A few diabetes papers of interest

i. Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control.

“Despite U.S. Food and Drug Administration (FDA) approval of over 40 new treatment options for type 2 diabetes since 2005, the latest data from the National Health and Nutrition Examination Survey show that the proportion of patients achieving glycated hemoglobin (HbA1c) <7.0% (<53 mmol/mol) remains around 50%, with a negligible decline between the periods 2003–2006 and 2011–2014. The Healthcare Effectiveness Data and Information Set reports even more alarming rates, with only about 40% and 30% of patients achieving HbA1c <7.0% (<53 mmol/mol) in the commercially insured (HMO) and Medicaid populations, respectively, again with virtually no change over the past decade. A recent retrospective cohort study using a large U.S. claims database explored why clinical outcomes are not keeping pace with the availability of new treatment options. The study found that HbA1c reductions fell far short of those reported in randomized clinical trials (RCTs), with poor medication adherence emerging as the key driver behind the disconnect. In this Perspective, we examine the implications of these findings in conjunction with other data to highlight the discrepancy between RCT findings and the real world, all pointing toward the underrealized promise of FDA-approved therapies and the critical importance of medication adherence. While poor medication adherence is not a new issue, it has yet to be effectively addressed in clinical practice — often, we suspect, because it goes unrecognized. To support the busy health care professional, innovative approaches are sorely needed.”

“To better understand the differences between usual care and clinical trial HbA1c results, multivariate regression analysis assessed the relative contributions of key biobehavioral factors, including baseline patient characteristics, drug therapy, and medication adherence (21). Significantly, the key driver was poor medication adherence, accounting for 75% of the gap […]. Adherence was defined […] as the filling of one’s diabetes prescription often enough to cover ≥80% of the time one was recommended to be taking the medication (34). By this metric, proportion of days covered (PDC) ≥80%, only 29% of patients were adherent to GLP-1 RA treatment and 37% to DPP-4 inhibitor treatment. […] These data are consistent with previous real-world studies, which have demonstrated that poor medication adherence to both oral and injectable antidiabetes agents is very common (3537). For example, a retrospective analysis [of] adults initiating oral agents in the DPP-4 inhibitor (n = 61,399), sulfonylurea (n = 134,961), and thiazolidinedione (n = 42,012) classes found that adherence rates, as measured by PDC ≥80% at the 1-year mark after the initial prescription, were below 50% for all three classes, at 47.3%, 41.2%, and 36.7%, respectively (36). Rates dropped even lower at the 2-year follow-up (36)”

“Our current ability to assess adherence and persistence is based primarily on review of pharmacy records, which may underestimate the extent of the problem. For example, using the definition of adherence of the Centers for Medicare & Medicaid Services — PDC ≥80% — a patient could miss up to 20% of days covered and still be considered adherent. In retrospective studies of persistence, the permissible gap after the last expected refill date often extends up to 90 days (39,40). Thus, a patient may have a gap of up to 90 days and still be considered persistent.

Additionally, one must also consider the issue of primary nonadherence; adherence and persistence studies typically only include patients who have completed a first refill. A recent study of e-prescription data among 75,589 insured patients found that nearly one-third of new e-prescriptions for diabetes medications were never filled (41). Finally, none of these measures take into account if the patient is actually ingesting or injecting the medication after acquiring his or her refills.”

“Acknowledging and addressing the problem of poor medication adherence is pivotal because of the well-documented dire consequences: a greater likelihood of long-term complications, more frequent hospitalizations, higher health care costs, and elevated mortality rates (4245). In patients younger than 65, hospitalization risk in one study (n = 137,277) was found to be 30% at the lowest level of adherence to antidiabetes medications (1–19%) versus 13% at the highest adherence quintile (80–100%) […]. In patients over 65, a separate study (n = 123,235) found that all-cause hospitalization risk was 37.4% in adherent cohorts (PDC ≥80%) versus 56.2% in poorly adherent cohorts (PDC <20%) (45). […] Furthermore, for every 1,000 patients who increased adherence to their antidiabetes medications by just 1%, the total medical cost savings was estimated to be $65,464 over 3 years (45). […] “for reasons that are still unclear, the N.A. [North American] patient groups tend to have lower compliance and adherence compared to global rates during large cardiovascular studies” (46,47).”

