Alcohol dependence is a common disorder associated with significant morbidity and mortality. Naltrexone, an opioid antagonist, has been shown to be effective for treatment of alcohol dependence. ...However, adherence to daily oral pharmacotherapy can be problematic, and clinical acceptance and utility of oral naltrexone have been limited.
To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients.
A 6-month, randomized, double-blind, placebo-controlled trial conducted between February 2002 and September 2003 at 24 US public hospitals, private and Veterans Administration clinics, and tertiary care medical centers. Of the 899 individuals screened, 627 who were diagnosed as being actively drinking alcohol-dependent adults were randomized to receive treatment and 624 received at least 1 injection.
An intramuscular injection of 380 mg of long-acting naltrexone (n = 205) or 190 mg of long-acting naltrexone (n = 210) or a matching volume of placebo (n = 209) each administered monthly and combined with 12 sessions of low-intensity psychosocial intervention.
The event rate of heavy drinking days in the intent-to-treat population.
Compared with placebo, 380 mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days (P = .02) corrected and 190 mg of naltrexone resulted in a 17% decrease (P = .07). Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome, with men and those with lead-in abstinence both exhibiting greater treatment effects. Discontinuation due to adverse events occurred in 14.1% in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group. Overall, rate and time to treatment discontinuation were similar among treatment groups.
Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during 6 months of therapy. These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence.
Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed ...correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD
) synthesis, consistent with a potential role for the essential cofactor NAD
in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various polyadenosine 5'-diphosphate (ADP)-ribose polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD
and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD
levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD
biosynthesis. Replenishing NAD
stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr
mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD
repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD
may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.
Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).
To determine the effect of ...intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS.
The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018.
Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours.
The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours.
Among 167 randomized patients (mean SD age, 54.8 years 16.7; 90 men 54%), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group 3 points and from 10.3 to 6.8 in the placebo group 3.5 points; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours.
In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.
ClinicalTrials.gov Identifier: NCT02106975.
Marine plastic pollution has emerged as one of the most pressing environmental challenges of our time. Although there has been a surge in global investment for implementing interventions to mitigate ...plastic pollution, there has been little attention given to the cost of these interventions. We developed a decision support framework to identify the economic, social, and ecological costs and benefits of plastic pollution interventions for different sectors and stakeholders. We calculated net cost as a function of six cost and benefit categories with the following equation: cost of implementing an intervention (direct, indirect, and nonmonetary costs) minus recovered costs and benefits (monetary and nonmonetary) produced by the interventions. We applied our framework to two quantitative case studies (a solid waste management plan and a trash interceptor) and four comparative case studies, evaluating the costs of beach cleanups and waste‐to‐energy plants in various contexts, to identify factors that influence the costs of plastic pollution interventions. The socioeconomic context of implementation, the spatial scale of implementation, and the time scale of evaluation all influence costs and the distribution of costs across stakeholders. Our framework provides an approach to estimate and compare the costs of a range of interventions across sociopolitical and economic contexts.
Un Marco de Decisión para Estimar el Costo de Intervenciones en la Contaminación Marina por Plástico
Resumen
La contaminación marina por plásticos ha emergido como uno de los retos ambientales más prioritarios de nuestro tiempo. Mientras ha habido un aumento en la inversión global para implementar intervenciones para mitigar la contaminación por plásticos, se ha dado poca atención al costo de estas intervenciones. Desarrollamos un marco de soporte a las decisiones para identificar los costos y beneficios económicos, sociales y ecológicos de las intervenciones en la contaminación por plástico para diferentes sectores y partes interesadas. Calculamos el costo neto como una función de 6 categorías de costo y beneficio con la siguiente ecuación: costo de la implementación de una intervención (costos directos, indirectos y no monetarios) menos los costos y beneficios recuperados (monetarios y no monetarios) producidos por las intervenciones. Aplicamos nuestro marco a 2 estudios de caso cuantitativos (un plan de manejo de residuos sólidos y un interceptor de basura) y 4 casos de estudio comparativos evaluando los costos de limpieza de playas y plantas de transformación de desechos a energía en varios contextos para identificar los factores que influyen en los costos de las intervenciones de la contaminación por plástico. El contexto socioeconómico de la implementación, la escala espacial de la implementación y la escala de tiempo de evaluación influyen en los costos y distribución de costos entre las partes interesadas. Nuestro marco proporciona una aproximación para estimar y comparar los costos de una gama de intervenciones en contextos sociopolíticos y económicos.
