide was introduced, gonorrhea therapy involved local genital irrigation with antiseptic solutions such as silver nitrate […] By 1944 […] many gonococci had become sulfanilamide resistant […] Fortunately, in 1943 the first reports of the near 100% utility of penicillin for gonorrhea therapy were published,[127] and by the end of World War II, as penicillin became available to the general public, it quickly became the therapy of choice. Since then, continuing development of antimicrobial resistance by N. gonorrhoeae[128,129] led to regular revisions of recommended gonorrhea therapy. From the 1950s until the mid-1970s, gradually increasing chromosomal penicillin resistance led to periodic increases in the amount of penicillin required for reliable therapy. […] by the late 1980s, penicillins and tetracyclines were no longer recommended for gonorrhea therapy.
In addition to resistance to penicillin, tetracyclines, and erythromycin, in 1987, clinically significant chromosomally mediated resistance to spectinomycin — another drug recommended for gonorrhea therapy — was described in U.S. military personnel in Korea.[132] In Korea, because of the high prevalence of PPNG [spectinomycin-resistant Penicillinase-Producing Neisseria Gonorrhoeae], in 1981, spectinomycin had been adopted as the drug of choice for gonorrhea therapy. By 1983, however, spectinomycin treatment failures were beginning to occur in patients with gonorrhea […] Following recognition of the outbreak of spectinomycin-resistant gonococci in Korea, ceftriaxone became the drug of choice for treatment of gonorrhea in U.S. military personnel in that country.[132] […] Beginning in 1993, fluoroquinolone antibiotics were recommended for therapy of uncomplicated gonorrhea in the United States […] [However] in 2007 the CDC opted to no longer recommend fluoroquinolone antibiotics for therapy of uncomplicated gonorrhea. This change meant that ceftriaxone and other cephalosporin antibiotics had become the sole class of antibiotics recommended as first-line therapy for gonorrhea. […] For over two decades, ceftriaxone — a third-generation cephalosporin—has been the most reliable single-dose regimen used for gonorrhea worldwide. […] there are currently few well-studied therapeutic alternatives to ceftriaxone for gonorrhea treatment.”

November 1, 2014 Posted by | Books, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology, Pharmacology | Leave a comment

Sexually Transmitted Viral Pathogens

The stuff below covers material from the last half of part V in Holmes et al. This previous post also dealt with this topic (the title of this post is the title of part 5 of the book, which if not hidden away in a 2000+ page textbook might well have been a book of its own; I’m quite sure you can find entire books on these topics which go into much less detail than does part 5 of this book). Some of the stuff was really hard to read; I’ve tried to include in this post mainly stuff people who have not read the rest of the coverage might be expected to understand without too much difficulty.

“Antibody to EBV [Epstein-Barr Virus] can be detected in 90-95% of the population by adulthood.10 Primary exposure often occurs in the first years of life, with seroconversion evident before the age of 5 years in 50% of children studied in the United States and Great Britain.22,23 In economically advantaged communities, primary infection may be delayed until adolescence or early adulthood,24 at which time acquisition of virus produces the clinical syndrome acute infectious mononucleosis. […] Primary EBV infection in infancy or early childhood is usually subclinical, but when delayed until the second decade of life, it manifests as infectious mononucleosis in up to 50% of patients. A self-limiting lymphoproliferative disease, the syndrome consists of fever, headache, pharyngitis, lymphadenopathy, and general malaise. Resolution of symptoms may take weeks to months, but primary infection is always followed by the establishment of a permanent viral carrier state.”

“a highly significant correlation between seropositivity for EBV, sexual intercourse, and an increasing number of sexual partners was found in a cross-sectional analysis of 1006 new University students.50 In this study, two-thirds of infectious mononucleosis cases were statistically attributable to sexual intercourse, whereas only a tenth of asymptomatic primary infections were linked to sexual activity.” [This is of course just a cross-sectional analysis, but even so – ‘kissing disease‘ may perhaps be a slightly inaccurate term…]

“The overall size of the EBV-infected B cell reservoir is largely controlled by CD8+, HLA class I-restricted, EBV-specific cytotoxic T lymphocytes (CTLs). Up to 5% of the total circulating CD8+ T cell pool may be committed to this single virus in the EBV-carrier state,110 indicating the critical role for T-cell surveillance in maintaining the host: virus balance. Impaired CTL responses in immunosuppressed patients such as transplant recipients or HIV-1-infected individuals32,111 leads to an expansion of the infected B cell population and potentially fatal lymphoproliferative disease. The contribution of virus-specific CTLs in immune regulation of EBV-induced lymphoproliferation has been made clear by recent therapeutic interventions involving adoptive transfer of virus-specific T lymphocytes to restore immunity against EBV infection in bone marrow transplant recipients.112, 113, 114

Non-Hodgkin’s lymphoma, an AIDS-defining cancer some 60 times more common in AIDS patients than in the general population,122 can be divided morphologically into Burkitt-like and immunoblastic lymphomas […]. Both have a higher association with EBV (30-40% and 75-80%, respectively) in AIDS than in non-AIDS groups.123,124 […] Burkitt’s lymphomas appear early in the course of AIDS, prior to profound immunosuppression, whereas immunoblastic lymphomas typically occur in late-stage AIDS when cellular immunity is compromised. […] Hodgkin’s lymphomas in the setting of AIDS contain EBV in 75-90% of the cases,140,141 reflecting the unusually high frequency in the HIV-infected population of mixed-cellularity and lymphocyte-depletion subtypes142 known to be most closely associated with EBV in the general population.15,16 Although not considered an AIDS-defining illness, Hodgkin’s lymphoma occurs with increased frequency in the setting of HIV infection. […] Our understanding of the precise role of EBV in the biology of each malignancy remains rudimentary.”

“Papillomaviruses are a group of small DNA viruses that primarily induce epithelial cell proliferation, or papillomas, in higher vertebrates. Infections are strictly genus or species specific and there is considerable tropism among the viruses for particular anatomic sites. […] The genomes of over 100 human papillomavirus (HPV) types have been molecularly cloned and completely sequenced and partial sequences for potentially up to another hundred types have been detected by PCR-based assays.9,10

[You can skip this part without missing out on anything important:] “A basal level of transcription from the p97/p105 promoter is regulated by the keratinocyte-dependent enhancer in the NCR and can be repressed by binding of E2 to its cognate recognition sequences located adjacent to the p97/p105 TATA boxes.82,87 E2 has a role in repressing transcription from the viral promoter and its loss on viral DNA integration allows increased expression of the oncogenic proteins E6 and E7. E2 also activates transcription under some circumstances.88 Variations in binding to four different E2 binding sites may contribute to transcriptional regulation.89 Interestingly, the E8E2C protein of HPV-31 had an ability to repress transcription from a single promoter-distal E2 binding site. This activity was lacking in the full-length E2, suggesting that E8E2C has a role in regulating transcription.90 E2 binds the general transcription factor TFIIB91 and is thought to directly inhibit HPV transcription at a step subsequent to binding of TBP or TFIID to the TATA box.92 It interacts with numerous other transcription factors and chromatin modification factors including CBP,93 p/CAF,94 C/EBP,95 nucleosome assembly protein 1,96 and Top BP1.97 An interaction between bromodomain protein 4 and E2 is required for transcriptional activation by E2.98 Two crystal structure studies of the amino terminal transcription activation domain of E2 suggested that dimerization of E2 helps recruit distal transcription factors to the viral transcription complex99 …” [I decided to include a quote like this as well to indicate what kind of stuff the book is also full of, and illustrate why it was hard to read. There’s a lot of stuff in some of these chapters which I had a really hard time following.]

“Predictions about the role of HPV in neoplasia obtained from experimental studies are consistent with the natural history of cervical cancer. Among women who develop squamous intraepithelial lesions, the time from first detection of viral DNA to lesions is short, ~2 years, though factors like number of partners and infection with other STDs may influence the interval […]. Even mildly dysplastic lesions show an increase in proliferation and polyploidization. These changes result as a direct consequence of expression of E6/E7. The median age of carcinoma in situ (CIS) in the United States is 29,223,224 indicating that approximately a decade has elapsed between the initial infection and severe dysplasia. CIS lesions are characterized by their aneuploid DNA content and thus reflect the genetic instability that accompanies prolonged expression of E6/E7. The preneoplastic lesions can regress spontaneously. One principle explanation for their regression is likely to be an effective immune response, and generalized T-cell deficiency has been associated with increased dysplasia […]. Other explanations may include the fact that some, perhaps most, alterations will be deleterious, resulting in cell death. The median age of invasive cervical cancer in the United States is 49, indicating that additional changes required for invasion and metastasis are acquired slowly over time.”

“All HPV types are linked to the development of low-grade cervical SILs [squamous intraepithelial lesions],16 whereas high-grade cervical SILs are usually positive for oncogenic HPV types.272 In a cohort of young women in the United States, Moscicki et al.155 reported that 15% developed LSIL within 3 years after initial HPV infection, and in the UK, Woodman et al.70 reported that the 3-year cumulative incidence of any cytologic abnormality after initial infection was 33%. In another cohort of young women in the United States, Winer et al.132 reported that approximately 50% developed a low-grade lesion within 3 years after initial HPV infection […]. The latter study also reported that rates of lesion detection tend to increase with increased screening frequency, due to spontaneous regression of most low-grade lesions. Therefore, the shorter interval between follow-up visits (4 vs. 6 months) may explain why that study detected LSIL in a higher proportion of women. Half of newly detected low-grade lesions appear to regress within 6-9 months.70,132,273 It also appears that vaginal SIL is not uncommon among women with incident HPV infections. While less commonly detected than cervical SIL, one study reported that almost 30% of women with incident HPV infections developed vaginal SIL within 3 years (Fig. 28-3B), and the median duration of these lesions was less than 5 months.132

Results from natural history studies suggest that LSILs are transient manifestations of productive HPV infections, whereas HSILs are cervical cancer precursor lesions. This is in contrast to the previously held theory that cervical carcinogenesis always follows a progression from persistent HPV infection to development of low- and then high-grade lesions. Several recent studies have shown that cervical highgrade lesions are a relatively early manifestation of HPV infections in young women. Woodman et al.70 reported that the risk of high-grade lesions was highest in the first 6 months after initial HPV infection. It has also been shown that histologically confirmed high-grade lesions are common after infection with HPV 16 and 18 infections,132,274 with one study reporting that 27% of women with incident HPV 16 or 18 infections developed histologically confirmed CIN grade 2 or 3 within 3 years […] and that the median time to development was 14 months.132

“Although viral hepatitis is unquestionably an ancient disease, it is only in the past 40 years that an appreciation has emerged of the diversity of infectious agents capable of causing the clinical syndrome of acute hepatitis. […] at least five distinctly different human viruses (classified as hepatitis A through E) are now generally recognized to be causative agents of acute and/or chronic viral hepatitis […].

Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus (HDV), and hepatitis E virus (HEV) all share a remarkable tropism for the liver despite profound differences in their physical structure, pathobiology, and epidemiology. Each of these viruses is a cause of clinically overt acute hepatitis associated with frank jaundice. The severity of the liver disease, which frequently accompanies acute infection with these viruses, generally distinguishes them from cytomegalovirus and Epstein-Barr virus, which typically cause much milder liver dysfunction during primary infections. Within the United States, almost all cases of acute hepatitis are caused by infection with HAV (51%), HBV (40%), or HCV (9%).3 These acute hepatitis virus infections cannot be distinguished from each other without serologic testing. Acute hepatitis represents a considerable disease burden within the United States, with an estimated 40,000-60,000 clinical cases occurring annually during the past 5 years. Only a fraction of these cases are reported to public health authorities, and a substantial number of additional infections do not come to medical attention because they are asymptomatic. Fulminant hepatic failure and death occur in a very small proportion of patients with acute hepatitis A or B, but these clinical endpoints are rarely associated with acute HCV infection in the United States.4,5

“The major burden of disease due to hepatitis virus infections stems from the chronic liver damage that occurs in individuals who develop persistent infections. The proportion of persons who become persistently infected is highly dependent on the infecting virus. Persistent infections with HAV are not well documented and may never occur. On the other hand, more than 50% of persons infected with HCV fail to clear the virus and most eventually develop biochemical and histologic evidence of chronic liver disease.6 HBV has an intermediate tendency to establish persistence, with the risk of persistent infection being highly dependent on the age at the time of infection and immunologic competence of the individual.

It is appropriate to focus attention on the hepatitis viruses in a textbook concerned with sexually transmitted diseases (STDs). Although these are systemic infections that are also commonly transmitted by other means, HBV is a sexually transmitted infection, and sexual activity may profoundly influence the risks for acquisition of HAV. To a lesser extent, sexual behavior may also influence the risk of infection with HCV and HDV.”

“Several factors account for the high risk of HBV infection among MSM [Males who have Sex with Males], which was noted in […] early studies. One of the most important factors was the number of sexual partners. The typical homosexually active male frequenting Denver’s steam baths in the late 1970s had eight different male sexual contacts per month.206 These contacts were largely anonymous and could total as many as 1000 over the lifetime of a gay man.”

“The endemicity of HBV infection varies greatly worldwide and is influenced primarily by the predominant age at which infection occurs.121,190 Endemicity of infection is considered high in those parts of the world where at least 8% of the population is HBsAg positive, and 70-90% of the population has serological evidence of previous HBV infection. Almost all infections occur during either the perinatal period or early in childhood, which accounts for the high rates of chronic HBV infection in these populations. Risk of HBV infection continues after the first 5 years of life, but its eventual contribution to the high rate of chronic infection is less significant. Chronic infection with HBV is strongly associated with HCC [liver cancer], and areas with a high endemicity of chronic HBV infection have the highest death rates from this neoplasm. […]

In most developed parts of the world, including the United States and Western Europe, the prevalence of chronic HBV infection is <1%, and the overall infection rate is 5-7%. The highest incidence of acute hepatitis B is among young adults, and high-risk sexual activity and injectable drug use account for most cases of newly acquired hepatitis B.191, 192, 193, 194 In the United States, heterosexual activity accounts for 40% of new hepatitis B cases, while MSM represent 15% of new cases.”

“HCV infection accounts for 15% of acute viral hepatitis cases within the United States. However, it is by far the leading cause of chronic viral hepatitis and is present in over 40% of persons with chronic liver disease. The morbidity and mortality associated with HCV infection are due to its unique propensity to cause persistent infection in most persons, a feature that distinguishes this virus from other hepatitis viruses. The specific mechanisms underlying viral persistence are not known.

Although it has been controversial, the balance of evidence now favors the occasional sexual transmission of HCV. The risk of infection with HCV, like HBV, has been independently related to numbers of sexual partners in some STD clinic studies.226,285 Although the risk of HCV infection has been shown to correlate with numbers of partners and/or specific sexual practices in some studies of homosexual men,286,287 the risk of infection is overwhelmingly more closely tied to injection drug use. […] About 60-85% of all infections lead to virus persistence, and this is often associated with evidence of chronic liver disease […]. After many years, this process may culminate in cirrhosis and liver failure, or the development of hepatocellular carcinoma. These end-stage events in chronic hepatitis C may claim as many as 10,000 lives annually in the United States.326 […] As many as a third of patients found to have chronic hepatitis C will ultimately develop cirrhosis6,284,333,334; although it is not well defined, the fraction of all patients who are infected with the virus and progress to cirrhosis is undoubtedly far lower. Cirrhosis may be present within as little as 60 months of the initial infection but is identified typically in persons who have been infected for decades. Factors associated with disease progression include age at infection, regular alcohol consumption, coinfection with HIV or HBV, and more recently obesity and insulin resistance.335, 336 Some patients, usually with well-established cirrhosis, develop primary hepatocellular carcinoma.283 Chronic HCV infection is the most important etiology of hepatocellular carcinoma in western countries.

The major challenge to clinical investigators has been the discovery of specific markers that are predictive of progression of chronic hepatitis C to a clinically significant disease state. This remains an exceptionally difficult problem. There is no good correlation between biochemical markers and the extent of fibrosis or the presence or absence of cirrhosis. Indeed, many patients with cirrhosis have no obvious laboratory abnormalities.333 In addition, quantitative measurements of the viremia (“virus load”) are not useful in determining the extent of disease resistance.335, 336

July 20, 2014 Posted by | Books, Cancer/oncology, Epidemiology, Immunology, Infectious disease, Medicine | Leave a comment

Infectious Agents and Cancer

“[H]uman papilloma virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human herpes virus 8, human T-cell lymphotropic virus 1, human immunodeficiency virus, Merkel cell polyomavirus, Helicobacter pylori, Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium […] are recognized as carcinogens and probable carcinogens by [the] International Agency for Research on Cancer (IARC). They are not considered in this book […] The aim of this monograph is to analyze associations of other infectious agents with cancer risk […] virology is not considered in our monograph: although there are some viruses that can be connected with cancer but are not included into the IARC list (John Cunningham virus, herpes simplex virus-1 and -2, human cytomegalovirus, simian virus 40, xenotropic murine leukemia virus-related virus), we decided to leave them for the virologists and to concentrate our efforts on other infectious agents (bacteria, protozoa, helminths and fungi) […] To the best of our knowledge, this is the first book devoted to this problem”

Here’s what I wrote on goodreads:

“This book is written by three Russian researchers, and you can tell; the language is occasionally hilariously bad, but it’s not too difficult to figure out what they’re trying to say. The content partially made up for the poor language, as the book covers quite a bit of ground considering the low page count.”

I gave the book two stars. I’m glad they wrote the book, because it covered some stuff I didn’t know much about. I think I’m closer to one star than three, but it’s mostly because it’s terribly written, not because I have major objections to the coverage as such. What I mean by this is that they talk about a lot of studies and they include a lot of data – they’re scientists who write about scientific research, they just happen to be Russian scientists who are not very good at English. It’s terribly written, but the stuff is interesting.

As mentioned above there are quite a few viruses which we know may lead to cancer in humans. I’ve recently read a lot of stuff about this topic as it was covered in both Boffetta at el. and also rather extensively in part 5 of the Sexually Transmitted Diseases text, which covered sexually transmitted viral pathogens (that section of the book was with its 230 pages actually a ‘book-length section’; it was significantly longer than this book is..). I’ve even covered some of that stuff here on the blog, e.g. here. I may incidentally write more about these things and related stuff later, as I’m quite far behind in terms of my intended coverage of the STD book at the moment.

Anyway, viruses aren’t the only bad guys around. So these guys decided to write a book about some other infectious diseases affecting humans, and how these infectious diseases may relate to cancer risk. As they point out in the book, “there is only one bacterium, Helicobacter pylori, which is recognized by IARC as an established human carcinogen.” After reading this book you’ll realize that there are some others which perhaps look a bit suspicious as well. In some cases a lot of studies have been done and you have both animal-models, lab-analyses, case-control studies, cohort studies, … In other cases you have just a few small studies to judge from. As is always the case when people have a close look at epidemiological research, this stuff is messy. Sometimes studies that looked really convincing turn out to not replicate in larger samples, sometimes dramatically different effect sizes are found in different areas of the world (which may of course both be interpreted as an indicator that the ‘true’ effect sizes are different in the different subpopulations, or it may be interpreted as a result e.g. of faulty study design which makes those Swedish data look really fishy..), sometimes different results can be explained by differences in data quality/type of data applied/etc. (classic cases are different effects based on whether you rely on self reports or biological disease markers, and different results from analyses of bacterial cultures vs PCR analyses), and so on and so forth. There are a lot of details, and they cover them in the book. I occasionally see people criticize epidemiological research online on the grounds that many (‘all?’) results published in this area are just random correlations without any deeper meaning. Sometimes this criticism may well be warranted, and the authors of this book certainly in some cases seem to go quite a bit further than I would do based on the same data. But there’s another part of the story here. When you start out with a couple of case-control studies indicating that guys with cancer type X are more likely to have positive lab cultures for this specific micro-organism, that may not be a big deal. But perhaps then a few microbiologists show up and tell you that it would actually make a lot of sense if there was a connection here (and they might start talking about fancy stuff like various ‘modulations of host immune responses’, ‘inflammatory markers’, ‘the role of nitric oxides’, …). They conduct some studies as well and perhaps one of the things they find is that the observed cancer grades in the patients seem to depend quite a lot upon which of the pathogen subtypes the individual happen to be infected with (perhaps suddenly also providing an explanation for some previously surprising negative results in specific cases). And then perhaps you get a couple of animal studies that show that these animals get cancer when you infect them with these bugs and don’t treat the infection. Perhaps you have a few more studies as well in different populations, because Chinese people get cancer too, and you start seeing that people around the world who happen to be infected with these bugs are all more likely to get cancer, compared to the locals who are not infected (…or perhaps not, and then it just gets more fun…). This process goes on for a while, until at some point it starts getting really hard to think these positive correlations are all just the result of random p-value hunting done by bored researchers who don’t know what else to do with their time, and you start asking yourself if perhaps this idea is not as stupid as it was when you first encountered it. Most of the time the process stops before then because the proposed link isn’t there, but modern epidemiology is not just random collections of correlations.

In the context of the specific infectious diseases covered in the book the people who have in some sense the final say in these things (the IARC) think we’re not quite there yet, but you have some cases where some different lines of evidence all seem to indicate that a link may be present and relevant. It would be highly surprising to me if in 20 years time we’d have realized that none of the infectious diseases they talk about in this book are at all involved in cancer pathogenesis. A related point is that most likely we’ve missed some ‘true connections’ along the way, and will continue to do so in the future, because even if a link is there, it’s sometimes really hard to find it and easy to overlook it, for many different reasons.

I have quoted a bit from the book below and added some comments here and there. I have corrected some of the spelling/language errors the authors made to ease reading; if a word is placed in brackets, it’s an indicator that I’ve replaced a misspelled word by the correct one (‘they meant to use’). The authors do not even have any clue how and when to use the word ‘the’, often using it when it’s not needed and forgetting to use it in cases where it is needed, which made quoting from the book painful. Read it for the content.

“Chronic inflammation substantially increases the probability of neoplastic transformation of the surrounding cells, inducing mutations and epigenetic alterations by the activity of inflammatory molecules […] through the formation of free radicals and DNA damage […] Since infectious agents persisting in the organism may cause chronic inflammation, they can also promote local carcinogenesis. […] Chronic inflammation can also specifically affect the functioning of [an] organ, for instance, promoting cholelithiasis and urolithiasis that increase the time of exposure of the gallbladder, bile ducts, urinary bladder and ureters to chemical carcinogens and carcinogenic bacteria. […] In addition to […] metabolic and immune mechanisms, a number of bacteria […] and protozoa […] [produce] or [contain] in their cell wall their own toxins […] possessing [carcinogenic] activity, affecting cell-cell interactions, intracellular signal transduction or induction of mutations and epigenetic alterations that can influence vital cell processes (apoptosis, proliferation, survival, growth, differentiation, invasion). Intracellular protozoan (Toxoplasma gondii) may induce resistance to multiple mechanisms of apoptosis […]. So, bacterial and [protozoan toxins] may function like initiating or like promoting agents.”

“Typhoid fever, which is a systemic infection caused by Salmonella enterica serovar Typhi (S. typhi), is a major health problem in developing countries. There are approximately 21.6 million cases of typhoid fever worldwide and an estimated 200,000 deaths every year. It is known that S. typhi may colonize the gallbladder, causing […] chronic inflammation. Welton et al. (1979) were the very first to [establish] an association between the typhoid-carrier state and death due to malignancies of the hepatobiliary tract. They recruited 471 U.S. carriers of [S. typhi] , matched them with 942 controls and demonstrated that chronic typhoid carriers died of hepatobiliary cancer six times more often than the controls. […] The absence of basic research analyzing the carcinogenic properties of S. typhi does not allow placing it in the short list of the infectious agents that may be a cause of cancer development but are not included in the IARC roster, but this bacterium undoubtedly should be [on] the extended list. If [basic] studies on cell lines and animal models [support] the results of [the] epidemiological investigations, S. typhi can be placed [on] the short list.” [I included this in part because it is one of several examples in the book of how even strong correlations and high relative risks are not considered sufficient on their own by epidemiologists to settle matters. Some relative risks in other studies have been even higher – a study on gall-bladder cancer found an RR of 12.7].

“Tuberculosis (TB), a destructive disease [affecting] the lungs […] is a major global health burden, with about nine million of new cases and 1.1 million deaths annually. When the host protective immunity fails to control M. tuberculosis growth, progression to active disease occurs. […] According to the data of the last comprehensive systematic review and [meta-analysis] published by Brenner et al. (2011), there were 30 studies […] conducted in North America, Europe and Asia, which investigated the association of tuberculosis on lung cancer risk with adjustment for smoking. The relative risk (RR) of lung cancer development among patients with TB history was 1.76 (95% CI = 1.49–2.08).”

“22 studies from North America, Europe and East Asia [have] investigated the association between pneumonia and lung cancer risk while adjusting for smoking […] A significant increase in lung cancer risk was observed among all studies (RR = 1.43, 95% CI = 1.22–1.68). […] To sum up, there are basic as well as extensive epidemiological evidence that С. pneumoniae may cause lung cancer” [However effect sizes seem to be different in different countries. I was skeptical about this one in part because a non-smoker’s absolute risk of getting lung cancer is very low, meaning that relative risks in the neighbourhood reported above although statistically significant probably are clinically insignificant. How pneumonia and smoking interact seems to me a much more important question. Then again we haven’t got an explanation for all of the non-smoking-related lung cancers yet, and they are caused by something, so it’s also not like researching this is a complete waste of time.]

“Primary infection with C. trachomatis [Chlamydia], the most prevalent sexually transmitted bacterium worldwide with an estimated 90 million new cases occurring each year, is often asymptomatic and may persist for several months or years. The first study analyzing possible association of C. trachomatis with cervical cancer was carried out by Schachter et al. (1975) who assessed the prevalence of antibodies to TRIC (trachoma-inclusion conjunctivitis) agents in women with cervical dysplasia and in women attending selected clinics […]. According to this investigation, antibodies to chlamydiae were identified in 77.6% of the women with dysplasia or cervical cancer whereas antichlamydial antibodies were less prevalent in the other clinic populations. Four years later, Paavonen et al. (1979) obtained [similar] results in 93 of patients with cervical dysplasia comparing them to the controls. […] Smith et al. (2001, 2002) examined 499 women with incident invasive cervical cancer cases and 539 control patients from Brazil and the Philippines, detecting that C. trachomatis increased risk of squamous cervical cancer among HPV-positive women (OR=2.1; 95% CI=1.1–4.0). The results were similar in both countries.” [As I recently pointed out elsewhere, “Chronic infection with HPV is a necessary cause of cervical cancer. Using sensitive molecular techniques, virtually all tumours are positive for the virus.” But as this finding (and other related findings) indicate, other infectious processes may play a role as well in HPV-related cancers. Synergistic effects are common in this area (recall for example also the herpes simplex virus-HIV link).]