“There are many potential contributors to poor medication adherence, including depressive affect, negative treatment perceptions, lack of patient-physician trust, complexity of the medication regimen, tolerability, and cost (48). […] A recent review of interventions addressing problematic medication adherence in type 2 diabetes found that few strategies have been shown consistently to have a marked positive impact, particularly with respect to HbA1c lowering, and no single intervention was identified that could be applied successfully to all patients with type 2 diabetes (53). Additional evidence indicates that improvements resulting from the few effective interventions, such as pharmacy-based counseling or nurse-managed home telemonitoring, often wane once the programs end (54,55). We suspect that the efficacy of behavioral interventions to address medication adherence will continue to be limited until there are more focused efforts to address three common and often unappreciated patient obstacles. First, taking diabetes medications is a burdensome and often difficult activity for many of our patients. Rather than just encouraging patients to do a better job of tolerating this burden, more work is needed to make the process easier and more convenient. […] Second, poor medication adherence often represents underlying attitudinal problems that may not be a strictly behavioral issue. Specifically, negative beliefs about prescribed medications are pervasive among patients, and behavioral interventions cannot be effective unless these beliefs are addressed directly (35). […] Third, the issue of access to medications remains a primary concern. A study by Kurlander et al. (51) found that patients selectively forgo medications because of cost; however, noncost factors, such as beliefs, satisfaction with medication-related information, and depression, are also influential.”

ii. Diabetes Research and Care Through the Ages. An overview article which might be of interest especially to people who’re not much familiar with the history of diabetes research and -treatment (a topic which is also very nicely covered in Tattersall’s book). Despite including a historical review of various topics, it also includes many observations about e.g. current (and future?) practice. Some random quotes:

“Arnoldo Cantani established a new strict level of treatment (9). He isolated his patients “under lock and key, and allowed them absolutely no food but lean meat and various fats. In the less severe cases, eggs, liver, and shell-fish were permitted. For drink the patients received water, plain or carbonated, and dilute alcohol for those accustomed to liquors, the total fluid intake being limited to one and one-half to two and one-half liters per day” (6).

Bernhard Naunyn encouraged a strict carbohydrate-free diet (6,10). He locked patients in their rooms for 5 months when necessary for “sugar-freedom” (6).” […let’s just say that treatment options have changed slightly over time – US]

“The characteristics of insulin preparations include the purity of the preparation, the concentration of insulin, the species of origin, and the time course of action (onset, peak, duration) (25). From the 1930s to the early 1950s, one of the major efforts made was to develop an insulin with extended action […]. Most preparations contained 40 (U-40) or 80 (U-80) units of insulin per mL, with U-10 and U-20 eliminated in the early 1940s. U-100 was introduced in 1973 and was meant to be a standard concentration, although U-500 had been available since the early 1950s for special circumstances. Preparations were either of mixed beef and pork origin, pure beef, or pure pork. There were progressive improvements in the purity of preparations as chemical techniques improved. Prior to 1972, conventional preparations contained 8% noninsulin proteins. […] In the early 1980s, “human” insulins were introduced (26). These were made either by recombinant DNA technology in bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae) or by enzymatic conversion of pork insulin to human insulin, since pork differed by only one amino acid from human insulin. The powerful nature of recombinant DNA technology also led to the development of insulin analogs designed for specific effects. These include rapid-acting insulin analogs and basal insulin analogs.”

“Until 1996, the only oral medications available were biguanides and sulfonylureas. Since that time, there has been an explosion of new classes of oral and parenteral preparations. […] The management of type 2 diabetes (T2D) has undergone rapid change with the introduction of several new classes of glucose-lowering therapies. […] the treatment guidelines are generally clear in the context of using metformin as the first oral medication for T2D and present a menu approach with respect to the second and third glucose-lowering medication (3032). In order to facilitate this decision, the guidelines list the characteristics of each medication including side effects and cost, and the health care provider is expected to make a choice that would be most suited for patient comorbidities and health care circumstances. This can be confusing and contributes to the clinical inertia characteristic of the usual management of T2D (33).”

“Perhaps the most frustrating barrier to optimizing diabetes management is the frequent occurrence of clinical inertia (whenever the health care provider does not initiate or intensify therapy appropriately and in a timely fashion when therapeutic goals are not reached). More broadly, the failure to advance therapy in an appropriate manner can be traced to physician behaviors, patient factors, or elements of the health care system. […] Despite clear evidence from multiple studies, health care providers fail to fully appreciate that T2D is a progressive disease. T2D is associated with ongoing β-cell failure and, as a consequence, we can safely predict that for the majority of patients, glycemic control will deteriorate with time despite metformin therapy (35). Continued observation and reinforcement of the current therapeutic regimen is not likely to be effective. As an example of real-life clinical inertia for patients with T2D on monotherapy metformin and an HbA1c of 7 to <8%, it took on the average 19 months before additional glucose-lowering therapy was introduced (36). The fear of hypoglycemia and weight gain are appropriate concerns for both patient and physician, but with newer therapies these undesirable effects are significantly diminished. In addition, health care providers must appreciate that achieving early and sustained glycemic control has been demonstrated to have long-term benefits […]. Clinicians have been schooled in the notion of a stepwise approach to therapy and are reluctant to initiate combination therapy early in the course of T2D, even if the combination intervention is formulated as a fixed-dose combination. […] monotherapy metformin failure rates with a starting HbA1c >7% are ∼20% per year (35). […] To summarize the current status of T2D at this time, it should be clearly emphasized that, first and foremost, T2D is characterized by a progressive deterioration of glycemic control. A stepwise medication introduction approach results in clinical inertia and frequently fails to meet long-term treatment goals. Early/initial combination therapies that are not associated with hypoglycemia and/or weight gain have been shown to be safe and effective. The added value of reducing CV outcomes with some of these newer medications should elevate them to a more prominent place in the treatment paradigm.”

iii. Use of Adjuvant Pharmacotherapy in Type 1 Diabetes: International Comparison of 49,996 Individuals in the Prospective Diabetes Follow-up and T1D Exchange Registries.

“The majority of those with type 1 diabetes (T1D) have suboptimal glycemic control (14); therefore, use of adjunctive pharmacotherapy to improve control has been of clinical interest. While noninsulin medications approved for type 2 diabetes have been reported in T1D research and clinical practice (5), little is known about their frequency of use. The T1D Exchange (T1DX) registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria are two large consortia of diabetes centers; thus, they provide a rich data set to address this question.

For the analysis, 49,996 pediatric and adult patients with diabetes duration ≥1 year and a registry update from 1 April 2015 to 1 July 2016 were included (19,298 individuals from 73 T1DX sites and 30,698 individuals from 354 DPV sites). Adjuvant medication use (metformin, glucagon-like peptide 1 [GLP-1] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT2] inhibitors, and other noninsulin diabetes medications including pramlintide) was extracted from participant medical records. […] Adjunctive agents, whose proposed benefits may include the ability to improve glycemic control, reduce insulin doses, promote weight loss, and suppress dysregulated postprandial glucagon secretion, have had little penetrance as part of the daily medical regimen of those in the registries studied. […] The use of any adjuvant medication was 5.4% in T1DX and 1.6% in DPV (P < 0.001). Metformin was the most commonly reported medication in both registries, with 3.5% in the T1DX and 1.3% in the DPV (P < 0.001). […] Use of adjuvant medication was associated with older age, higher BMI, and longer diabetes duration in both registries […] it is important to note that registry data did not capture the intent of adjuvant medications, which may have been to treat polycystic ovarian syndrome in women […here’s a relevant link, US].”

iv. Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study. I recently covered a closely related paper here (paper # 2) but the two papers cover different data sets so I decided it would be worth including this one in this post anyway. Some quotes:

“We previously reported results from a small pilot study comparing the prevalence of DPN in a subset of youth enrolled in the SEARCH for Diabetes in Youth (SEARCH) study and found that 8.5% of 329 youth with T1D (mean ± SD age 15.7 ± 4.3 years and diabetes duration 6.2 ± 0.9 years) and 25.7% of 70 youth with T2D (age 21.6 ± 4.1 years and diabetes duration 7.6 ± 1.8 years) had evidence of DPN (9). […this is the paper I previously covered here, US] Recently, we also reported the prevalence of microvascular and macrovascular complications in youth with T1D and T2D in the entire SEARCH cohort (10).

