Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). Significance: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments

PRIMARY AND SECONDARY PREVENTION OF HEPATITIS C VIRUS AMONG RURAL APPALACHIAN PEOPLE WHO USE DRUGS

Hepatitis C virus (HCV) remains a major cause of morbidity and mortality worldwide, with 3% of the global population chronically infected. Clinical impacts in the United States are projected to increase for two decades, and mortality attributed to HCV now exceeds HIV. Injection drug use (IDU) is the most common route of transmission in the developed world. Advances in treatment offer hope of mitigating HCV impacts, but substantial barriers obstruct people who inject drugs (PWID) from receiving care, particularly in medically underserved regions including Central Appalachia. This study assessed IDU paraphernalia sharing longitudinally over 24 months in a sample of 283 rural PWID recruited by respondent‐driven sampling. Medical follow‐up among 254 seropositive participants was also assessed using discrete‐time survival analysis. HCV‐positive screening was associated with reduced IDU sharing frequency 18 months after testing compared to seronegative participants (adjusted OR [aOR]=1.4, 95% confidence interval [CI]: 1.0‐1.9), but this effect was not sustained. HCV‐positive participants were less likely to cease IDU 6 months after testing (aOR=0.4, 95% CI: 0.2‐0.7). Predictors negatively associated with decreased IDU sharing included recent unprotected sex, sedative use, and frequency of prescription opioid IDU; protective associations included female gender and religious affiliation. IDU cessation was negatively associated with ever being incarcerated, recent unprotected sex with PWID, heavy alcohol use, lifetime use of OxyContin®, and baseline frequency of prescription opioid IDU; protective associations included number of dependents, receiving disability payments, and substance abuse treatment. Drug‐specific associations decreasing IDU cessation included recent illicit use of OxyContin®, other oxycodone, and cocaine. 150 of 254 (59%) seropositive participants saw a clinician after HCV‐positive screening and counseling, 35 (14%) sought treatment, and 21 (8%) received treatment. Positive predictors of following up with a clinician following testing and counseling included health insurance, internet access, past substance abuse treatment, generalized anxiety disorder, and recent marijuana use. Factors decreasing odds of follow‐up included major depression, lifetime illicit methadone use, and recent legal methadone. These analyses shed valuable light on determinants of behavior impacting primary and secondary HCV prevention. Integrated, multidisciplinary approaches are recommended to meaningfully impact epidemic levels of HCV among rural PWID in Eastern Kentucky

Preferred providers, health insurance and primary health care in Chile

PhDReforms in the early 1980s created Chile's mixed system of health care provision and finance. Since then Chileans have had to choose between a statesubsidised public health insurance system or the private health plans offered by several insurance companies. In the public system, users may be restricted to the public facility network, with no choice of doctor or medical centre, or they may opt for a free choice mode (preferred providers), which lets them choose both doctor and place of attention. Private insurance providers offer a wide variety of health plans, giving the customer a reasonable range of care options. Although this public-private mix has now been operating for more than 20 years, there has been no empirical study of the factors determining the choice of the preferred providers' mode by public beneficiaries. Likewise, few studies have looked at the determinants in the choice between public and private insurance, and the relationship between the latter choice and the use of health services. The first two empirical chapters of this thesis look at the determinants of these sources of choice, using different econometric tools: the choice of preferred providers is examined using a logit model; the analysis into the choice between public and private insurance uses a probit model; and the impact of holding private insurance as a factor in determining use of health services is estimated through a two-stage tobit model. A further significant aspect of the reforms of the '80s was the process of decentralisation for primary health care provision. Since then a substantial part of preventive health care and promotion occurs locally, and among these services children's health checks are an important policy objective. To encourage attendance parents are given free food supplements if they keep to the timetable for their child's check-ups. However these free food handouts partially account for attendance at the check-ups. Thus the final empirical chapter of the thesis uses a probabilistic model to look at the monetary and non-monetary factors that lead parents to request health checks for their children

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations. METHODS: We assayed myosin ATP binding to define the proportion of myosins in the super relaxed state (SRX) conformation or the disordered relaxed state (DRX) conformation in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology, we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants of unknown clinical significance that were identified in patients with HCM, predicted functional consequences and associations with heart failure and arrhythmias. RESULTS: Myosins undergo physiological shifts between the SRX conformation that maximizes energy conservation and the DRX conformation that enables cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacological modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased the proportion of myosins in the SRX conformation, whereas pathogenic variants destabilized these and increased the proportion of myosins in the DRX conformation, which enhanced cardiomyocyte contractility, but impaired relaxation and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify variants of unknown clinical significance, we showed that the variants that destabilized myosin conformations were associated with higher rates of heart failure and arrhythmias in patients with HCM. CONCLUSIONS: Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy-conserving states promotes contractile abnormalities, morphological and metabolic remodeling, and adverse clinical outcomes in patients with HCM. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in patients with HCM

Planning clinically relevant biomarker validation studies using the "number needed to treat" concept

Purpose: Despite an explosion of translational research to exploit biomarkers in diagnosis, prediction and prognosis, the impact of biomarkers on clinical practice has been limited. The elusiveness of clinical utility may partly originate when validation studies are planned, from a failure to articulate precisely how the biomarker, if successful, will improve clinical decision-making for patients. Clarifying what performance would suffice if the test is to improve medical care makes it possible to design meaningful validation studies. But methods for tackling this part of validation study design are undeveloped, because it demands uncomfortable judgments about the relative values of good and bad outcomes resulting from a medical decision. Methods: An unconventional use of "number needed to treat" (NNT) can structure communication for the trial design team, to elicit purely value-based outcome tradeoffs, conveyed as the endpoints of an NNT "discomfort range". The study biostatistician can convert the endpoints into desired predictive values, providing criteria for designing a prospective validation study. Next, a novel "contra-Bayes" theorem converts those predictive values into target sensitivity and specificity criteria, to guide design of a retrospective validation study. Several examples demonstrate the approach. Conclusion: In practice, NNT-guided dialogues have contributed to validation study planning by tying it closely to specific patient-oriented translational goals. The ultimate payoff comes when the report of the completed study includes motivation in the form of a biomarker test framework directly reflecting the clinical decision challenge to be solved. Then readers will understand better what the biomarker test has to offer patients

Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Abstract Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7\%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1\%) was not significant. The rates of ADRs were highest for topiramate (45.5\%) and valproate (37.5\%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2 vs 92.6\%, P = 0.001). Significance In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments

Higher education reform: getting the incentives right

This study is a joint effort by the Netherlands Bureau for Economic Policy Analysis (CPB) and the Center for Higher Education Policy Studies. It analyses a number of `best practices¿ where the design of financial incentives working on the system level of higher education is concerned. In Chapter 1, an overview of some of the characteristics of the Dutch higher education sector is presented. Chapter 2 is a refresher on the economics of higher education. Chapter 3 is about the Australian Higher Education Contribution Scheme (HECS). Chapter 4 is about tuition fees and admission policies in US universities. Chapter 5 looks at the funding of Danish universities through the so-called taximeter-model, that links funding to student performance. Chapter 6 deals with research funding in the UK university system, where research assessments exercises underlie the funding decisions. In Chapter 7 we study the impact of university-industry ties on academic research by examining the US policies on increasing knowledge transfer between universities and the private sector. Finally, Chapter 8 presents food for thought for Dutch policymakers: what lessons can be learned from our international comparison