Trichomonas vaginalis (T. vaginalis), a protozoan parasite, is the causative agent of trichomoniasis, the most common nonviral sexually transmitted disease in humans. This parasite has a worldwide distribution and it infects 250–350 million people worldwide. [wiki says ~150 mil, but these guesstimates should always be taken with a grain of salt. Either way it affects a lot of people] […] Zhang et al. (1995) observed a relationship between T. vaginalis infection and cervical cancer in [their] prospective study in a cohort of 16,797 Chinese women. T. vaginalis-infection correlated with higher cervical cancer risk (RR=3.3, 95% CI=1.5–7.4). In a large cohort study conducted in Finland by Viikki et al. (2000) T. vaginalis was associated with a high RR of cervical cancer, 6.4 (95% CI = 3.7–10) and SIR [standardized incidence ratio]=5.5 (95% CI=4.2–7.2s), respectively. […] Mekki and Ivić (1979), detected that T. vaginalis were of a significantly smaller diameter in invasive carcinoma and carcinoma in situ in comparison with dysplasia. In the control group with trichomoniasis alone, the diameter of T. vaginalis was twice as large as that in carcinoma and larger compared to dysplasia, indicating that small forms of T. vaginalis are more carcinogenic than large ones. […] To sum up, there are basic as well as epidemiological evidence that T. vaginalis may be a cause of cervical and prostate cancer […] For cervical cancer it is evident, for prostate cancer it is arguable. According to our criteria, it is possible to include it in the short list of the infectious agents that may be a cause of cancer development but are not placed in the IARC roster.”

“At the moment of publication, IARC [recognizes] Schistosoma haematobium [and] [S. mansoni], Opisthorchis viverrini, and Clonorchis sinensis as causative agents of cancer, leaving a possibility to enlarge this list by [Schistosoma japonicum] [and] Opisthorchis felineus.” [The authors think the list should be enlarged even more, but I did not find their helmith data/coverage very convincing (not much research has been done in this area), so I decided not to cover these things here].

July 12, 2014 Posted by | Books, Cancer/oncology, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

Wikipedia articles of interest

i. Albert Stevens.

Albert Stevens (1887–1966), also known as patient CAL-1, was the subject of a human radiation experiment, and survived the highest known accumulated radiation dose in any human.[1] On May 14, 1945, he was injected with 131 kBq (3.55 µCi) of plutonium without his knowledge or informed consent.[2]

Plutonium remained present in his body for the remainder of his life, the amount decaying slowly through radioactive decay and biological elimination. Stevens died of heart disease some 20 years later, having accumulated an effective radiation dose of 64 Sv (6400 rem) over that period. The current annual permitted dose for a radiation worker in the United States is 5 rem. […] Steven’s annual dose was approximately 60 times this amount.”

“Plutonium was handled extensively by chemists, technicians, and physicists taking part in the Manhattan Project, but the effects of plutonium exposure on the human body were largely unknown.[2] A few mishaps in 1944 had caused certain alarm amongst project leaders, and contamination was becoming a major problem in and outside the laboratories.[2] […] As the Manhattan Project continued to use plutonium, airborne contamination began to be a major concern.[2] Nose swipes were taken frequently of the workers, with numerous cases of moderate and high readings.[2][5] […] Tracer experiments were begun in 1944 with rats and other animals with the knowledge of all of the Manhattan project managers and health directors of the various sites. In 1945, human tracer experiments began with the intent to determine how to properly analyze excretion samples to estimate body burden. Numerous analytic methods were devised by the lead doctors at the Met Lab (Chicago), Los Alamos, Rochester, Oak Ridge, and Berkeley.[2] The first human plutonium injection experiments were approved in April 1945 for three tests: April 10 at the Manhattan Project Army Hospital in Oak Ridge, April 26 at Billings Hospital in Chicago, and May 14 at the University of California Hospital in San Francisco. Albert Stevens was the person selected in the California test and designated CAL-1 in official documents.[2] […] The plutonium experiments were not isolated events.[2] During this time, cancer researchers were attempting to discover whether certain radioactive elements might be useful to treat cancer.[2] Recent studies on radium, polonium, and uranium proved foundational to the study of Pu toxicity. […] The mastermind behind this human experiment with plutonium was Dr. Joseph Gilbert Hamilton, a Manhattan Project doctor in charge of the human experiments in California.[6] Hamilton had been experimenting on people (including himself) since the 1930s at Berkeley. […] Hamilton eventually succumbed to the radiation that he explored for most of his adult life: he died of leukemia at the age of 49.”

“Although Stevens was the person who received the highest dose of radiation during the plutonium experiments, he was neither the first nor the last subject to be studied. Eighteen people aged 4 to 69 were injected with plutonium. Subjects who were chosen for the experiment had been diagnosed with a terminal disease. They lived from 6 days up to 44 years past the time of their injection.[2] Eight of the 18 died within 2 years of the injection.[2] All died from their preexisting terminal illness, or cardiac illnesses. […] As with all radiological testing during World War II, it would have been difficult to receive informed consent for Pu injection studies on civilians. Within the Manhattan Project, plutonium was referred to often by its code “49” or simply the “product.” Few outside of the Manhattan Project would have known of plutonium, much less of the dangers of radioactive isotopes inside the body. There is no evidence that Stevens had any idea that he was the subject of a secret government experiment in which he would be subjected to a substance that would have no benefit to his health.[2][6]

The best part is perhaps this: Stevens was not terminal: “He had checked into the University of California Hospital in San Francisco with a gastric ulcer that was misdiagnosed as terminal cancer.” It seems pretty obvious from the fact that one of the people involved in these experiments survived for 44 years and the fact that four other experimentees were still alive by the time Stevens died that he was not the only one who was misdiagnosed, and one interpretation of the fact that more than half survived beyond two years might be that the definition of ‘terminal’ applied in this context may have been, well, slightly flexible (especially considering how large injections of radioactive poisons in these people may not exactly have increased their life expectancies). Today people usually use this term for conditions which people can expect to die from within 6 months – 2 years is a long time in this context. It may however also to some extent just have reflected the state of medical science at the time – also illustrative in that respect is how the surgeons screwed him over during his illness: “Half of the left lobe of the liver, the entire spleen, most of the ninth rib, lymph nodes, part of the pancreas, and a portion of the omentum… were taken out”[1] to help prevent the spread of the cancer that Stevens did not have.” In case you were wondering, not only did they not tell him he was part of an experiment; they also did not ever tell him he had been misdiagnosed with cancer.

ii. Aberration of light.

“The aberration of light (also referred to as astronomical aberration or stellar aberration) is an astronomical phenomenon which produces an apparent motion of celestial objects about their locations dependent on the velocity of the observer. Aberration causes objects to appear to be angled or tilted towards the direction of motion of the observer compared to when the observer is stationary. The change in angle is typically very small, on the order of v/c where c is the speed of light and v the velocity of the observer. In the case of “stellar” or “annual” aberration, the apparent position of a star to an observer on Earth varies periodically over the course of a year as the Earth’s velocity changes as it revolves around the Sun […] Aberration is historically significant because of its role in the development of the theories of light, electromagnetism and, ultimately, the theory of Special Relativity. […] In 1729, James Bradley provided a classical explanation for it in terms of the finite speed of light relative to the motion of the Earth in its orbit around the Sun,[1][2] which he used to make one of the earliest measurements of the speed of light. However, Bradley’s theory was incompatible with 19th century theories of light, and aberration became a major motivation for the aether drag theories of Augustin Fresnel (in 1818) and G. G. Stokes (in 1845), and for Hendrick Lorentzaether theory of electromagnetism in 1892. The aberration of light, together with Lorentz’ elaboration of Maxwell’s electrodynamics, the moving magnet and conductor problem, the negative aether drift experiments, as well as the Fizeau experiment, led Albert Einstein to develop the theory of Special Relativity in 1905, which provided a conclusive explanation for the aberration phenomenon.[3] […]

Aberration may be explained as the difference in angle of a beam of light in different inertial frames of reference. A common analogy is to the apparent direction of falling rain: If rain is falling vertically in the frame of reference of a person standing still, then to a person moving forwards the rain will appear to arrive at an angle, requiring the moving observer to tilt their umbrella forwards. The faster the observer moves, the more tilt is needed.

The net effect is that light rays striking the moving observer from the sides in a stationary frame will come angled from ahead in the moving observer’s frame. This effect is sometimes called the “searchlight” or “headlight” effect.

In the case of annual aberration of starlight, the direction of incoming starlight as seen in the Earth’s moving frame is tilted relative to the angle observed in the Sun’s frame. Since the direction of motion of the Earth changes during its orbit, the direction of this tilting changes during the course of the year, and causes the apparent position of the star to differ from its true position as measured in the inertial frame of the Sun.

While classical reasoning gives intuition for aberration, it leads to a number of physical paradoxes […] The theory of Special Relativity is required to correctly account for aberration.”

The article has much more, in particular it has a lot of stuff about historical aspects pertaining to this topic.

iii. Spanish Armada.

“The Spanish Armada (Spanish: Grande y Felicísima Armada or Armada Invencible, literally “Great and Most Fortunate Navy” or “Invincible Fleet”) was a Spanish fleet of 130 ships that sailed from A Coruña in August 1588 under the command of the Duke of Medina Sidonia with the purpose of escorting an army from Flanders to invade England. The strategic aim was to overthrow Queen Elizabeth I of England and the Tudor establishment of Protestantism in England, with the expectation that this would put a stop to English interference in the Spanish Netherlands and to the harm caused to Spanish interests by English and Dutch privateering.

The Armada chose not to attack the English fleet at Plymouth, then failed to establish a temporary anchorage in the Solent, after one Spanish ship had been captured by Francis Drake in the English Channel, and finally dropped anchor off Calais.[10] While awaiting communications from the Duke of Parma‘s army the Armada was scattered by an English fireship attack. In the ensuing Battle of Gravelines the Spanish fleet was damaged and forced to abandon its rendezvous with Parma’s army, who were blockaded in harbour by Dutch flyboats. The Armada managed to regroup and, driven by southwest winds, withdrew north, with the English fleet harrying it up the east coast of England. The commander ordered a return to Spain, but the Armada was disrupted during severe storms in the North Atlantic and a large portion of the vessels were wrecked on the coasts of Scotland and Ireland. Of the initial 130 ships over a third failed to return.[11] […] The expedition was the largest engagement of the undeclared Anglo-Spanish War (1585–1604). The following year England organised a similar large-scale campaign against Spain, the Drake-Norris Expedition, also known as the Counter-Armada of 1589, which was also unsuccessful. […]

The fleet was composed of 130 ships, 8,000 sailors and 18,000 soldiers, and bore 1,500 brass guns and 1,000 iron guns. […] In the Spanish Netherlands 30,000 soldiers[17] awaited the arrival of the armada, the plan being to use the cover of the warships to convey the army on barges to a place near London. All told, 55,000 men were to have been mustered, a huge army for that time. […] The English fleet outnumbered the Spanish, with 200 ships to 130,[18] while the Spanish fleet outgunned the English—its available firepower was 50% more than that of the English.[19] The English fleet consisted of the 34 ships of the royal fleet (21 of which were galleons of 200 to 400 tons), and 163 other ships, 30 of which were of 200 to 400 tons and carried up to 42 guns each; 12 of these were privateers owned by Lord Howard of Effingham, Sir John Hawkins and Sir Francis Drake.[1] […] The Armada was delayed by bad weather […], and was not sighted in England until 19 July, when it appeared off The Lizard in Cornwall. The news was conveyed to London by a system of beacons that had been constructed all the way along the south coast.”

“During all the engagements, the Spanish heavy guns could not easily be run in for reloading because of their close spacing and the quantities of supplies stowed between decks […] Instead the gunners fired once and then jumped to the rigging to attend to their main task as marines ready to board enemy ships, as had been the practice in naval warfare at the time. In fact, evidence from Armada wrecks in Ireland shows that much of the fleet’s ammunition was never spent.[26] Their determination to fight by boarding, rather than cannon fire at a distance, proved a weakness for the Spanish; it had been effective on occasions such as the battles of Lepanto and Ponta Delgada (1582), but the English were aware of this strength and sought to avoid it by keeping their distance. With its superior manoeuvrability, the English fleet provoked Spanish fire while staying out of range. The English then closed, firing repeated and damaging broadsides into the enemy ships. This also enabled them to maintain a position to windward so that the heeling Armada hulls were exposed to damage below the water line. Many of the gunners were killed or wounded, and the task of manning the cannon often fell to the regular foot soldiers on board, who did not know how to operate the guns. The ships were close enough for sailors on the upper decks of the English and Spanish ships to exchange musket fire. […] The outcome seemed to vindicate the English strategy and resulted in a revolution in naval battle tactics with the promotion of gunnery, which until then had played a supporting role to the tasks of ramming and boarding.”