In the current study, we examined the cross-sectional and longitudinal risk factors for DPN. The aims were 1) to estimate prevalence of DPN in youth with T1D and T2D, overall and by age and diabetes duration, and 2) to identify risk factors (cross-sectional and longitudinal) associated with the presence of DPN in a multiethnic cohort of youth with diabetes enrolled in the SEARCH study.”

“The SEARCH Cohort Study enrolled 2,777 individuals. For this analysis, we excluded participants aged <10 years (n = 134), those with no antibody measures for etiological definition of diabetes (n = 440), and those with incomplete neuropathy assessment […] (n = 213), which reduced the analysis sample size to 1,992 […] There were 1,734 youth with T1D and 258 youth with T2D who participated in the SEARCH study and had complete data for the variables of interest. […] Seven percent of the participants with T1D and 22% of those with T2D had evidence of DPN.”

“Among youth with T1D, those with DPN were older (21 vs. 18 years, P < 0.0001), had a longer duration of diabetes (8.7 vs. 7.8 years, P < 0.0001), and had higher DBP (71 vs. 69 mmHg, P = 0.02), BMI (26 vs. 24 kg/m2, P < 0.001), and LDL-c levels (101 vs. 96 mg/dL, P = 0.01); higher triglycerides (85 vs. 74 mg/dL, P = 0.005); and lower HDL-c levels (51 vs. 55 mg/dL, P = 0.01) compared to those without DPN. The prevalence of DPN was 5% among nonsmokers vs. 10% among the current and former smokers (P = 0.001). […] Among youth with T2D, those with DPN were older (23 vs. 22 years, P = 0.01), had longer duration of diabetes (8.6 vs. 7.6 years; P = 0.002), and had lower HDL-c (40 vs. 43 mg/dL, P = 0.04) compared with those without DPN. The prevalence of DPN was higher among males than among females: 30% of males had DPN compared with 18% of females (P = 0.02). The prevalence of DPN was twofold higher in current smokers (33%) compared with nonsmokers (15%) and former smokers (17%) (P = 0.01). […] [T]he prevalence of DPN was further assessed by 5-year increment of diabetes duration in individuals with T1D or T2D […]. There was an approximately twofold increase in the prevalence of DPN with an increase in duration of diabetes from 5–10 years to >10 years for both the T1D group (5–13%) (P < 0.0001) and the T2D group (19–36%) (P = 0.02). […] in an unadjusted logistic regression model, youth with T2D were four times more likely to develop DPN compared with those with T1D, and though this association was attenuated, it remained significant independent of age, sex, height, and glycemic control (OR 2.99 [1.91; 4.67], P < 0.001)”.

“The prevalence estimates for DPN found in our study for youth with T2D are similar to those in the Australian cohort (8) but lower for youth with T1D than those reported in the Danish (7) and Australian (8) cohorts. The nationwide Danish Study Group for Diabetes in Childhood reported a prevalence of 62% among 339 adolescents and youth with T1D (age 12–27 years, duration 9–25 years, and HbA1c 9.7 ± 1.7%) using the vibration perception threshold to assess DPN (7). The higher prevalence in this cohort compared with ours (62 vs. 7%) could be due to the longer duration of diabetes (9–25 vs. 5–13 years) and reliance on a single measure of neuropathy (vibration perception threshold) as opposed to our use of the MNSI, which includes vibration as well as other indicators of neuropathy. In the Australian study, Eppens et al. (8) reported abnormalities in peripheral nerve function in 27% of the 1,433 adolescents with T1D (median age 15.7 years, median diabetes duration 6.8 years, and mean HbA1c 8.5%) and 21% of the 68 adolescents with T2D (median age 15.3 years, median diabetes duration 1.3 years, and mean HbA1c 7.3%) based on thermal and vibration perception threshold. These data are thus reminiscent of the persistent inconsistencies in the definition of DPN, which are reflected in the wide range of prevalence estimates being reported.”