抽象
摘要: 海洋塑料污染已成为本时代最紧迫的环境挑战之一。虽然全球在实施干预措施以减轻塑料污染方面的投资激增, 但很少有人关注这些干预措施的成本。我们开发了一个决策支持框架, 以确定塑料污染干预措施对不同部门和利益相关方在经济、社会和生态方面的成本和收益。我们计算净成本作为六种成本及收益类别之间的函数, 计算公式如下: 实施干预的成本 (直接、间接及非货币成本) 减去干预产生的回收成本和收益 (货币及非货币) 。我们将该框架应用于两个定量案例研究 (固体废物管理计划和垃圾拦截器) 和四个比较案例研究, 评估在不同环境下海滩清理和将垃圾转化为能源工厂的成本, 以确定影响塑料污染干预成本的因素。我们发现, 实施干预措施的社会经济背景、空间尺度和评估的时间尺度都会影响成本及成本在利益相关方之间的分配情况。我们的框架为估计和比较一系列跨社会政治和经济背景的干预措施成本提供了方法。【翻译: 胡怡思; 审校: 聂永刚】
Article impact statement: Identifying economic, social, and ecological costs and benefits of plastic pollution interventions supports conservation decision‐making.
Poverty and human capital development are inextricably linked and therefore research on human capital typically incorporates measures of economic well-being. In the context of randomized trials of ...health interventions, for example, such measures are used to: 1) assess baseline balance; 2) estimate covariate-adjusted analyses; and 3) conduct subgroup analyses. Many factors characterize economic well-being, however, and analysts often generate summary measures such as indices of household socio-economic status or wealth. In this paper, a household wealth index is developed and tested for participants in the cluster-randomized Sanitation, Hygiene, Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.
Building on the approach used in the Zimbabwe Demographic and Health Survey (ZDHS), we combined a set of housing characteristics, ownership of assets and agricultural resources into a wealth index using principal component analysis (PCA) on binary variables. The index was assessed for internal and external validity. Its sensitivity was examined considering an expanded set of variables and an alternative statistical approach of polychoric PCA. Correlation between indices was determined using the Spearman's rank correlation coefficient and agreement between quintiles using a linear weighted Kappa statistic. Using the 2015 ZDHS data, we constructed a separate index and applied the loadings resulting from that analysis to the SHINE study population, to compare the wealth distribution in the SHINE study with rural Zimbabwe.
The derived indices using the different methods were highly correlated (r>0.9), and the wealth quintiles derived from the different indices had substantial to near perfect agreement (linear weighted Kappa>0.7). The indices were strongly associated with a range of assets and other wealth measures, indicating both internal and external validity. Households in SHINE were modestly wealthier than the overall population of households in rural Zimbabwe.
The SHINE wealth index developed here is a valid and robust measure of wealth in the sample.
Inducible loss of gene function experiments are necessary to uncover mechanisms underlying development, physiology and disease. However, current methods are complex, lack robustness and do not work ...in multiple cell types. Here we address these limitations by developing single-step optimized inducible gene knockdown or knockout (sOPTiKD or sOPTiKO) platforms. These are based on genetic engineering of human genomic safe harbors combined with an improved tetracycline-inducible system and CRISPR/Cas9 technology. We exemplify the efficacy of these methods in human pluripotent stem cells (hPSCs), and show that generation of sOPTiKD/KO hPSCs is simple, rapid and allows tightly controlled individual or multiplexed gene knockdown or knockout in hPSCs and in a wide variety of differentiated cells. Finally, we illustrate the general applicability of this approach by investigating the function of transcription factors (OCT4 and T), cell cycle regulators (cyclin D family members) and epigenetic modifiers (DPY30). Overall, sOPTiKD and sOPTiKO provide a unique opportunity for functional analyses in multiple cell types relevant for the study of human development.
Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent ...cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke.
In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes.
The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval CI, 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10).
Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)
An anatomic transcriptional atlas of human glioblastoma Puchalski, Ralph B; Shah, Nameeta; Miller, Jeremy ...
Science (American Association for the Advancement of Science),
05/2018, Letnik:
360, Številka:
6389
Journal Article
Recenzirano
Odprti dostop
Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor's molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for ...diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.
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