“In September 1588 the Armada sailed around Scotland and Ireland into the North Atlantic. The ships were beginning to show wear from the long voyage, and some were kept together by having their hulls bundled up with cables. Supplies of food and water ran short. The intention would have been to keep well to the west of the coast of Scotland and Ireland, in the relative safety of the open sea. However, there being at that time no way of accurately measuring longitude, the Spanish were not aware that the Gulf Stream was carrying them north and east as they tried to move west, and they eventually turned south much further to the east than planned, a devastating navigational error. Off the coasts of Scotland and Ireland the fleet ran into a series of powerful westerly winds […] Because so many anchors had been abandoned during the escape from the English fireships off Calais, many of the ships were incapable of securing shelter as they reached the coast of Ireland and were driven onto the rocks. Local men looted the ships. […] more ships and sailors were lost to cold and stormy weather than in direct combat. […] Following the gales it is reckoned that 5,000 men died, by drowning, starvation and slaughter at the hands of English forces after they were driven ashore in Ireland; only half of the Spanish Armada fleet returned home to Spain.[30] Reports of the passage around Ireland abound with strange accounts of hardship and survival.[31]

In the end, 67 ships and fewer than 10,000 men survived.[32] Many of the men were near death from disease, as the conditions were very cramped and most of the ships ran out of food and water. Many more died in Spain, or on hospital ships in Spanish harbours, from diseases contracted during the voyage.”

iv. Viral hemorrhagic septicemia.

Viral hemorrhagic septicemia (VHS) is a deadly infectious fish disease caused by the Viral hemorrhagic septicemia virus (VHSV, or VHSv). It afflicts over 50 species of freshwater and marine fish in several parts of the northern hemisphere.[1] VHS is caused by the viral hemorrhagic septicemia virus (VHSV), different strains of which occur in different regions, and affect different species. There are no signs that the disease affects human health. VHS is also known as “Egtved disease,” and VHSV as “Egtved virus.”[2]

Historically, VHS was associated mostly with freshwater salmonids in western Europe, documented as a pathogenic disease among cultured salmonids since the 1950s.[3] Today it is still a major concern for many fish farms in Europe and is therefore being watched closely by the European Community Reference Laboratory for Fish Diseases. It was first discovered in the US in 1988 among salmon returning from the Pacific in Washington State.[4] This North American genotype was identified as a distinct, more marine-stable strain than the European genotype. VHS has since been found afflicting marine fish in the northeastern Pacific Ocean, the North Sea, and the Baltic Sea.[3] Since 2005, massive die-offs have occurred among a wide variety of freshwater species in the Great Lakes region of North America.”

The article isn’t that great but I figured I should include it anyway because I find it sort of fascinating how almost all humans alive can and do live their entire lives without necessarily ever knowing anything about stuff like this. Humans have some really obvious blind spots when it comes to knowledge about some of the stuff we put into our mouths on a regular basis.

v. Bird migration.

Bird migration is the regular seasonal movement, often north and south along a flyway between breeding and wintering grounds, undertaken by many species of birds. Migration, which carries high costs in predation and mortality, including from hunting by humans, is driven primarily by availability of food. Migration occurs mainly in the Northern Hemisphere where birds are funnelled on to specific routes by natural barriers such as the Mediterranean Sea or the Caribbean Sea.”


“Historically, migration has been recorded as much as 3,000 years ago by Ancient Greek authors including Homer and Aristotle […] Aristotle noted that cranes traveled from the steppes of Scythia to marshes at the headwaters of the Nile. […] Aristotle however suggested that swallows and other birds hibernated. […] It was not until the end of the eighteenth century that migration as an explanation for the winter disappearance of birds from northern climes was accepted […] [and Aristotle’s hibernation] belief persisted as late as 1878, when Elliott Coues listed the titles of no less than 182 papers dealing with the hibernation of swallows.”

“Approximately 1800 of the world’s 10,000 bird species are long-distance migrants.[9][10] […] Within a species not all populations may be migratory; this is known as “partial migration”. Partial migration is very common in the southern continents; in Australia, 44% of non-passerine birds and 32% of passerine species are partially migratory.[17] In some species, the population at higher latitudes tends to be migratory and will often winter at lower latitude. The migrating birds bypass the latitudes where other populations may be sedentary, where suitable wintering habitats may already be occupied. This is an example of leap-frog migration.[18] Many fully migratory species show leap-frog migration (birds that nest at higher latitudes spend the winter at lower latitudes), and many show the alternative, chain migration, where populations ‘slide’ more evenly North and South without reversing order.[19]

Within a population, it is common for different ages and/or sexes to have different patterns of timing and distance. […] Many, if not most, birds migrate in flocks. For larger birds, flying in flocks reduces the energy cost. Geese in a V-formation may conserve 12–20% of the energy they would need to fly alone.[21][22] […] Seabirds fly low over water but gain altitude when crossing land, and the reverse pattern is seen in landbirds.[25][26] However most bird migration is in the range of 150 m (500 ft) to 600 m (2000 ft). Bird strike aviation records from the United States show most collisions occur below 600 m (2000 ft) and almost none above 1800 m (6000 ft).[27] Bird migration is not limited to birds that can fly. Most species of penguin migrate by swimming.”

“Some Bar-tailed Godwits have the longest known non-stop flight of any migrant, flying 11,000 km from Alaska to their New Zealand non-breeding areas.[36] Prior to migration, 55 percent of their bodyweight is stored fat to fuel this uninterrupted journey. […] The Arctic Tern has the longest-distance migration of any bird, and sees more daylight than any other, moving from its Arctic breeding grounds to the Antarctic non-breeding areas.[37] One Arctic Tern, ringed (banded) as a chick on the Farne Islands off the British east coast, reached Melbourne, Australia in just three months from fledging, a sea journey of over 22,000 km (14,000 mi). […] The most pelagic species, mainly in the ‘tubenose’ order Procellariiformes, are great wanderers, and the albatrosses of the southern oceans may circle the globe as they ride the “roaring forties” outside the breeding season. The tubenoses spread widely over large areas of open ocean, but congregate when food becomes available. Many are also among the longest-distance migrants; Sooty Shearwaters nesting on the Falkland Islands migrate 14,000 km (8,700 mi) between the breeding colony and the North Atlantic Ocean off Norway. Some Manx Shearwaters do this same journey in reverse. As they are long-lived birds, they may cover enormous distances during their lives; one record-breaking Manx Shearwater is calculated to have flown 8 million km (5 million miles) during its over-50 year lifespan.[39]

“Bird migration is primarily, but not entirely, a Northern Hemisphere phenomenon.[50] This is because land birds in high northern latitudes, where food becomes scarce in winter, leave for areas further south (including the Southern Hemisphere) to overwinter, and because the continental landmass is much larger in the Northern Hemisphere [see also this post]. In contrast, among (pelagic) seabirds, species of the Southern Hemisphere are more likely to migrate. This is because there is a large area of ocean in the Southern Hemisphere, and more islands suitable for seabirds to nest.[51]

July 10, 2014 Posted by | Biology, History, Infectious disease, Medicine, Physics, Wikipedia, Zoology | Leave a comment

Sexually Transmitted Diseases (4th edition) (IV)

Here’s a link to a previous post about the book, which includes links to the first two posts I wrote about it.

I was not super impressed with the coverage in part 3, although there was a lot of interesting stuff as well. However the level of coverage and amount of detail included is high in part four and five. There were a lot of details which evaded me in some of the recent chapters, but I also learned a great deal. There’s quite a lot of coverage of various ‘related topics’ (microbiology, biochemistry, immunology, oncology) in the parts of the book I’ve read recently, and like many other medical texts this book will help you realize that many things you in your mind had thought of as unrelated actually are connected in various interesting ways. It’s worth noting that given how many aspects of these things the book covers (again, 2000+ pages…) you actually get to know a lot of stuff about a lot of other things besides just ‘classic STDs’. It turns out that in Jamaica and Trinidad, over 70% of all lymphoid malignancies are attributable to exposure to a specific herpes virus most people probably haven’t heard about, HTLV-1 (prevalence is also high in other parts of the world, e.g. southern Japan). I didn’t expect to learn this from a book about sexually transmitted diseases, but there we are.

I hope that I’ve picked out stuff from this part of the coverage which is also intelligible to people who didn’t read the 95+% of those chapters I didn’t quote (I always like feedback on such aspects).

“At the simplest level, infection of a cell by a virus or bacterium may lead to cell death. In the case of viruses, specific disease syndromes may be caused by destruction of certain subsets of cells that express essential differentiated functions. A classic example of this is the development of the AIDS following HIV-1 mediated depletion of the CD4 lymphocyte population. Virus-induced cell death may result from one or more specific mechanisms. Many viruses express specific proteins that have as their major function the induction of a blockade in normal host cell metabolism (cellular translation and transcription) such that the metabolic machinery of the cell is subverted preferentially to viral replication. For obvious reasons, the expression of such proteins is usually highly toxic to the cell. Cellular destruction or “direct cytopathic effect” is considered responsible for the disease manifestations of many lytic viruses, including, for example, HSV and poliovirus. On the other hand, many cells may respond to the presence of an invading virus by the induction of apoptosis and the initiation of programmed cell death. Some viruses appear to have evolved mechanisms to prevent or delay apoptosis, thus potentially prolonging productive infection and maximizing replication. For example, HSV-1 infection induces apoptosis at multiple metabolic checkpoints but has also evolved mechanisms to block apoptosis at each point.28 Importantly, the inhibition of apoptosis by HSV-1 also prevents apoptosis induced by virus-specific cytotoxic T lymphocytes, thereby conferring on the infected cell a certain measure of resistance to the host’s cell-mediated immune responses.29

However, many viruses are not intrinsically cytopathic. HBV is a prime example, as many infected HBsAg carriers are asymptomatic and without overt evidence of active liver disease. Despite this, such carriers may be very infectious […] The presence or absence of liver disease is largely determined by the T-cell response to the virus.30 Thus, chronic hepatitis B results from a relatively vigorous but unsuccessful attempt on the part of the host to eliminate the infection. […] chronic liver inflammation and the occurrence of hepatocellular carcinoma reflect the immune response to the virus, rather than specific virus effects. Similar indirect mechanisms may contribute to the progressive immune destruction of infected CD4-positive lymphocytes in patients with HIV-1 infection.

Some bacterial disease processes may also be caused largely to immunopathologic responses. For instance, there is substantial evidence that complications of genital chlamydia infections (salpingitis, Reiter’s syndrome) are correlated with and may be owing to stimulation of antibodies against a heatshock protein (hsp60).33,34 […] In contrast, gonococcal tissue damage appears to be caused by the direct toxic effects of lipid A and peptidoglycan fragments”

“Some viruses are capable of altering differentiated cellular functions, resulting in the production of disease by mechanisms that do not exist among bacteria. A prime example is the altered cellular growth that follows infections by molluscum contagiosum virus (MCV) […]. A more extreme example is the proliferation of epithelial cells that is induced by infection with HPVs. HPV-related epithelial malignancies and cellular transformation are related to the expression of two specific HPV proteins, the E6 and E7 oncoproteins, by high-risk HPV subtypes.22 These proteins interact with p53 and pRb, both promoting cellular proliferation and cell survival. Oncogenic transformation is usually associated with high-level expression of E7 from integrated HPV DNA. The Kaposi’s sarcoma-associated herpes virus (KSHV) also expresses a number of proteins that mimic important host regulators of cellular proliferation and survival […] Expression of these proteins may result in deregulation of cell growth, with changes in the cellular morphology and/or acquisition of the ability of the cells to form colonies in soft agar, changes that are indicative of transformation.

On the other hand, hepatocellular cancers occurring in the context of chronic viral hepatitis are likely to have an alternative explanation. Although it is possible that integration of HBV DNA may be responsible for altered cellular growth control in some hepatitis B-associated cases, liver cancer in this setting may be primarily immunopathogenic.30,32 Chronic inflammation accompanied by oxidative stress and cellular DNA damage are likely to pla[y] important roles.”

“The human immunodeficiency viruses (HIV-1 and HIV-2) and the simian immunodeficiency viruses (SIV) (with a subscript indicating the species of origin) are members of the lentivirus genus of the Retroviridae family, commonly called retroviruses. […] Retroviruses are divided into two subfamilies: Orthoretrovirinae and Spumaretrovirinae […] The spumaretroviruses have distinctive features of their replication cycle that require this more distant classification. They have been isolated from primates, but not humans, and are not associated with any known disease. The orthoretroviruses are divided into six genera and represent viruses that infect snakes, fish, birds, and mammals. […] Human infections occur with viruses from two of these genera. The Deltaretrovirus genus includes human T-cell leukemia virus type I (HTLV-I), the causative agent of adult T-cell leukemia,5, 6, 7 and human T-cell leukemia virus type II (HTLV-II), which is not known to be associated with any disease syndrome. HTLV-I is also associated with another syndrome called HTLV-associated myelopathy (HAM). HTLV-I and HTLV-II are related to viruses found in primates and more distantly related to bovine leukemia virus. The lentivirus genus includes HIV-18 and HIV-29 as well as viruses found in a variety of mammals ranging from primates to sheep. Viruses within these different genera vary widely in the diseases they cause and the mechanisms of disease induction, in contrast to the many common features of their replication cycle. […] In its DNA form the viral genome is inserted into the host genome […]. This step in the virus life cycle has important implications for several features of virus-host interactions. For example, viral DNA that integrates into the genome of a cell but is not expressed becomes silently carried in the descendents of that cell. When this happens in a germline cell, or in the cell of an early embryo that becomes a germline cell, this copy of viral DNA becomes a linked physical part of the host genome, is present in every cell in the body, and is passed on to subsequent generations. Such a genetic element is called an endogenous retrovirus. Most of the elements that become fixed are defective, as there is probably a strong selective pressure against elements that can activate to produce infectious virus. Thus, they represent an archive within the host genome of previous waves of retroviral infections. In fact, the human genome carries a record of retroviral infections over the last 40 million years of primate evolution. These are viruses that we do not recognize as active in the human population at present but are represented by 110,000 genomic inserts of gammaretroviruses, 10,000 inserts of betaretroviruses, and 80,000 inserts of a genus that may be distantly related to spumaretroviruses or may represent an uncharacterized lineage.10 Most of these elements contain large deletions; however, if these deletions had been retained, our genomes would be 40% endogenous retroviruses by mass and outnumber our normal genes 7 to 1.”