“The alarming rise in rates of DPN for every 5-year increase in duration, coupled with poor glycemic control and dyslipidemia, in this cohort reinforces the need for clinicians rendering care to youth with diabetes to be vigilant in screening for DPN and identifying any risk factors that could potentially be modified to alter the course of the disease (2830). The modifiable risk factors that could be targeted in this young population include better glycemic control, treatment of dyslipidemia, and smoking cessation (29,30) […]. The sharp increase in rates of DPN over time is a reminder that DPN is one of the complications of diabetes that must be a part of the routine annual screening for youth with diabetes.”

v. Diabetes and Hypertension: A Position Statement by the American Diabetes Association.

“Hypertension is common among patients with diabetes, with the prevalence depending on type and duration of diabetes, age, sex, race/ethnicity, BMI, history of glycemic control, and the presence of kidney disease, among other factors (13). Furthermore, hypertension is a strong risk factor for atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications. ASCVD — defined as acute coronary syndrome, myocardial infarction (MI), angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin — is the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. Numerous studies have shown that antihypertensive therapy reduces ASCVD events, heart failure, and microvascular complications in people with diabetes (48). Large benefits are seen when multiple risk factors are addressed simultaneously (9). There is evidence that ASCVD morbidity and mortality have decreased for people with diabetes since 1990 (10,11) likely due in large part to improvements in blood pressure control (1214). This Position Statement is intended to update the assessment and treatment of hypertension among people with diabetes, including advances in care since the American Diabetes Association (ADA) last published a Position Statement on this topic in 2003 (3).”

“Hypertension is defined as a sustained blood pressure ≥140/90 mmHg. This definition is based on unambiguous data that levels above this threshold are strongly associated with ASCVD, death, disability, and microvascular complications (1,2,2427) and that antihypertensive treatment in populations with baseline blood pressure above this range reduces the risk of ASCVD events (46,28,29). The “sustained” aspect of the hypertension definition is important, as blood pressure has considerable normal variation. The criteria for diagnosing hypertension should be differentiated from blood pressure treatment targets.

Hypertension diagnosis and management can be complicated by two common conditions: masked hypertension and white-coat hypertension. Masked hypertension is defined as a normal blood pressure in the clinic or office (<140/90 mmHg) but an elevated home blood pressure of ≥135/85 mmHg (30); the lower home blood pressure threshold is based on outcome studies (31) demonstrating that lower home blood pressures correspond to higher office-based measurements. White-coat hypertension is elevated office blood pressure (≥140/90 mmHg) and normal (untreated) home blood pressure (<135/85 mmHg) (32). Identifying these conditions with home blood pressure monitoring can help prevent overtreatment of people with white-coat hypertension who are not at elevated risk of ASCVD and, in the case of masked hypertension, allow proper use of medications to reduce side effects during periods of normal pressure (33,34).”

“Diabetic autonomic neuropathy or volume depletion can cause orthostatic hypotension (35), which may be further exacerbated by antihypertensive medications. The definition of orthostatic hypotension is a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min of standing when compared with blood pressure from the sitting or supine position (36). Orthostatic hypotension is common in people with type 2 diabetes and hypertension and is associated with an increased risk of mortality and heart failure (37).

It is important to assess for symptoms of orthostatic hypotension to individualize blood pressure goals, select the most appropriate antihypertensive agents, and minimize adverse effects of antihypertensive therapy.”

