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In nonalcoholic fatty liver disease (NAFLD) the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well-characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2-4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported. Funding Agencies|ALF Grants, Region Ostergotland; Astra Zeneca; Forskningsradet i Sydostra Sverige

Alzheimer’s disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

Results from two long-term studies (ROADMAP and ORIENT) indicated a numerical imbalance in the number of cardiovascular deaths between the olmesartan medoxomil (OM) and placebo groups. Our objective was to conduct an individual patient data meta-analysis to provide more complete information regarding OM-associated cardiovascular risks and/or benefits. We created an integrated database based on 191 clinical trials from the OM development program. Events were identified and adjudicated by an independent, blinded clinical events committee. The incidence of major cardiovascular events and total mortality for OM versus placebo/active control were evaluated, and the effect of OM on cardiovascular mortality (main endpoint of interest) and morbidity was calculated using a two-stage approach (Tian method). A total of 46 studies (~27,000 patients) met the US FDA-specified inclusion criteria (phase II–IV randomized, double-blind, placebo- or active-controlled studies [OM-based monotherapy or combination, double-blind period ≥28 days] and adult patients). The incidence of known adjudicated endpoints in the analysis of all studies combined was low among OM (0.11–0.53 %) and placebo/active control (0.08–0.76 %) groups. For cardiovascular mortality, the estimated risk difference (OM vs. control) was 0.00070 (95 % confidence interval [CI] −0.0011 to 0.0024; p = 0.60); the risk difference for each endpoint was

Importance Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. Objective To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. Design, Setting, and Participants AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. Interventions Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. Main Outcomes and Measures The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. Results Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. Conclusions and Relevance Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. Trial Registration ClinicalTrials.gov identifiers:NCT02245737andNCT02783573

The extent to which liability costs cause physicians to restrict their scope of practice or cease practicing is controversial in policy debates over malpractice “crises.” We used insuranc...

Subjective tinnitus is the perception of sound in the absence of a corresponding external sound for which there is no known medical etiology. For a minority of individuals with tinnitus, the condition impacts their ability to lead a normal lifestyle and is severely debilitating. There is no known cure for tinnitus, so current therapy focuses on reducing the effect of tinnitus on the patient’s quality of life. Tinnitus retraining therapy (TRT) uses nonpsychiatric tinnitus-specific educational counseling and sound therapy in a habituation-based protocol to reduce the patient’s tinnitus-evoked negative reaction to, and awareness of, the tinnitus, with the ultimate goal of reducing the tinnitus impact on the patient’s quality of life. Some studies support the efficacy of TRT, but no trial to date has compared TRT with the current standard of care or evaluated the separate contributions of TRT counseling and sound therapy. The Tinnitus Retraining Therapy Trial (TRTT) is a randomized, double-blind, placebo-controlled, multicenter trial for individuals with intolerable tinnitus. The TRTT is enrolling active-duty and retired military personnel and their dependents with functionally adequate hearing sensitivity and severe tinnitus at US Air Force, Navy, and Army medical centers. Eligible study participants are randomized to TRT, partial TRT, or standard care to determine the efficacy of TRT and its components (TRT counseling and sound therapy). The primary outcome is change in score on the Tinnitus Questionnaire assessed longitudinally between baseline and follow-up (3, 6, 12, and 18 months following treatment). Secondary outcomes include subscale score changes in the Tinnitus Questionnaire, overall and subscale score changes in the Tinnitus Functional Index and Tinnitus Handicap Inventory, and change in the visual analog scale of the TRT Interview Form. Audiological outcomes include tinnitus pitch and loudness match and measures of loudness discomfort levels. The incidence of depression as a safety measure is assessed at each visit using the Beck Depression Inventory Fast Screen. Clinicaltrials.gov NCT01177137 .

Non-inferiority trials test whether a new product is not unacceptably worse than a product already in use. This paper introduces concepts related to non-inferiority, and discusses the regulatory views of both the European Medicines Agency and the United States Food and Drug Administration.

Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments.After an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898.All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p0.0001 for all).Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.

Understanding how long-term clinical outcomes relate to short-term response to therapy is an important topic of research with a variety of applications. In HIV, early measures of viral RNA levels are known to be a strong prognostic indicator of future viral load response. However, mutations observed in the high-dimensional viral genotype at an early time point may change this prognosis. Unfortunately, some subjects may not have a viral genetic sequence measured at the early time point, and the sequence may be missing for reasons related to the outcome. Complete-case analyses of missing data are generally biased when the assumption that data are missing completely at random is not met, and methods incorporating multiple imputation may not be well-suited for the analysis of high-dimensional data. We propose a semiparametric multiple testing approach to the problem of identifying associations between potentially missing high-dimensional covariates and response. Following the recent exposition by Tsiatis, unbiased nonparametric summary statistics are constructed by inversely weighting the complete cases according to the conditional probability of being observed, given data that is observed for each subject. Resulting summary statistics will be unbiased under the assumption of missing at random. We illustrate our approach through an application to data from a recent AIDS clinical trial, and demonstrate finite sample properties with simulations.

Viral genotype data aid in understanding the development of antiretroviral drug resistance and in identifying appropriate treatments. Using HIV-1 protease sequences and measures of in vitro sensitivity to the drug amprenavir, we develop a novel statistical approach that can be used to investigate combinations of mutations that alter drug susceptibility. Our method is based on the use of order statistics whose null distributions are estimated through resampling and used for formal hypothesis testing. We present a step-down testing method that preserves the overall family-wise error rate in finite samples via an application of the monotonicity condition of Romano and Wolf. Simulations demonstrate that the power of this new approach is comparable to a traditional resampling method; however, this approach can also be used as a visual diagnostic that may be informative even when specified hypotheses are not rejected, for example, in suggesting candidate regression models. Analysis of the data from the Stanford HIV database shows that while M46I/L mutations are associated with drug resistance, addition of the L88D/S mutation leads to hypersusceptible virus. Further addition of T90M/L mutations results in highly resistant virus. Use of this order statistics method allows the investigation of how mutations act in the presence of others and may suggest mechanisms by which resistance occurs or is reversed through the accumulation of mutations.

The extent to which liability costs cause physicians to restrict their scope of practice or cease practicing is controversial in policy debates over malpractice "crises." We used insurance department administrative data to analyze specialist physician scope-of-practice changes and exits in Pennsylvania in 1993-2002. In most specialties the proportions of high-risk specialists restricting their scope of practice did not increase during the crisis; however, the supply of obstetrician-gynecologists decreased by 8 percent in the three years following premium increases in 1999. We discuss methodological issues that could explain the disparate findings regarding physician supply effects in studies using administrative data sets and survey data.

Standard methods for computing prediction intervals in nonlinear regression can be effectively applied to neural networks when the number of training points is large. Simulations show, however, that these methods can generate unreliable prediction intervals on smaller datasets when the network is trained to convergence. Stopping the training algorithm prior to convergence, to avoid overfitting, reduces the effective number of parameters but can lead to prediction intervals that are too wide. We present an alternative approach to estimating prediction intervals using weight decay to fit the network and show via a simulation study that this method may be effective in overcoming some of the shortcomings of the other approaches.