“Most histories of retroviruses start with the dramatic discovery by Peyton Rous in 1911 that a virus, Rous sarcoma virus (RSV), could cause cancer. […] The isolation of other tumor-causing retroviruses followed and in time it became apparent that there were two broad classes of agents: one class of viruses caused cancer after a long latency period […], while the other class caused tumors that appeared rapidly […]. We now know that the acutely transforming retroviruses carry a cell-derived oncogene that is responsible for the transforming activity,14 while the slowly transforming retroviruses act by the chance integration of viral DNA near these cellular oncogenes in the host genome to induce their expression and promote tumor formation.15,16 Importantly, many of these same genes can be mutated or overexpressed in human cancers, and the proteins they encode are now the targets of new generations of specific antitumor therapies […] One can confidently surmise that the remnants of the beta- and gammaretroviruses littered in our genomes had such oncogenic effects when they were active. Ironically, for the active human retroviruses, HTLV-I causes tumors by a different but still poorly understood mechanism, and HIV is involved in tumor formation only indirectly through immune suppression. […] There are two fundamental differences between lentiviruses and most other retroviruses: Lentiviruses do not cause cancer [directly…] and they establish chronic infections that result in a long incubation period followed by a chronic symptomatic disease. The “slow” (lenti is Latin for slow), chronic nature of these viral infections was first appreciated for a disease of sheep called maedi-visna (maedi = labored breathing, visna = paralysis and wasting).”

“Using the current sequence diversity in the HIV-1 population, the 1959 sequence, and estimates of the rate of sequence change per year, it has been possible to suggest that the cross-species transmission event that gave rise to the M group of HIV-1 occurred early in the twentieth century.38 If we accept that SIVcpz [HIV in chimps…] has entered the human population three times in the last century (the three groups N,O, and M), then it follows that this virus likely has been transmitted to humans any number of times over the last 10,000 years. Only in the last century the human institutions of large cities and efficient transportation corridors have given these transmission events access to a human environment that could support an epidemic.”

“Over 100 herpesviruses have been identified, with at least eight infecting humans [I had no idea there were that many of them, and I had no clue some of the ones mentioned were actually herpes viruses…]. All human herpesviruses are well adapted to their natural host, being endemic in all human populations studied and carried by a significant fraction of persons in each population. The human herpesviruses include herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma (KS)-associated herpesvirus. Disease caused by human herpesviruses tends to be relatively mild and self-limited in immunocompetent persons, although severe and quite unusual disease can be seen with immunosuppression. […] all herpesviruses share biologic traits. These include expression of a large number of viral enzymes, assembly of the nucleocapsid in the cell nucleus, cytopathic effects on the cell during productive infection, and ability to establish latent infections in an infected host.”

“Vaccine development poses great challenges in the case of herpesviruses because recovery from natural disease is not associated with elimination of virus and does not always protect against another episode of disease.
Live-attenuated, killed, and recombinant subunit herpesvirus vaccines have all been studied. Whole-virus vaccines have the advantage of exposing the immune system to all viral antigens. Live-attenuated vaccines have tended to produce longer-lasting immunity than killed preparations. However, live-attenuated herpesvirus vaccines may be capable of establishing latent infections. The risks are not clear and there is concern that vaccine recipients who subsequently become immunosuppressed may develop disease caused by reactivated virus. Two avirulent HSV strains have been shown to generate lethal recombinants in mice.127 Thus, recombination between an attenuated vaccine strain and a superinfecting wild-type strain could occur. Because several herpesviruses have been associated with malignancies in humans, the long-term safety of any live-attenuated vaccine needs careful study.”

“In the most recent data from NHANES, the prevalence of HSV-1 appears to have fallen slightly from 62% in the years 1988-1994 to 57.7% in the years 1999-2004 in the general population.30 In Western Europe, the prevalence of HSV-1 infection in young adults remains 10-20% higher than that in the United States.31 In STD clinics in the United States, about 60% of attendees have HSV-1 antibodies. In Asia and Africa, HSV-1 infection remains almost universal […] The cumulative lifetime incidence of HSV-2 reaches 25% in white women, 20% in white men, 80% in African American women and 60% in African American men […] Transmission of HSV between sexual partners has been addressed most often in prospective studies of serologically discordant couples, i.e., in couples in whom one partner has and the other does not have HSV-2. Longitudinal studies of such couples have shown that the transmission rate varies from 3% to 12% per year. […] Unlike other STDs, persons usually acquire genital HSV-1 and genital HSV-2 in the context of a steady rather than casual relationship.91 Women have higher rates of acquisition than men; in one study the attack rate among seronegative women approached 30% per year.88 […] Subclinical or asymptomatic viral shedding is an important aspect of the clinical and epidemiologic understanding of genital herpes, as most episodes of sexual and vertical transmission appear to occur during such shedding. […] the risk of HSV transmission is likely similar regardless of the presence of lesions, supporting the epidemiologic observation that most HSV is acquired from asymptomatic partners. […] Subclinical HSV reactivation is highest in the first year after acquisition of infection. During this time period, HSV can be detected from genital sites by PCR on a mean of 25-30% of days […]. This is about 1.5 times higher than patients sampled later in their disease course.”

“The major morbidity of recurrent genital herpes is its frequent reactivation rate. Most likely, all HSV-2 seropositive persons reactivate HSV-2 in the genital region. Moreover, because of the extensive area enervated by the sacral nerve root ganglia, reactivation of HSV-2 is widespread over a large anatomic area.

A prospective study of 457 patients with documented first-episode genital herpes infection has shown that 90% of patients with genital HSV-2 developed recurrences in the first 12 months of infection.93 The median recurrence rate was 0.33 recurrences/month. Most patients experienced multiple clinical reactivations. After primary HSV-2 infection, 38% of patients had at least 6 recurrences and 20% had more than 10 recurrences in the first year of infection. Men had slightly more frequent recurrences than women, median 5 per year compared with 4 recurrences per year [it’s important to note that the recurrence rate is substantial even in patients on suppressive therapy: “About 25% of persons on suppressive therapy will develop a breakthrough recurrence each 3-month period”] […] Recently, long-term cohort studies indicate that the frequency of symptomatic recurrences gradually decreases over time. In the initial years of infection, reported recurrence rate decreases by a median of 1 recurrence per year. […] subclinical shedding episodes account for one-third to one-half of the total episodes of HSV reactivation as measured by viral isolation and for 50-75% of reactivations as measured by PCR. […] Rather than regarding HSV-2 as a predominantly silent infection with occasional clinical outbreaks with marked viral shedding, HSV is a dynamic infection, with very frequent reactivation, mostly subclinical, and active effort on the part of the immune system of the host is required to control mucosal viral replication. […] Immunocompromised patients have frequent and prolonged mucocutaneous HSV infections.226, 227, 228 Over 70% of renal and bone marrow transplant recipients who have serologic evidence of HSV infection reactivate HSV infection clinically within the first month after transplantation […] Recurrent genital herpes in immunosuppressed patients often results in the development of large numbers of vesicles which coalesce into extensive deep, often necrotic, ulcerative lesions.228 […] about 70% of HIV-infected persons in the developed world and 95% in the developing world have HSV-2 antibody. […] The epidemiologic interactions between HIV and HSV-2 have led to calculation of potential population-level impact of these intersecting epidemics. […] The population attributable risk will depend on the prevalence of HSV-2 in the population at risk; at 50% HSV-2 prevalence, common among MSM [Males who have Sex with Males, US], or African Americans in the United States, or general population in sub-Saharan Africa, 35% of HIV infections will be attributable to HSV-2. […] the risk of transmitting HSV [from the mother] to the neonate is 30-50% in women with newly acquired HSV [during the last part of the pregnancy] versus <1% in women with established infection.” [This is relevant not only because herpes sucks, but also because it sucks even more when a newborn child gets it].

“More than 50% of individuals in most populations throughout the world demonstrate serological evidence of prior CMV infection.6 The coevolution with and adaptation to its human host over millions of years may account for the observation that in most cases, CMV infection causes few if any symptoms.5 However, in immunocompromised individuals, primary infection or reactivation of latent virus can be life-threatening. As well, congenital infections are common and can result in serious lifelong sequelae. […] Although CMV does not typically come to medical attention as a result of genital tract lesions or disease, it can be transmitted sexually and has important consequences for the sexually active, child-bearing population. […] As with many viruses that cause chronic infection, CMV seems to have coevolved with humans to a balanced state in which the virus persists but generally causes little clinical illness. The host’s innate and adaptive immune responses are usually successful at limiting CMV infection as is evident by the clear association of immune system dysfunction with CMV disease. In the absence of prophylactic antiviral treatment, CMV often reactivates in seropositive individuals who undergo hematopoietic stem cell transplantation (HSCT).41 Immunosuppression resulting from drugs used to treat cancer and autoimmune disorders, and from impaired T-cell function that occurs with advanced AIDS, is also associated with reactivation of CMV. […] The development of primary CMV infection has been noted in up to 79% of liver transplants and 58% of kidney or heart transplants in which the donor is seropositive and the recipient is seronegative.134,135 In the setting of HSCT, several studies have documented that CMV seropositivity of the recipient results in significantly increased overall posttransplant mortality compared to CMV seronegative recipients with a seronegative donor.136 When the recipient is CMV seronegative, overall mortality is increased when the donor is seropositive compared to the situation where the donor is seronegative.137 […] the transplant recipient is at particularly high risk of CMV reactivation during periods of potent immunosuppression that accompany graft rejection or graft-versus-host disease.”

July 7, 2014 Posted by | Books, Epidemiology, Evolutionary biology, Genetics, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

Sexually Transmitted Diseases (4th edition) (III)

I read the first nine chapters of this very long book a while back, and I decided to have another go at it. I have now read chapters 10-18, the first seven of which deal with ‘Profiles of Vulnerable Populations’ (including chapters about: Gender and Sexually Transmitted Diseases (10), Adolescents and STDs Including HIV Infection (11), Female Sex Workers and Their Clients in the Epidemiology and Control of Sexually Transmitted Diseases (12), Homosexual and Bisexual Behavior in Men in Relation to STDs and HIV Infection (13), Lesbian Sexual Behavior in Relation to STDs and HIV Infection (14) (some surprising stuff in that chapter, but I won’t cover that here), HIV and Other Sexually Transmitted Infections in Injection Drug Users and Crack Cocaine Smokers (15), and STDs, HIV/AIDS, and Migrant Populations (16)), and the last two of which deal with ‘Host Immunity and Molecular Pathogenesis and STD’ (Chapters about: ‘Genitourinary Immune Defense’ (17) and ‘Normal Genital Flora’ (19 as well as ‘Pathogenesis of Sexually Transmitted Viral and Bacterial Infections’ (19) – I have only read the first two chapters in that section so far, and so I won’t cover the last chapter here. I also won’t cover the content of the first of these chapters, but for different reasons). The book has 108 chapters and more than 2000 pages, so although I’ve started reading the book again I’m sure I won’t finish the book this time either. My interest in the things covered in this book is purely academical in the first place.

You can read my first two posts about the book here and here.

Some observations and comments below…

“A major problem when assessing the risk of men and women of contracting an STI [sexually transmitted infection], is the differential reporting of sexual behavior between men and women. It is believed that women tend to underreport sexual activity, whereas men tend to over-report. This has been highlighted by studies assessing changes in reported age at first sexual intercourse between successive birth cohorts15 and by studies that compared the numbers of sex partners reported by men and by women.10,13,16, 17, 18 […] There is widespread agreement that women are more frequently and severely affected by STIs than men. […] In the studies in the general population that have assessed the prevalence of gonorrhea, chlamydial infection, and active syphilis, the prevalence was generally higher in women than in men […], with differences in prevalence being more marked in the younger age groups. […] HIV infection is also strikingly more prevalent in women than in men in most populations where the predominant mode of transmission is heterosexual intercourse and where the HIV epidemic is mature […] It is generally accepted that the male-to-female transmission of STI pathogens is more efficient than female-to-male transmission. […] The high vulnerability to STIs of young women compared to young men is [however] the result of an interplay between psychological, sociocultural, and biological factors.33

“Complications of curable STIs, i.e., STIs caused by bacteria or protozoa, can be avoided if infected persons promptly seek care and are managed appropriately. However, a prerequisite to seeking care is that infected persons are aware that they are infected and that they seek treatment. A high proportion of men and of women infected with N. gonorrhoeae, C. trachomatis, or T. vaginalis, however, never experience symptoms. Women are asymptomatic more often than men. It has been estimated that 55% of episodes of gonorrhea in men and 86% of episodes in women remain asymptomatic; 89% of men with chlamydial infection remain asymptomatic and 94% of women.66 For chlamydial infection, it has been well documented that serious complications, including infertility due to tubal occlusion, can occur in the absence of a history of symptoms of pelvic inflammatory disease.65

“Most population-based STD rates underestimate risk for sexually active adolescents because the rate is inappropriately expressed as cases of disease divided by the number of individuals in this age group. Yet only those who have had intercourse are truly at risk for STDs. For rates to reflect risk among those who are sexually experienced, appropriate denominators should include only the number of individuals in the demographic group who have had sexual intercourse. […] In general, when rates are corrected for those who are sexually active, the youngest adolescents have the highest STD rates of any age group.5

“Although risk of HPV acquisition increases with number of partners,67,74,75 prevalence of infection is substantial even with limited sexual exposure. Numerous clinic-based studies,76,77 supported by population-based data, indicate that HPV prevalence typically exceeds 10% among young women with only one or two partners.71

“while 100 years ago young men in the United States spent approximately 7 years between [sexual] maturation and marriage, more recently the interval was 13 years, and increasing; for young women, the interval between menarche and marriage has increased from 8 years to 14. […] In 1970, only 5% of women in United States had had premarital intercourse by age 15, whereas in 1988, 26% had engaged in intercourse by this age. However, in 1988, 37% of never married 15-17-year-olds had engaged in intercourse but in 2002, only 30% had. Comparable data from males demonstrated even greater declines — 50% of never married 15-17-year-olds reported having had intercourse in 1988, compared with only 31% in 200299

“Infection with herpes simplex type 2 (HSV-2) is extremely common among FSWs [female sex workers], and because HSV-2 infection increases the likelihood of both HIV acquisition in HIV-uninfected individuals, and HIV transmission in HIV-infected individuals, HSV-2 infection plays a key role in HIV transmission dynamics.100 Studies of FSWs in Kenya,67 South Africa,101 Tanzania,36 and Mexico72 have found HSV-2 prevalences ranging from 70% to over 80%. In a prospective study of HIV seronegative FSWs in Nairobi, Kenya, 72.7% were HSV-2 seropositive at baseline.67 Over the course of over two years of observation […] HSV-2 seropositive FSWs were over six times more likely to acquire HIV infection than women who were HSV-2 seronegative.”

