Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Author Correction:Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article

AIDS Susceptibility in a Migrant Population: Perception and Behavior

Within the framework of the Health Belief Model, this paper examines correlates of perception of AIDS susceptibility among 846 drug-using migrant farm workers and their sex partners. Significant but relatively small differences by ethnicity and gender were found. The data showed a consistent significant statistical relationship between frequency of drug use, high- risk sexual behavior, and perception of AIDS susceptibility. Perception of AIDS susceptibility was significantly related to a subsequent reduction in sexual risk behaviors. Consistent with the Health Belief Model, the data suggest that increasing perception of AIDS susceptibility may be an important motivator in reducing high-risk behaviors

Association of sleep-related problems with CKD in the United States, 2005-2008

Background: Sleep-related problems, which have been associated with poor health outcomes, have not been investigated thoroughly in people with chronic kidney disease (CKD). We examined the prevalence of a variety of sleep-related problems in persons with and without CKD. Study Design: National cross-sectional survey (National Health and Nutrition Examination Survey 2005-2008). Setting & Participants: Community-based survey of 9,110 noninstitutionalized US civilian residents 20 years or older. Predictor: CKD, defined as estimated glomerular filtration rate (eGFR) of 15-59 mL/min/1.73 m 2 (stages 3 and 4) or eGFR \u3c60 mL/min/1.73 m 2 and albumin-creatinine ratio \u3c30 mg/g (stages 1 and 2). Outcome: Sleep quality, defined using self-report in a multi-item sleep questionnaire including items from previously validated instruments. Measurements: Albuminuria and eGFR assessed from urine and blood samples; sleep, demographics, and comorbid conditions assessed using a standardized questionnaire. Results: Inadequate sleep (≤6 hours per night) differed by CKD severity (37.4%, 43.0%, and 30.9% for no CKD, CKD stages 1 and 2, and CKD stages 3 and 4, respectively; P = 0.003). Frequent sleeping pill use (8.4%, 9.9%, and 16.6%), leg symptoms (39.2%, 48.0%, and 50.9%), and nocturia (20.9%, 35.2%, and 43.6%; P \u3c 0.001 for all) also differed by CKD severity. After adjustment for age, sex, race/ethnicity, obesity, diabetes, and cardiovascular disease, the prevalence of these sleep-related problems remained higher in people with CKD stages 1 and 2 relative to no CKD. Most other measures of sleep quality, disorder, and functional outcomes did not differ by CKD. Limitations: Inability to establish causality and possible unmeasured confounding. Conclusion: Providers should be aware of early sleep-related CKD manifestations, including inadequate sleep, leg symptoms, and nocturia, and of the high rate of reported sleep medication use in this population. © 2011 National Kidney Foundation, Inc

Process evaluation of an intervention to test the effectiveness of foam border dressings in preventing hospital-acquired sacral pressure injuries (the EEPOC trial): A protocol

Background: Prophylactic foam border dressings are recommended for high-risk patients in addition to standard pressure injury prevention protocols despite limited high-quality evidence regarding their effectiveness. This protocol describes the process evaluation that will be undertaken alongside a multisite randomised controlled trial investigating the clinical and cost-effectiveness of these dressings in reducing hospital-acquired sacral pressure injury incidence. Methods: This theory informed parallel process evaluation using qualitative and quantitative methods will be undertaken in medical and surgical units. To evaluate fidelity, recruitment, reach, dose delivered and received, and context, process data will include: research nurses' self-reported adherence to intervention protocols; semi-structured interviews with participants and research nurses and focus groups with nursing staff; participants' satisfaction and comfort with the dressings and perceived level of participation in pressure injury prevention; and nurses’ attitudes toward pressure injury prevention. The proportion of the target population recruited, participant characteristics, and adherence to intervention protocols will be reported using descriptive statistics. Chi square or t-tests will compare differences in demographic characteristics between groups, and non-participants, and multivariate modelling will investigate potential moderators on the trial outcomes. Analysis of qualitative data will be guided by the Framework Method, which provides a clear, systematic process for developing themes. Discussion: This process evaluation will provide valuable insights into mechanisms of impact and contextual and moderating factors influencing trial outcomes. Process data will enhance reproducibility of the intervention and trustworthiness of findings, and inform clinicians, researchers, and policy makers about the extent to which foam border dressings can be feasibly implemented in clinical practice. Trial registration: ACTRN12619000763145p

Repositioning for pressure injury prevention in adults: An abridged Cochrane systematic review and meta-analysis.

Background: A pressure injury is an area of localised damage to the skin and underlying tissues. Patient repositioning is an important prevention strategy, as those with limited mobility are at increased risk of developing pressure injury. Objectives: To assess the clinical and cost-effectiveness of repositioning schedules on the prevention of pressure injury in adults. Design: Systematic review and meta-analysis. Data sources: The Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials; MEDLINE (Ovid); Embase (Ovid) and Cumulative Index of Nursing and Allied Health Literature Plus (EBSCO) were searched in February 2019. No restrictions were applied to language or date of publication. Review methods: Studies were eligible if they were randomised controlled trials including cluster trials, published or unpublished, and undertaken in any healthcare setting that assessed the clinical and/or cost effectiveness of repositioning schedules for prevention of pressure injury in adults. Methodological quality of the studies was independently assessed by three authors. Heterogeneity between studies was assessed using the I2 statistic, and the pooled risk ratios along with their 95% confidence intervals were estimated using either fixed and random effects models, as indicated. Grading of Recommendations Assessment, Development and Evaluation was used to appraise the certainty of evidence. Results: Eight eligible trials involving 3,941 participants published between 2004 and 2018 were identified. Trials compared either different repositioning frequencies or positioning regimens. Three trials (1074 participants) compared 2-hourly with 4-hourly repositioning (risk ratio 1.06, 95% confidence interval 0.80 to 1.41; I2 = 45%). Two other trials (252 participants) compared a 30-degree tilt with a 90-degree tilt (risk ratio0.62, 95% confidence interval 0.10 to 3.97; I2 =69%). Only two trials included economic analyses, both amongst nursing home residents. One study estimated the costs of repositioning to be Canadian dollars $11.05 and Canadian dollars$16.74 less per resident per day for the 3-hourly or 4-hourly regimens, respectively, when compared to 2-hourly regimen. The second study reported 3-hourly repositioning using a 30-degree tilt to cost €46.50 (95% confidence interval €1.25 to €74.60) less per patient in nursing time compared with 6-hourly repositioning with a 90-degree lateral rotation. Conclusion: It remains unclear which repositioning frequencies or positions are most effective in preventing pressure injury in adults. There is limited evidence to support the cost effectiveness of repositioning frequencies and positions

Urea Derivatives of 2‑Aryl-benzothiazol-5-amines: A New Class of Potential Drugs for Human African Trypanosomiasis

A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. <b>2016</b>, 24, 2451–2465) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)­ethyl-4-phenylthiazole (<b>1</b>), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (<i>S</i>)-2-(3,4-difluorophenyl)-5-(3-fluoro-<i>N</i>-pyrrolidylamido)­benzothiazole (<b>57</b>) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease