Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial

IMPORTANCE: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. OBJECTIVE: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. INTERVENTIONS: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). MAIN OUTCOMES AND MEASURES: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. RESULTS: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001). CONCLUSIONS AND RELEVANCE: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01601704

Wellness and Multiple Sclerosis: The National MS Society Establishes a Wellness Research Working Group and Research Priorities

Background: People with multiple sclerosis (MS) have identified “wellness” and associated behaviors as a high priority based on “social media listening” undertaken by the National MS Society (i.e. the Society). Objective: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. Method: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. Results: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society’s Wellness Research Working Group. Conclusion: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences

Trophic Dynamics of the Boreal Forests of the Kluane Region

The trophic dynamics of the Yukon boreal forest have been under investigation at the Kluane Lake Research Station since 1973. We monitored and conducted experiments on the major species in this ecosystem, except the large mammals (for logistic reasons). The central problem has been to determine the causes of the 9 – 10 year cycle of snowshoe hares, and to achieve this we carried out several large-scale experiments manipulating food supplies, predator pressure, and soil nutrient availability to test hypotheses that food, predation, or habitat quality regulate populations. The hare cycle is driven top-down by predators, and most hares die because they are killed by predators. Predators also cause stress in female hares, and the stress response seems to be responsible for the loss of reproductive potential in the decline and low phases of the hare cycle. Many of the specialist predators and some herbivores in this ecosystem fluctuate with the hare cycle. Arctic ground squirrels do, but red squirrels do not, being linked closely to white spruce seed masting years. Small rodents fluctuate in numbers in two patterns. Red-backed voles and four species of Microtus voles have a 3 – 4 year cycle that seems to be driven by food supplies and social behaviour. Deer mice, in contrast, have fluctuated dramatically in the 38 years we have monitored them, but not cyclically. White spruce seed production varies with temperature and rainfall, but was not affected by adding nutrients in fertilizer. Global warming and reduced hare browsing in the last 20 years have helped to increase the abundance of shrubs in these forests. It will be challenging to predict how this system will change as climatic warming proceeds, because even closely related species in the same trophic level respond differently to perturbations. We recommend continued monitoring of the major species in these boreal forests.La dynamique trophique de la forêt boréale du Yukon fait l’objet d’une étude à la station de recherche du lac Kluane depuis 1973. Nous avons fait des expériences et surveillé les espèces importantes de cet écosystème, sauf en ce qui a trait aux principaux mammifères (pour des raisons de logistique). Le problème central a consisté à déterminer les causes du cycle de 9 à 10 ans du lièvre d’Amérique. Pour ce faire, nous avons effectué plusieurs expériences à grande échelle dans le cadre desquelles nous avons manipulé les disponibilités alimentaires, la pression exercée par les prédateurs et la disponibilité en nutriments dans le sol afin de mettre à l’épreuve les hypothèses selon lesquelles la nourriture, la prédation ou la qualité de l’habitat régularisent les populations. Le cycle du lièvre est dicté par les prédateurs de haut en bas, et la plupart des lièvres meurent parce qu’ils sont tués par les prédateurs. Par ailleurs, les prédateurs sont une source de stress chez les lièvres femelles, et la réaction au stress semble responsable de la perte de capacité de reproduction dans la phase du déclin et la phase basse du cycle du lièvre. Grand nombre des prédateurs spécialistes et certains herbivores de cet écosystème fluctuent en fonction du cycle du lièvre. C’est le cas du spermophile arctique, mais ce n’est pas le cas de l’écureuil roux, car il est étroitement lié aux années de paisson de graines d’épinette blanche. Le nombre de petits rongeurs fluctue en fonction de deux modèles. Le campagnol à dos roux et quatre espèces de campagnols Microtus ont un cycle de trois à quatre ans qui semble dicté par les disponibilités alimentaires et le comportement social, tandis que la souris sylvestre a connu d’énormes fluctuations pendant les 38 années qui ont fait l’objet d’une surveillance, sans toutefois afficher de cycles. La production de graines d’épinette blanche varie en fonction des températures et des chutes de pluie, mais n’a pas été influencée par l’ajout de nutriments au fertilisant. Le réchauffement planétaire et le broutage réduit des lièvres ces 20 dernières années ont aidé à accroître l’abondance d’arbustes dans ces forêts. Il sera difficile de prévoir comment ce système changera au fur et à mesure du réchauffement climatique, car même les espèces étroitement liées du même niveau trophique réagissent aux perturbations de manière différente. Nous recommandons la surveillance continue des principales espèces de ces forêts boréales

Using eye-tracking in applied linguistics and second language research

With eye-tracking technology the eye is thought to give researchers a window into the mind. Importantly, eye-tracking has significant advantages over traditional online processing measures: chiefly that it allows for more ‘natural’ processing as it does not require a secondary task, and that it provides a very rich moment-to-moment data source. In recognition of the technology’s benefits, an ever increasing number of researchers in applied linguistics and second language research are beginning to use it. As eye-tracking gains traction in the field, it is important to ensure that it is established in an empirically sound fashion. To do this it is important for the field to come to an understanding about what eye-tracking is, what eye-tracking measures tell us, what it can be used for, and what different eye-tracking systems can and cannot do. Further, it is important to establish guidelines for designing sound research studies using the technology. The goal of the current review is to begin to address these issues

Use of complementary and alternative medicine and breast cancer survival in the Health, Eating, Activity, and Lifestyle Study