“Surveys in the UK133 and New Zealand134 found that approximately 7% of men reported ever paying for sex. A more recent telephone survey in Australia found that almost 16% of men reported having ever paid for sex, with 1.9% reporting that they had paid for sex in the past 12 months.135 Two national surveys in Britain found that the proportion of men who reported paying women for sex in the previous 5 years increased from 2.0% in 1990 to 4.2% in 2000.14 A recent review article summarizing the findings of various surveys in different global regions found that the median proportion of men who reported “exchanging gifts or money for sex” in the past 12 months was approximately 9-10%, whereas the proportion of men reporting who engaged in “paid sex” or sex with a sex worker was 2-3%.136

“There are currently around 175-200 million people documented as living outside their countries of birth.3 This number includes both voluntary migrants, people who have chosen to leave their country of origin, and forced migrants, including refugees, trafficked people, and internally displaced people.4 […] Each year about 700 million people travel internationally with an estimated 50 million originating in developed countries traveling to developing ones.98 […] Throughout history, infectious diseases of humans have followed population movements. The great drivers of population mobility including migration, economic changes, social change, war, and travel have been associated with disease acquisition and spread at individual and population levels. There have been particularly strong associations of these key modes of population mobility and mixing for sexually transmitted diseases (STDs), including HIV/AIDS. […] Epidemiologists elucidated early in the HIV/AIDS epidemic that there was substantial geographic variability in incidence, as well as different risk factors for disease spread. As researchers better understood the characteristics of HIV transmission, its long incubation time, relatively low infectivity, and chronic disease course, it became clear that mobility of infected persons was a key determinant for further spread to new populations.6 […] mobile populations are more likely to exhibit high-risk behaviors”

“Studies conducted over the past decade have relied on molecular techniques to identify previously noncultivable organisms in the vagina of women with “normal” and “abnormal” flora. […] These studies have confirmed that the microflora of some women is predominated by species belonging to the genus Lactobacillus, while women having BV [bacterial vaginosis] have a broad range of aerobic and anaerobic microorganisms. It has become increasingly clear that even with these more advanced tools to characterize the microbial ecology of the vagina the full range of microorganisms present has yet to be fully described. […] the frequency and concentration of many facultative organisms depends upon whether the woman has BV or Lactobacillus-predominant microflora.36 However, even if “normal” vaginal microflora is restricted to those women having a Lactobacillus-dominant flora as defined by Gram stain, 46% of women are colonized by G. vaginalis, 78% are colonized by Ureaplasma urealyticum, and 31% are colonized by Candida albicans.36 […] Nearly all women are vaginally colonized by obligately anaerobic gram-negative rods and cocci,36 and several species of anaerobic bacteria, which are not yet named, are also present. While some species of anaerobes are present at higher frequencies or concentrations among women with BV, it is clear that the microbial flora is complex and cannot be defined simply by the presence or absence of lactobacilli, Gardnerella, mycoplasmas, and anaerobes. This observation has been confirmed with molecular characterization of the microflora.26, 27, 28, 29, 30, 31, 32, 33, 34, 35

Vaginal pH, which is in some sense an indicator of vaginal health, varies over the lifespan (I did not know this..): In premenarchal girls vaginal pH is around 7, whereas it drops to 4.0-4.5 in healthy women of reproductive age. It increases again in post-menopausal women, but postmenopausal women receiving hormone replacement therapy have lower average vaginal pH and higher numbers of lactobacilli in their vaginal floras than do postmenopausal women not receiving hormone replacement therapy, one of several findings indicating that vaginal pH is under hormonal control (estrogen is important). Lactobacilli play an important role because those things produce lactic acid which lowers pH, and women with a reduced number of lactobacilli in their vaginal floras have higher vaginal pH. Stuff like sexual intercourse, menses, and breastfeeding all affect vaginal pH and -microflora, as does antibiotic usage, and such things may play a role in disease susceptibility. Aside from lowering pH some species of Lactobacilli also play other helpful roles which are likely to be important in terms of disease susceptibility, such as producing hydrogen peroxide in their microenvironments, which is the kind of stuff a lot of (other) bacteria really don’t like to be around: “Several clinical studies conducted in populations of pregnant and nonpregnant women in the United States and Japan have shown that the prevalence of BV is low (4%) among women colonized with H2O2-producing strains of lactobacilli. By comparison, approximately one third of women who are vaginally colonized by Lactobacillus that do not produce H2O2 have BV.45, 46, 47“.

My interest in the things covered in this book is as mentioned purely academical, but I’m well aware that some of the stuff may not be as ‘irrelevant’ to other people reading along here as it is to me. One particularly relevant observation I came across which I thought I should include here is this:

“The lack of reliable plenotypic methods for identification of lactobacilli have led to a broad misunderstanding of the species of lactobacilli present in the vagina, and the common misperception that dairy and food derived lactobacilli are similar to those found in the vagina. […] Acidophilus in various forms have been used to treat yeast vaginitis.144 Some investigators have gone so far as to suggest that ingestion of yogurt containing acidophilus prevents recurrent Candida vaginitis.145 Nevertheless, clinical studies of women with acute recurrent vulvovaginitis have demonstrated that women who have recurrent yeast vaginitis have the same frequency and concentration of Lactobacillus as women without recurrent infections.146 […] many women who seek medical care for chronic vaginal symptoms report using Lactobacillus-containing products orally or vaginally to restore the vaginal microflora in the mistaken belief that this will prevent recurrent vaginitis.147 Well-controlled trials have failed to document any decrease in vaginal candidiasis whether orally or vaginally applied preparations of lactobacilli are used by women.148 Microbial interactions in the vagina probably are much more complex than have been appreciated in the past.”

As illustrated above, there seems to be some things ‘we’ know which ‘people’ (including some doctors..) don’t know. But there are also some really quite relevant things ‘we’ don’t know a lot about yet. One example would be whether/how hygiene products mediate the impact of menses on vaginal flora: “It is unknown whether the use of tampons, which might absorb red blood cells during menses, may minimize the impact of menses on colonization by lactobacilli. However, some observational data suggests that women who routinely use tampons for catamenial protection are more likely to maintain colonization by lactobacilli compared to women who use pads for catamenial protection”. Just to remind you, colonization by lactobacilli is desirable. On a related and more general note: “Many young women use vaginal products including lubricants, contraceptives, antifungals, and douches. Each of these products can alter the vaginal ecosystem by changing vaginal pH, altering the vaginal fluid by direct dilution, or by altering the capacity of organisms to bind to the vaginal epithelium.” There are a lot of variables at play here and my reading of the results indicate that it’s not always obvious what is actually the best advice. For example an in this context large (n=235) prospective study about the effect of N-9, a compound widely used in contraceptives, on vaginal flora “demonstrated that N-9 did have a dose-dependent impact on the prevalence of anaerobic gram-negative rods, and was associated with a twofold increase in BV (OR 2.3, 95% CI 1.1-4.7).” Using spermicides like those may on the one hand perhaps decrease the likelihood of getting pregnant and perhaps lower the risk of contracting a sexually transmitted disease during intercourse, but on the other hand usage of such preparations may also affect the vaginal flora in a way which may make users more vulnerable to sexually transmitted diseases by promoting E. coli colonization of the vaginal flora. On a more general note, “The impact of contraceptives on the vaginal ecosystem, including their impact on susceptibility to infection, has not been adequately investigated to date.” The book does cover various studies on different types of contraceptives, but most of the studies are small and probably underpowered, so I decided not to go into this stuff in more detail. An important point to take away here is however that there’s no doubt that the vaginal flora is important for disease susceptibility: “longitudinal studies [have] showed a consistent link between increased incidence of HIV, HSV-2 and HPV and altered vaginal microflora […] there is a strong interaction between the health of the vaginal ecosystem and susceptibility to viral STIs.” Unfortunately, “use of probiotic products for treatment of BV has met with limited success.”

I should note that although multiple variables and interactions are involved in ‘this part of the equation’, it is of course only part of the bigger picture. One way in which it’s only part of the bigger picture is that the vaginal flora plays other roles besides the one which relates to susceptibility to sexually transmitted disease – one example: “Studies have established that some organisms considered to be part of the normal vaginal microflora are associated with an increased risk of preterm and/or low birth weight delivery when they are present at high-density concentrations in the vaginal fluid”. (And once again the lactobacilli in particular may play a role: “high-density vaginal colonization by Lactobacillus species has been linked with a decreased risk of most adverse outcomes of pregnancy”). Another major way in which this stuff is only part of the equation is that human females have a lot of other ways to defend themselves as well besides relying on bacterial colonists. If you don’t like immunology there are some chapters in here which you’d be well-advised to skip.

July 5, 2014 Posted by | Books, Data, Demographics, Epidemiology, Immunology, Infectious disease, Medicine, Microbiology | Leave a comment

A Quick Guide to Cancer Epidemiology

“Neoplasms include several hundreds of diseases, which can be distinguished by localization, morphology, clinical behaviour and response to therapy. […] Malignant neoplasms are characterized by progressive growth of tissue with structural and functional alterations with respect to the normal tissue. In some cases, the alterations can be so important that it becomes difficult to identify the tissue of origin. A peculiarity of most malignant tumours is the ability to migrate and colonize other organs (metastatization) via blood and lymph vessel penetration. The presence and extension of metastases are often the critical factors to determine the success of therapy and the survival of cancer patients. The pace of growth of malignant neoplasms varies widely, and asymptomatic neoplasms are often found at autopsy of individuals deceased from other causes. […] Most malignant neoplasms (about 90 %) in adults arise from epithelial tissues and are defined as carcinomas. […] Knowledge about the causes and the possible preventive strategies for malignant neoplasms has greatly advanced during the last decades. This has been largely based on the development of cancer epidemiology.”

I finished this book yesterday. I complained in my coverage of Managing Cardiovascular Complications in Diabetes that that book was full of formatting errors and that it seemed that nobody had proofread the book before publication, and I said in that post that ‘It’s much rarer, I think, to see stuff like that in Springer publications.’ I might be wrong about this, or at least I’ve updated my priors on that one; this specific book was even worse than the Managing Cardiovascular complications book in that respect – errors are all over the place. It’s odd and also slightly annoying, because if not for that problem I would consider this book to be a really nice little resource.

The book deals mainly with the data, and it is not a methodology text. Occasionally how we know what we know is important and the limits of our knowledge is important, so methodological questions are addressed here and there; but you certainly don’t need to have read a book like this to understand it, and although many specific details in the book presumably would not be understood by a random guy who’d just finished high school, most of the book is relatively easy to follow. This disease is this common in this area and that common in that area and the difference between these two areas may be due to these things; it kills this many people; these are some of the risk factors we know about, and the role they play is this – most of the book deals with questions such as these, and there are only so many ways you can make stuff like that impossible to understand by using a lot of fancy medical terms.

The book provides an excellent overview and the data and the level of coverage is actually quite excellent considering the length of the book – if not for the many errors and general sloppiness I’d feel tempted to give it a high rating. We know more than I thought we knew about these things, which is nice, and a few of the observations included were surprising to me. Of course a lot of details are missing but this is to be expected – people have written books about topics covered in a few pages here (e.g. this). If you read Mukherjee and this book, I think you’ll be off to a great start in terms of understanding cancer better; the obvious next step would be a book like this, but most people are probably not going to read stuff like that.

I should point out that perhaps I was a bit too hard on the lecture about the UK million women study in the recent Open Thread – I find it important to note in particular that specific topics also covered in this book, such as the role of birth control and hormone replacement therapy in cancer development, are covered in more detail in that lecture than they are in this book; so I refer you to that lecture, rather than covering that stuff below. Some of this stuff is the sort of stuff I’d probably want to know about if I were of the opposite gender. I should point out as well here that one of the reasons I did not think too highly of her lecture relates to her comments about cancer screening during the lecture (I think it’s around the 35 minute mark or so). Those comments annoyed me because I think she’s being intellectually dishonest during her lecture by not addressing the main problems with the pro-screening position, but only presents a weaker argument (to an audience unlikely to know any better) which is much easier to knock down – in the context of breast cancer screening the main argument against them, from what I’ve gathered, is not that these things do not save any lives (though there’s also a lively debate about how many lives are actually saved and how you should go about estimating this number), but rather that the costs – both monetary and non-monetary (the latter e.g. relating to the mental anguish experienced by the many, many women who get a false positive test result) – are not justified; there’s much more about these and related things in this book. In general it’s safe to say that it’s quite a bit harder to ‘properly justify’ screening programmes than many doctors often seem to think it is. Anyway the book doesn’t go into much detail about these things, and you’ll have to look elsewhere (e.g. Juth and Munthe) for detailed coverage of stuff like that.

