Search

Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

When the COVID-19 virus first arrived in the United States in early 2020, many epidemiologists and public health officers counseled for shutdowns and advised policymakers to prepare for a major pandemic. In 2020, though, US society was rife with major political and cultural divides. Some elected leaders promoted policies at odds with the experts, and many people refused to heed the public health-based communications about the coming pandemic. Additionally, the capacity to respond to a pandemic was distributed in the country in a highly unequal fashion. This paper analyzes the noteworthy geopolitical patterns of COVID-19 illnesses, subsequent demands on hospitals, and resulting deaths. This description is based on a snapshot of archival data gathered in the midst of the pandemic during late January and early February of 2021. Demographic data, indicators of political party support, indicators of citizen attitudes, and public health compliance behaviors are combined in a multivariate analysis to explain COVID-19 outcomes at the local government (county) level. The analysis suggests strongly that regional political culture and local demographics played a substantial role in determining the severity of the public health impact of the COVID-19 pandemic.当COVID‐19病毒于2020年初首次传入美国时，许多流行病学家和公共卫生官员建议实行关闭措施，并建议政策制定者为大流行做好准备。不过，2020年的美国社会充斥着重大的政治分歧和文化分歧。一些当选领导人推行的政策与专家意见相左，并且许多人忽视了有关即将到来的大流行的公共卫生传播。此外，应对大流行的能力在该国以高度不平等的方式进行分配。本文分析了值得注意的COVID‐19地缘政治模式、对医院的需求量以及由此导致的死亡数。该描述基于2021年1月下旬和2月上旬大流行期间收集的档案数据简介。人口统计数据、政党支持指标、公民态度指标以及公共卫生合规行为被用于多变量分析，以期解释地方政府（县级）的COVID‐19影响。分析强烈表明，区域政治文化和地方人口统计数据在“确定 COVID‐19大流行对公共卫生影响的严重程度”方面发挥了重要作用。.Cuando el virus COVID‐19 llegó por primera vez a los Estados Unidos a principios de 2020, muchos epidemiólogos y funcionarios de salud pública recomendaron cierres y aconsejaron a los legisladores que se prepararan para una gran pandemia. Sin embargo, en 2020, la sociedad estadounidense estaba plagada de grandes divisiones políticas y culturales. Algunos líderes electos promovieron políticas en desacuerdo con los expertos, y muchas personas se negaron a prestar atención a las comunicaciones basadas en la salud pública sobre la próxima pandemia. Además, la capacidad de respuesta ante una pandemia se distribuyó en el país de manera muy desigual. Este documento analiza los patrones geopolíticos notables de las enfermedades de COVID‐19, las demandas posteriores en los hospitales y las muertes resultantes. Esta descripción se basa en una instantánea de los datos de archivo recopilados en medio de la pandemia a fines de enero y principios de febrero de 2021. Los datos demográficos, los indicadores de apoyo a los partidos políticos, los indicadores de las actitudes de los ciudadanos y los comportamientos de cumplimiento de la salud pública se combinan en un modelo multivariado. análisis para explicar los resultados de COVID‐19 a nivel del gobierno local (condado). El análisis sugiere fuertemente que la cultura política regional y la demografía local desempeñaron un papel importante en la determinación de la gravedad del impacto de la pandemia de COVID‐19 en la salud pública.

Interview Date: November 15, 2019Editorial Note: Founded in 2015 by Michael Marks (former CEO of Flextronics and Interim CEO of Tesla), Fritz Wolff (executive chairman of the Wolff Company), and Ji...

The election of Donald Trump in 2016 has renewed concerns about nonrational decision making in American government. One view of the decision-making process, bounded rationality, is that decisions b...

The advent of new technology presents new opportunities for forwarding thinking law enforcement administrators and new legal challenges for the courts. One such new technology is portable mass spec...

The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis]. In the phase I study, plasma exposures (area under the concentration–time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration–time curve over the 24-h dosing interval; AUCtau) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant. No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.