PURPOSE: Use of complementary and alternative medicine (CAM) is common among breast cancer patients, but less is known about whether CAM influences breast cancer survival. METHODS: Health Eating, Activity, and Lifestyle (HEAL) Study participants (n = 707) were diagnosed with stage I-IIIA breast cancer. Participants completed a 30-month post-diagnosis interview including questions on CAM use (natural products such as dietary and botanical supplements, alternative health practices, and alternative medical systems), weight, physical activity, and comorbidities. Outcomes were breast cancer-specific and total mortality, which were ascertained from the Surveillance Epidemiology and End Results registries in Western Washington, Los Angeles County, and New Mexico. Cox proportional hazards regression models were fit to data to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for mortality. Models were adjusted for potential confounding by sociodemographic, health, and cancer-related factors. RESULTS: Among 707 participants, 70 breast cancer-specific deaths and 149 total deaths were reported. 60.2 % of participants reported CAM use post-diagnosis. The most common CAM were natural products (51 %) including plant-based estrogenic supplements (42 %). Manipulative and body-based practices and alternative medical systems were used by 27 and 13 % of participants, respectively. No associations were observed between CAM use and breast cancer-specific (HR 1.04, 95 % CI 0.61-1.76) or total mortality (HR 0.91, 95 % CI 0.63-1.29). CONCLUSION: Complementary and alternative medicine use was not associated with breast cancer-specific mortality or total mortality. Randomized controlled trials may be needed to definitively test whether there is harm or benefit from the types of CAM assessed in HEAL in relation to mortality outcomes in breast cancer survivors

3,4-Diaminopyridine Base Effectively Treats the Weakness of Lambert-Eaton Myasthenia

Introduction: 3,4-diaminopyridine has been used to treat Lambert Eaton myasthenia (LEM) for thirty years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double-blind placebo-controlled withdrawal study in LEM patients who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in Triple Timed Up-and-Go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM–related weakness (W-SAS). Results: 32 participants were randomized to continuous 3,4-DAP or placebo. None of the 14 receiving continuous 3,4-DAP had >30% deterioration in 3TUG time vs 72% of the 18 who tapered to placebo (p<0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (p<0.0001). Need for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM

Validation of the triple timed up‐and‐go test in Lambert‐Eaton myasthenia

Introduction There are no validated, practical, and quantitative measures of disease severity in Lambert‐Eaton myasthenia (LEM). Methods Data from the Effectiveness of 3,4‐Diaminopyridine in Lambert‐Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up‐and‐go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. Results The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4‐diaminopyridine free base. Worsening patient‐reported Weakness Self‐Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. Discussion The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM

The Piper Fatigue Scale-12 (PFS-12): psychometric findings and item reduction in a cohort of breast cancer survivors

Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study’s primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model)

Deriving clinically meaningful cut-scores for fatigue in a cohort of breast cancer survivors: a Health, Eating, Activity, and Lifestyle (HEAL) Study

PURPOSE: To empirically determine clinically meaningful cut-scores on the 0-10 response scale of the revised Piper Fatigue Scale (PFS-R) and its shorter version (PFS-12). Breast cancer survivors were classified (i.e., none, mild, moderate, or severe fatigue) based on the cut-scores, and relationships between these cut-scores and decrements in health-related quality of life (HRQOL) were examined. METHODS: A total of 857 breast cancer survivors, stages in situ-IIIa, from the Health, Eating, Activity, and Lifestyle (HEAL) Study were eligible. Survivors completed the PFS-R, SF-36, and a sexual health scale approximately 3 years after diagnosis. Multivariate analysis of covariance was used to examine five fatigue severity cut-score models, controlling for demographics, clinical characteristics, comorbidity, and antidepressant use. Multivariate regression was used to examine HRQOL decrements by cut-score category. RESULTS: Analyses supported two similar fatigue severity cut-score models for the PFS-R and PFS-12: Model A.) none (0), mild (1-3), moderate (4-6), and severe (7-10); and Model D.) none (0), mild (1-2), moderate (3-5), and severe (6-10). For every threshold increase in fatigue severity, clinically meaningful decrements in physical, mental, and sexual health scores were observed, supporting construct validity of the fatigue cut-scores. CONCLUSION: Standardized fatigue cut-scores may enhance interpretability and comparability across studies and populations and guide treating planning

Programmatic Evaluation of a Combined Antigen and Antibody Test for Rapid HIV Diagnosis in a Community and Sexual Health Clinic Screening Programme

Background A substantial proportion of HIV-infected individuals in the UK are unaware of their status and late presentations continue, especially in low prevalence areas. Fourth generation antigen/antibody rapid test kits could facilitate earlier diagnosis of HIV in non-clinical settings but lack data on performance under programmatic conditions. Methods and Findings We evaluated the performance of Determine HIV-1/2 Ag/Ab Combo Test (Determine Combo), a rapid test with indicators for both HIV antibodies and p24 antigen, in participants recruited from community outreach and hospital-based sexual health clinics. HIV infection was confirmed using laboratory enzyme-linked immunosorbent assay (EIA), Line Immuno Assay (LIA) and quantitative polymerase chain reaction (PCR). In total, 953 people underwent HIV testing. HIV antibody (Ab) prevalence was 1.8% (17/953). Four false positive rapid tests were identified: two antibody and two p24 antigen (Ag) reactions. Of participants diagnosed as HIV Ab positive, 2/17 (12%) were recent seroconverters based on clinical history and HIV antibody avidity test results. However, none of these were detected by the p24 antigen component of the rapid test kit. There were no other true positive p24 Ag tests. Conclusion These data lend support to an increasing body of evidence suggesting that 4th generation rapid HIV tests have little additional benefit over 3rd generation HIV kits for routine screening in low prevalence settings and have high rates of false positives. In order to optimally combine community-based case-finding among hard-to-reach groups with reliable and early diagnosis 3rd generation kits should be primarily used with laboratory testing of individuals thought to be at risk of acute HIV infection. A more reliable point of care diagnostic is required for the accurate detection of acute HIV infection under programmatic conditions