I have added some observations from the book below and a few comments.

“Analytical studies (case–control and cohort) have shown the causal role of specific exposures in the aetiology of several malignant neoplasms. One limitation of the epidemiological approach, which may prove of critical importance in trying to detect comparatively small increases in risk, as in the case of environmental pollutants, is that even in the best conditions it is impossible to confidently identify by epidemiological means an increase in risk smaller than say 10–20 % (and serious problems arise in the interpretation of increases below 50 %), as the biases inherent in any observational study are of at least this order of magnitude (Adami et al. 2008).”

“In addition to lead-time bias, three types of bias are peculiar to the assessment of screening programmes. Because of self-selection, persons who elect to receive early detection may be different from those who do not: for instance, they may belong to better educated classes, be generally healthier and health conscious, and this could produce a longer survival independent of any effect of early detection. In addition, cancers with longer pre-clinical phases, which may mean less biological aggressiveness and better prognosis, are, in any case, more likely to be intercepted by a programme of periodical screening than cancers with a short pre-clinical phase, and a rapid, aggressive clinical course (length bias). Finally, because of criteria of positivity adopted to maximize yield of early cases, a number of lesions which in fact would never become malignant growths are included as ‘cases’, thus falsely improve the survival statistics (over-diagnosis bias).”

“The number of new cases of cancer which occurred worldwide in 2008 has been estimated at about 12,700,000 […]. Of these, 6,600,000 occurred in men and 6,000,000 in women. About 5,600,000 cases occurred in high-resource countries (North America, Japan, Europe including Russia, Australia and New Zealand) and 7,100,000 in low- and medium-resource countries. Among men, lung, stomach, colorectal, prostate and liver cancers are the most common malignant neoplasms […], while breast, colorectal, cervical, lung and stomach are the most common neoplasms among women […] The number of deaths from cancer was estimated at about 7,600,000 in 2008 […] No global estimates of survival from cancer are available: data from selected cancer registries suggest wide disparities between high- and low-resource countries for neoplasms with effective but expensive treatment, such as leukaemia, while the gap is narrow for neoplasms without an effective therapy, such as lung cancer […] The overall 5-year survival of cases diagnosed during 1995–1999 in 23 European countries was 49.6 % (Sant et al. 2009).”

“Survival from breast cancer has slowly increased in high-resource countries, where it now achieves 85 %, following improvements in screening practices and treatments. Survival in low-resource countries remains poor, in the order of 50–60 %. Breast cancer is the most common cancer among women worldwide: the estimated number of new cases in 2012 was 1,680,000” [I had no idea survival rates were that high in ‘high-resource countries’, though it’s a bit problematic that it is not spelled out what is actually meant by ‘survival’; I gather from this link that it’s the 5-year survival rate.]

“Tobacco smoking is the main single cause of human cancer worldwide (IARC 2004) and the largest cause of death and disease. It is the key cause of lung cancer, and a major cause of cancers of the oral cavity, pharynx, nasal cavity, larynx, oesophagus, stomach, pancreas, uterine cervix, kidney and bladder, as well as of myeloid leukemia. In high-resource countries, tobacco smoking causes approximately 30 % of all human cancers (Doll and Peto 2005). […] A benefit of quitting tobacco smoking in adulthood has been shown for all major cancers causally associated with the habit. Smokers who stop around age 50 avoid over 50 % of overall excess mortality from all causes (Doll et al. 2004; Jha et al. 2013; Pirie et al. 2013), from lung cancers (Peto et al. 2000) and well as from other tobacco-related cancers (Bosetti et al. 2008a), and those who stop around age 40 or earlier avoid most of their tobacco-related cancer risk. […] “The risk of lung cancer among smokers relative to the risk among never-smokers is in the order of over 20-fold […] In the UK million women study, the RRs [relative risks] of lung cancer were 10.5 for current smokers of 10 cigarettes per day, 22.0 for 15, and 36.0 for ≥20 cigarettes per day. […] An association has been shown in many studies between exposure to involuntary smoking and lung cancer risk in non-smokers. The magnitude of the excess risk among non-smokers exposed to involuntary smoking is in the order 20 % (IARC 2004).” [You have a 20% risk increase from passive smoking and a twenty-fold increase from smoking. My conclusion from these observations would be that in terms of cancer risk passive smoking doesn’t really matter in the big picture, and that it is overhyped as a disease risk factor – the excess cancer risk attributable to smoking probably causes more than 100 cancers in smokers for each cancer case in a non-smoker, and most of the non-smokers who develop cancerous lesions will have been exposing themselves for years – questioning the assumption that they did not willingly take on this risk]. Lung cancer is “the most important cause of cancer death worldwide. It accounts for an estimated 1,250,000 new cases and 1,100,000 deaths each year among men and 580,000 cases and 500,000 deaths among women […]. Survival from lung cancer is poor (around 10 % at 5 years).”

“The role of dietary factors in causing human cancer remains largely obscure. For no dietary factor other than alcohol […] and aflatoxin (a carcinogen produced by some fungi in certain tropical areas) there is sufficient evidence of an increased or decreased risk of cancer. […] Alcohol drinking increases the risk of cancers of the oral cavity, pharynx, larynx, oesophagus and liver, colorectum and female breast (Baan et al. 2007). For all cancer sites, risk is a function of the amount of alcohol consumed […] The global burden of cancer attributable to alcohol drinking has been estimated at 3.6 and 3.5 % of cancer deaths (Boffetta 2006), although this figure is higher in high-resource countries (e.g., the figure of 6 % has been proposed for United Kingdom (Doll and Peto 2005) , and 9 % in Central and Eastern Europe). These included over 5 % of cancers and cancer deaths in men and about 1.5 % of cancers and cancer deaths in women. […] Systematic reviews have concluded that nutritional factors may be responsible for about one-fourth of human cancers in high-resource countries, although, because of the limitations of the current understanding of the precise role of diet in human cancer, the proportion of cancers known to be avoidable in practicable ways is much smaller (Doll and Peto 2005). The only justified dietary recommendation for cancer prevention is to reduce total caloric intake, which would contribute to a decrease in obesity, an established risk factor for human cancer […] There is sufficient evidence for a cancer preventive effect of avoidance of weight gain, based on a decreased risk of cancers of the colon, gallbladder, post- menopausal breast, endometrium, kidney and esophagus (adenocarcinoma) […] Estimates of the proportion of cancers attributable to overweight and obesity in Europe range from 2 % (Doll and Peto 2005) to 5 % (Bergstrom et al. 2001).”

“There is growing evidence that chronic infection with some viruses, bacteria and parasites represents a major risk factor for human cancer, in particular in low-income countries […] The population attributable fraction for infectious agents was 16.1 % in 2008, meaning that around two million new cancer cases were attributable to infections. HBV and HCV-related liver cancer, HPV-related cervical cancer and Helicobacter pylori-related stomach cancer overall are responsible for 95 % of the total number of infection-related cancers. The estimate of the attributable fraction is higher in less developed countries than in high-resource countries (22.9 % of total cancer versus 7.4 %). […] Cervical cancer is a major public health problem in many low and middle income countries. Incidence rates are high (20–40/100,000) in sub-Saharan Africa and Latin America countries, as well as in India and southern Asia. […] Chronic infection with HPV is a necessary cause of cervical cancer. Using sensitive molecular techniques, virtually all tumours are positive for the virus […]. Different types of HPV exist, and those associated with cervical cancer are mainly types 16, 18, 31, 45 and 58. In particular, HPV 16 is the main cervical carcinogen in most populations”.

“Approximately 40 occupational agents, groups of agents and mixtures have been classified as carcinogenic by IARC […] Estimates of the global burden of cancer attributable to occupation in high-income countries result in figures in the order of 1–5 % (Doll and Peto 2005 ; Schottenfeld et al. 2013). In the past, almost 50 % of these were due to asbestos alone, while in recent years the impact of asbestos on lung cancer […] is levelling off […] However, these cancers concentrate in some sectors of the population (mainly male blue-collar workers), among whom they may represent a sizable proportion of total cancers […] The available evidence suggests, in most populations, a small role of air, water, and soil pollutants. Global estimates are in the order of 1 % or less of total cancers (Doll and Peto 2005; Schottenfeld et al. 2013). This is in striking contrast with public perception, which often identifies pollution as a major cause of human cancer. However, in selected areas (e.g., residence near asbestos processing plants or in areas with drinking water contaminated by arsenic), environmental exposure to carcinogens may represent an important cancer hazard.”

“No precise estimates are available for the global contribution of drug use to human cancer. It is unlikely, however, that they represent more than 1 % in high-resource countries (Doll and Peto 2005). Furthermore, the benefits of therapies are usually much greater than the potential cancer risk.”

“A number of inherited mutations of a high-penetrance cancer gene increase dramatically the risk of some neoplasms. However, these are rare conditions in most populations and the number of cases attributable to them is rather small.” [An example: “breast cancer risk is greatly increased in carriers of mutations of several high-penetrance genes, in particular BRCA1, BRCA2, ATM, CHECK2 and p53. Although the cumulative lifetime risk in carriers of these genes is over 50 %, they are rare in most populations and explain only a small fraction (2–5 %) of total cases.”]

June 29, 2014 Posted by | Books, Cancer/oncology, Epidemiology, Infectious disease, Medicine | Leave a comment

100 Cases in Clinical Medicine

This book is another book in the same series as the 100 Cases in Acute Medicine book. Here’s part of the preface:

“Most doctors think that the most memorable way to learn medicine is to see patients. It is easier to recall information based on a real person than a page in a textbook. Another important element in the retention of information is the depth of learning. Learning that seeks to understand problems is more likely to be accessible later than superficial factual accumulation. This is the basis of problem-based learning, whereby students explore problems with the help of a facilitator. The cases in this book are designed to provide another useful approach, parallel to seeing patients and giving an opportunity for self-directed exploration of clinical problems. They are based on the findings of history taking and examination, together with the need to evaluate initial investigations such as blood investigations, X-rays and electrocardiograms.

These cases are no substitute for clinical experience with real patients, but they provide a safe environment for students to explore clinical problems and their own approach to diagnosis and management. Most are common problems that might present to a general practitioner’s surgery, a medical outpatients clinic or a session on call in hospital. There are a few more unusual cases to illustrate specific points and to emphasize that rare things do present, even if they are uncommon. The cases are written to try to interest students in clinical problems and to enthuse them to find out more. They try to explore thinking about diagnosis and management of real clinical situations.”

As for the ‘interest students in clinical problems and to enthuse them to find out more’-part they certainly succeeded, but I approached this book in a slightly different manner than I did the first one in the series. When I read the acute medicine book, I’d occasionally think to myself while reading the patient history and/or the reported lab results that ‘hey, this sounds a bit like…’ and I’d look up the diagnosis/condition I was considering in order to decide if I wanted to ‘guess’ at that, before moving on to reading the answer part of the case. I did this a few times as well here, but actually most of the pre-answer wiki peeks were related to the interpretation of specific lab results (‘how to interpret some of the arterial blood gas test results’). The reason why I tried to limit myself from looking up stuff before reading the answer was that I wanted to know a little bit about how much of the pathophysiology text (and stuff covered in related texts, such as e.g. Hall’s Handbook and Rogers et al., as well as various medical lectures e.g. from Khan Academy) I could remember. I actually realized when reading the first 100 cases book that there were very few conditions covered there which I had not already read about, or at least seen mentioned, elsewhere; the problem was figuring out which patients had which specific problems. Part of the reason why I often had trouble with that part was incidentally related to the fact that there are some other relevant books I have not read – books such as this one or this one (I’m not planning on reading these, just in case you were wondering). A related point is that doctors have a lot more information available to them than do the people who are sick, and that this is certainly a (small) part of the explanation for why they are better at figuring out what’s wrong than are the people who are sick – symptoms can be non-specific, but if so lab results will often tell you more about where to look and what to look for. I decided beforehand when reading this book that I’d try for fun to keep score and figure out in how many cases I guessed the correct diagnosis; it turned out that I guessed the right diagnosis in roughly one-fifth of the cases and in a few other cases the guess I made was a very plausible differential diagnosis which needed to be ruled out anyway. In a few of them I didn’t get ‘the complete picture’, and I learned something from many of the cases where I knew the (‘diagnosis’-part of the-) right answer. I feel quite certain I would have guessed more of them if I’d spent more time on individual cases; I read the entire book yesterday, and this is not a book you can read in a few hours (I think it took me 12 hours, at least, but I’m not really sure as I didn’t keep track and did take breaks occasionally. Ratios like these – me spending easily 5-10 hours or more on stuff which leads to a post which you’ll read in perhaps 10-15 minutes – are incidentally one reason why I sometimes feel that people reading along here are ‘cheating’ in a way. On the other hand I really can’t complain as long as I’m enabling such ‘cheating’ in the first place…). I got far most of my guesses correct, as in many cases I didn’t guess at all because I wasn’t completely sure what was going on. Of course treatment and management aspects I didn’t ‘guess at’, and that’s an important aspect of the book as well. The conditions I recognized spanned a rather broad range; from colon cancer over HIV seroconversion illness (main differential was malaria – I knew this as well) to COPD, rheumatoid arthritis, bacterial meningitis, obstructive sleep apnea, peripheral neuropathy secondary to undiagnosed type 2 diabetes mellitus, dementia, small cell lung cancer with associated paraneoplastic syndrome, and Parkinson’s disease. As you can probably tell from those diagnoses, like the acute medicine book this book also has some rather depressing cases. Some cases, e.g. a case of cerebral toxoplasmosis secondary to HIV infection (this is actually an AIDS-defining illness, so she had AIDS at the time of admission) and a diet-related vitamin B12 deficiency, were really obvious in retrospect, but in medicine there’s a lot of stuff to remember.