“Taken together, […] meta-analyses consistently show that treating patients with baseline blood pressure ≥140 mmHg to targets <140 mmHg is beneficial, while more intensive targets may offer additional though probably less robust benefits. […] Overall, compared with people without diabetes, the relative benefits of antihypertensive treatment are similar, and absolute benefits may be greater (5,8,40). […] Multiple-drug therapy is often required to achieve blood pressure targets, particularly in the setting of diabetic kidney disease. However, the use of both ACE inhibitors and ARBs in combination is not recommended given the lack of added ASCVD benefit and increased rate of adverse events — namely, hyperkalemia, syncope, and acute kidney injury (7173). Titration of and/or addition of further blood pressure medications should be made in a timely fashion to overcome clinical inertia in achieving blood pressure targets. […] there is an absence of high-quality data available to guide blood pressure targets in type 1 diabetes. […] Of note, diastolic blood pressure, as opposed to systolic blood pressure, is a key variable predicting cardiovascular outcomes in people under age 50 years without diabetes and may be prioritized in younger adults (46,47). Though convincing data are lacking, younger adults with type 1 diabetes might more easily achieve intensive blood pressure levels and may derive substantial long-term benefit from tight blood pressure control.”

“Lifestyle management is an important component of hypertension treatment because it lowers blood pressure, enhances the effectiveness of some antihypertensive medications, promotes other aspects of metabolic and vascular health, and generally leads to few adverse effects. […] Lifestyle therapy consists of reducing excess body weight through caloric restriction, restricting sodium intake (<2,300 mg/day), increasing consumption of fruits and vegetables […] and low-fat dairy products […], avoiding excessive alcohol consumption […] (53), smoking cessation, reducing sedentary time (54), and increasing physical activity levels (55). These lifestyle strategies may also positively affect glycemic and lipid control and should be encouraged in those with even mildly elevated blood pressure.”

“Initial treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACE inhibitors (65,66), angiotensin receptor blockers (ARBs) (65,66), thiazide-like diuretics (67), or dihydropyridine CCBs (68). For patients with albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g creatinine), initial treatment should include an ACE inhibitor or ARB in order to reduce the risk of progressive kidney disease […]. In the absence of albuminuria, risk of progressive kidney disease is low, and ACE inhibitors and ARBs have not been found to afford superior cardioprotection when compared with other antihypertensive agents (69). β-Blockers may be used for the treatment of coronary disease or heart failure but have not been shown to reduce mortality as blood pressure–lowering agents in the absence of these conditions (5,70).”

vi. High Illicit Drug Abuse and Suicide in Organ Donors With Type 1 Diabetes.

“Organ donors with type 1 diabetes represent a unique population for research. Through a combination of immunological, metabolic, and physiological analyses, researchers utilizing such tissues seek to understand the etiopathogenic events that result in this disorder. The Network for Pancreatic Organ Donors with Diabetes (nPOD) program collects, processes, and distributes pancreata and disease-relevant tissues to investigators throughout the world for this purpose (1). Information is also available, through medical records of organ donors, related to causes of death and psychological factors, including drug use and suicide, that impact life with type 1 diabetes.

We reviewed the terminal hospitalization records for the first 100 organ donors with type 1 diabetes in the nPOD database, noting cause, circumstance, and mechanism of death; laboratory results; and history of illicit drug use. Donors were 45% female and 79% Caucasian. Mean age at time of death was 28 years (range 4–61) with mean disease duration of 16 years (range 0.25–52).”

“Documented suicide was found in 8% of the donors, with an average age at death of 21 years and average diabetes duration of 9 years. […] Similarly, a type 1 diabetes registry from the U.K. found that 6% of subjects’ deaths were attributed to suicide (2). […] Additionally, we observed a high rate of illicit substance abuse: 32% of donors reported or tested positive for illegal substances (excluding marijuana), and multidrug use was common. Cocaine was the most frequently abused substance. Alcohol use was reported in 35% of subjects, with marijuana use in 27%. By comparison, 16% of deaths in the U.K. study were deemed related to drug misuse (2).”

“We fully recognize the implicit biases of an organ donor–based population, which may not be […’may not be’ – well, I guess that’s one way to put it! – US] directly comparable to the general population. Nevertheless, the high rate of suicide and drug use should continue to spur our energy and resources toward caring for the emotional and psychological needs of those living with type 1 diabetes. The burden of type 1 diabetes extends far beyond checking blood glucose and administering insulin.”


January 10, 2018 - Posted by | Cardiology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology, Psychiatry, Studies

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