I’ve added some quotes, observations and key points from the book below.

“Cystic fibrosis should always be considered when there is a story of repeated chest infections in a young person. Although it presents most often below the age of 20 years, diagnosis may be delayed until the 20s, 30s, 40s or later in milder cases.”

“Patients with a chronic persistent cough of unexplained cause should have a chest X-ray. When the X-ray is clear the cough is likely to be produced by one of three main causes in non-smokers. Around half of such cases have asthma or will go on to develop asthma over the next few years. Half of the rest have rhinitis or sinusitis with a postnasal drip. In around 20 per cent the cough is related to gastro-oesophageal reflux […] Cough is a common side effect in patients treated with angiotensin-converting enzyme (ACE) inhibitors.”

“This man has signs of chronic liver disease with ascites and oedema. […] The most common cause of chronic liver disease is alcohol. […] However, his alcohol intake is too low to be consistent with the diagnosis of alcoholic liver disease [15-20 units/week, according to the patient history. This was why I initially rejected alcohol-related pathology in this case and (very briefly) considered other causes instead, without coming up with anything (this was another one of those aforementioned obvious ones in retrospect)…]. When the provisional diagnosis is discussed with him, though, he eventually admits that his alcohol intake has been at least 40–50 units per week for the last 20 years. His alcohol intake has increased further during the last year after his marriage had ended.” [Patients sometimes lie to their doctors. This one did. In case you were wondering he died three years later from an esophageal variceal bleed.]

“Patients often become symptomatic due to renal failure only when their glomerular filtration rate (GFR) is less than 15 mL/min [normal range is 90+, US] and thus may present with end-stage renal failure.” [This is an example of a more general point in many medical contexts; our bodies often have a lot of ‘excess capacity’ and redundancies implemented in order to make us less likely to get sick/get symptoms which may decrease our likelihood of survival even if things aren’t optimal. The book actually has other examples illustrating this point, e.g. this: “Patients with central diabetes insipidus typically describe an abrupt onset of polyuria and polydipsia. This is because urinary concentration can be maintained fairly well until the number of AVP-secreting neurones in the hypothalamus decreases to 10–15 per cent of the normal number, after which AVP levels decrease to a range where urine output increases dramatically.”]

“Petechiae are small capillary haemorrhages that characteristically develop in crops in areas of increased venous pressure, such as the dependent parts of the body. Petechiae are the smallest bleeding lesions (pinhead in size), and suggest problems with platelet number or function. Purpura are larger in size than petechiae with variable shape and involve bleeding into subcutaneous tissues. Purpura can be seen in a variety of bleeding disorders […] AML is the most common acute leukaemia in adults with a mean age at presentation of 65 years. Patients with AML generally present with symptoms related to complications of pancytopenia (eg, anemia, neutropenia, and thrombocytopenia), including weakness, breathlessness and easy fatigability, infections of variable severity, and/or haemorrhagic findings such as gingival bleeding, ecchymoses, epistaxis, or menorrhagia.”

“Vegans who omit all animal products from their diet often have subclinical vitamin B12 deficiency […] Vitamin B12 deficiency may occur in strict vegetarians who eat no dairy products. […] Typical neurological signs are position and vibration sense impairment in the legs, absent reflexes and extensor plantars.”

“Malaria prophylaxis is often not taken regularly. Even when it is, it does not provide complete protection against malaria […] A traveller returning from a malaria endemic region who develops a fever has malaria until proven otherwise.”

“Peripheral oedema may occur due to local obstruction of lymphatic or venous outflow or because of cardiac, renal, pulmonary or liver disease. Unilateral oedema is most likely to be due to a local problem […] Bilateral oedema may be due to cardiac, liver or renal disease. […] Pitting oedema needs to be distinguished from lymphoedema, which is characteristically non-pitting. This is tested by firm pressure with the thumb for approximately 10 s. If the oedema is pitting, an indentation will be present after pressure is removed. […] frothy urine is a clue to the diagnosis of nephrotic syndrome and is commonly noted by patients with heavy proteinuria.”

“80% of C. difficile infections occur in people aged over 65 years since a lower density and fewer species of gut bacteria make them more susceptible to colonisation by C. difficile […] 20% of hospital patients and those in long-term care facilities are colonised with C. difficile. […] C. difficile infection should be suspected in any hospital patient who develops diarrhoea.”

“ADPKD [Autosomal Dominant Polycystic Kidney Disease] is the most common inherited renal disease, occurring in approximately 1:600 to 1:1000 individuals. Although the name ‘ADPKD’ is derived from renal manifestations of cyst growth leading to enlarged kidneys and renal failure, this is a systemic disorder manifested by the presence of hepatic cysts, diverticular disease, inguinal hernias, mitral valve prolapse, intracranial aneurysms and hypertension. […] Patients with ADPKD are often asymptomatic. […] Flank pain is the most common symptom […] Hypertension occurs early in the course of this disease, affecting 60% of patients with normal renal function. Approximately 50% of ADPKD patients will develop end-stage renal failure.”

“Transient small nodes in the neck or groin are common benign findings. However, a 3 × 4 cm mass of nodes for 2 months is undoubtedly abnormal. […] Lymph nodes are normally barely palpable, if at all. The character of enlarged lymph nodes is very important. In acute infections the nodes are tender, and the overlying skin may be red. Carcinomatous nodes are usually very hard, fixed and irregular. The nodes of chronic leukaemias and lymphomas are non-tender, firm and rubbery.  […] The typical systemic symptoms of lymphoma are malaise, fever, night sweats, pruritus, weight loss, anorexia and fatigue.”

“Colonic diverticula are small outpouchings that are most commonly found in the left colon. […] Inflammation in a diverticulum is termed diverticulitis. […] Diverticular disease is a common finding in the elderly Western population and may be asymptomatic or cause irritable bowel syndrome-type symptoms. […] Diverticular disease is a common condition; its presence can distract the unwary doctor from pursuing a coincident condition.”

“Tension type headaches are the commonest headaches in the general population. The typical presentation is of mild to moderate headache, nonthrobbing, bilateral with no associated symptoms. Cluster headaches are characterised by attacks of severe unilateral orbital or temporal pain, accompanied by autonomic features such as nasal congestion, lacrimation and rhinorrhoea. Migraines are often preceded by characteristic symptoms such as flashing lights and are often unilateral. Nausea and photophobia may occur during an attack. Brain tumours cause headaches by causing raised intracranial pressure. The headache is worse after coughing and is often associated with nausea and vomiting. […] The sudden onset of a headache within seconds or a few minutes is characteristic of a subarachnoid haemaorrhage (SAH). […] Patients with SAH often describe the pain as ‘the worst headache in my life’. [And in many cases it’s also the last headache they ever will have:] SAH is associated with a mortality rate of up to 50%.”

“He drinks 35 units of alcohol per week and smokes 30 cigarettes per day.” [Aargh! Another one of those! But at least this one didn’t lie about his drinking habits. … But it gets worse:] “No history was available from the patient [she’s in a coma], but her partner volunteered the information that they are both intravenous heroin addicts. She is unemployed, smokes 25 cigarettes per day, drinks 40 units of alcohol per week and has used heroin for the past 4 years.” [Dammit! Some of these histories are depressing in more than one way. The woman had been found unconscious by her partner. My first thought when reading the case story about the woman and the lab results was that, ‘This reminds me of that movie I saw a while back, what’s it called..?’ – I can’t remember the name of the movie, but it’s not important. I want to quote a bit more extensively from the answer part of this case because I thought it was sort of fascinating in a way; it illustrates how a drug overdose isn’t always just a problem because of the drug overdose:]

“This patient has acute renal failure as a result of rhabdomyolysis. Severe muscle damage causes a massively elevated serum creatine kinase (CK) level and a rise in serum potassium and phosphate levels. In this case, she has lain unconscious on her left arm for many hours due to an overdose of alcohol and intravenous heroin. As a result, she has developed severe ischaemic muscle damage, causing release of myoglobin, which is toxic to the kidneys. […] Acute renal failure due to rhabdomyolysis causes profound hypocalcaemia in the oliguric phase due to calcium sequestration in muscle and reduced 1,25-dihydroxycalciferol levels, often with rebound hypercalcaemia in the recovery phase. This woman’s consciousness level is still depressed as a result of opiate and alcohol toxicity, and she has clinical and radiological evidence of aspiration pneumonia. She has mixed metabolic and respiratory acidosis (low pH, bicarbonate) due to acute renal failure and respiratory depression (pCO2 elevated). Her arterial oxygenation is reduced due to hypoventilation and pneumonia. She also has compartment syndrome in her arm due to massive swelling of her damaged muscles. This patient has life-threatening hyperkalaemia with electrocardiogram (ECG) changes. […] Emergency treatment involves intravenous calcium gluconate, which stabilizes cardiac conduction, and intravenous insulin/glucose, intravenous sodium bicarbonate and nebulized salbutamol, all of which temporarily lower the plasma potassium by increasing the cellular uptake of potassium. However, these steps should be regarded as holding measures while urgent dialysis is being organized. The chest X-ray and clinical findings indicate consolidation of the left lower lobe. This patient should initially be managed on an intensive care unit. She will require antibiotics for her pneumonia and will require a naloxone infusion or mechanical ventilation for her respiratory failure. The patient should have vigorous rehydration with monitoring of her central venous pressure. If a good urinary flow can be maintained, urinary pH should be kept greater than 7.0 by bicarbonate infusion, which prevents the renal toxicity of myoglobin. This patient also needs to be considered urgently for surgical fasciotomy to relieve the compartment syndrome in her arm.”

Back when I read the Acute Muscle Injuries text, compartment syndrome was sort of a worst-case-scenario. Here it’s just one of multiple problems, each of which on their own would be quite terrible. I should incidentally note in case you were wondering if all of the patients in this book are alcoholics that most of them are not – but that they mention in the coverage that: “In some surveys alcohol is linked directly to around 25% of acute medical admissions.” I looked around very briefly for those numbers because they sounded very high to me, but I didn’t find much. This paper had an estimate of 6%, but that’s out of all hospital admissions and you’d expect the proportion of all admissions involving alcohol to be significantly lower than the proportion of acute admissions. Note in that context that ‘the true number’ in the former case is to some extent unknowable – though you can try to estimate it, as people do – as e.g. alcohol’s role in certain cancers is quite difficult to figure out in general, and impossible to figure out at the individual level; it makes sense to say that drinking alcohol increases your risk of breast cancer (and perhaps that’s not even the best example as we’re quite sure alcohol has a role there, a level of certainty we in other areas of oncology do not have), but deciding with certainty whether patient X’s specific case of breast cancer was alcohol-related or not is impossible – ‘it may have been a contributing factor’ is probably the closest you can get, we don’t have a test for that. Same goes for a cardiovascular event – ‘alcohol may have played a role’, but that’s it. Perhaps also worth remembering here is incidentally that on a related note some epidemiological findings trying to have a closer look at precisely these sorts of things may have results which are partially explained by statistical artifacts unrelated to the ‘true’ associated risk; a smoker who drinks a lot is highly likely to die from various alcohol- and smoking-related causes at a relatively early age. Such early deaths may well make people with such habits less likely to get old enough to get prostate cancer (the risk of which increases dramatically with age), even if alcohol and smoking on their own perhaps actually increase the risk of prostate cancer, in the sense that the effects of both alcohol and smoking may be to make those cells more likely to turn malignant (I don’t know if this is actually the case or not, it’s just the sort of thing you need to watch out for). There are ways around such problems – a competing risks framework is important to have in mind here – but problems of this sort are sometimes hard to avoid and/or deal with.

They don’t talk about these things in the book, but they talk about a lot of other interesting stuff, and I can’t cover all of it. One thing I have yet to cover which I thought I should include as a small favour to a friend reading along is this part, from the very last pages of the book:

“Traditional Chinese medicine includes herbal therapy, acupuncture, massage and dietary therapy. There is potential for developing novel treatments for diseases such as asthma and food allergies with Chinese herbs. However, there is concern over the lack of standardization and controlled clinical trials. Chinese herbal medicines containing aristolochic acid have been implicated in a specific nephropathy characterised by extensive interstitial fibrosis with atrophy and loss of the tubules, with thickening of the walls of the interlobular and afferent arterioles. Blood pressure is generally normal or only modestly elevated. Patients presenting with a creatinine < 200 will generally stabilise their renal function after stopping the Chinese medications, but patients with worse kidney function will generally progress to end-stage kidney failure.”

I liked the book and I gave it three stars on goodreads. You need to be fluent in ‘medical textbook’ in order to get much out of this book, but if you have some medical knowledge I believe you’ll be quite likely to find the books in this series quite interesting.

June 8, 2014 Posted by | alcohol, Books, Cancer/oncology, Epidemiology, Infectious disease, Medicine, Microbiology, Nephrology | Leave a comment