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Water quality surveillance can help to reduce waterborne diseases. Despite better access to safe drinking water in Sierra Leone, about a third of the population (3 million people) drink water from unimproved sources. In this cross-sectional study, we collected water samples from 15 standpipes and 5 wells and measured the physicochemical and bacteriological water quality, and the antimicrobial sensitivity of Escherichia coli (E. coli) in two communities in Freetown, Sierra Leone in the dry and wet seasons in 2021. All water sources were contaminated with E. coli, and all five wells and 25% of standpipes had at least an intermediate risk level of E. coli. There was no antimicrobial resistance detected in the E. coli tested. The nitrate level exceeded the WHO’s recommended standard (>10 parts per million) in 60% of the wells and in less than 20% of the standpipes. The proportion of samples from standpipes with high levels of total dissolved solids (>10 Nephelometric Turbidity Units) was much higher in the rainy season (73% vs. 7%). The level of water contamination is concerning. We suggest options to reduce E. coli contamination. Further research is required to identify where contamination of the water in standpipes is occurring.

Introduction: Good Infection prevention and control (IPC) is vital for tackling antimicrobial resistance and limiting health care-associated infections. We compared IPC performance before (2019) and during the COVID-19 (2021) era at the national IPC unit and all regional (4) and district hospitals (8) in Sierra Leone., Methods: Cross-sectional assessments using standardized World Health Organizations IPC checklists. IPC performance scores were graded as inadequate = 0-25%, basic = 25.1-50%, intermediate = 50.1-75%, and advanced = 75.1-100%., Results: Overall performance improved from 'basic' to 'intermediate' at the national IPC unit (41% in 2019 to 58% in 2021) and at regional hospitals (37% in 2019 to 54% in 2021) but remained 'basic' at district hospitals (37% in 2019 to 50% in 2021). Priority gaps at the national IPC unit included lack of: a dedicated IPC budget, monitoring the effectiveness of IPC trainings and health care-associated infection surveillance. Gaps at hospitals included no assessment of hospital staffing needs, inadequate infrastructure for IPC and lack of a well-defined monitoring plan with clear goals, targets and activities., Conclusion: Although there is encouraging progress in IPC performance, it is slower than desired in light of the COVID-19 pandemic. There is urgent need to mobilize political will, leadership and resources and make a quantum leap forward.

Energy diversification is a vital contribution to sustainable development. Many countries are accelerating the diversification of their energy mix to meet the challenges of the energy transition. This study aims to model and investigate the effects of energy diversification on the ecological footprint of production in Côte d'Ivoire. The study uses an autoregressive distributed lag model with structural breaks and covers the period 1971-2015. Energy diversification is measured by an "Energy Mix Concentration Index," a concentration indicator based on the Herfindahl-Hirschman Index. The results suggest that, in the short term, energy diversification reduces the ecological footprint of production in Côte d'Ivoire, and is conducive for environmental protection. In the long term, energy diversification also has a reducing effect on the ecological footprint of production up to a certain threshold where energy concentration increases the ecological footprint. The study finds that there is an optimal level of energy diversification that is ideal for achieving a lower impact of energy diversification activities and exploitation of energy production sources on the environment in Côte d'Ivoire. The commissioning of the Azito power plant in 1999, which produces electricity using natural gas, has also had a major impact, not only on the country's energy mix since then, but also on its ecological footprint of production., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Healthcare-associated infections (HAIs) result in millions of avoidable deaths or prolonged lengths of stay in hospitals and cause huge economic loss to health systems and communities. Primarily, HAIs spread through the hands of healthcare workers, so improving hand hygiene can reduce their spread. We evaluated hand hygiene practices and promotion across 13 public health hospitals (six secondary and seven tertiary hospitals) in the Western Area of Sierra Leone in a cross-sectional study using the WHO hand hygiene self-Assessment framework in May 2021. The mean score for all hospitals was 273 ± 46, indicating an intermediate level of hand hygiene. Nine hospitals achieved an intermediate level and four a basic level. More secondary hospitals 5 (83%) were at the intermediate level, compared to tertiary hospitals 4 (57%). Tertiary hospitals were poorly rated in the reminders in workplace and institutional safety climate domains but excelled in training and education. Lack of budgets to support hand hygiene implementation is a priority gap underlying this poor performance. These gaps hinder hand hygiene practice and promotion, contributing to the continued spread of HAIs. Enhancing the distribution of hand hygiene resources and encouraging an embedded culture of hand hygiene practice in hospitals will reduce HAIs.

The authorization of several high-efficacy vaccines for use against the novel SARS-CoV2 virus signals a transition in the global COVID-19 response. Vaccine acceptance is critical for pandemic control and has a variety of context- specific drivers that operate at the individual, group, and sociopolitical levels. Social and behavior change interventions can influence individual knowledge, attitudes, and intentions as well as community norms to facilitate widespread vaccine uptake. While considerable research has been done to explore vaccine confidence in high-income populations as well as with respect to childhood vaccinations, much work remains to be done in understanding attitudes and intentions in low and middle income countries for adult or novel vaccines. We conducted in-depth interviews with individuals who had recovered from COVID-19 (n = 8), people who had lost a family member to COVID-19 (n = 4), and health providers (n = 17). We also conducted focus group discussions with members of the general population (n = 24 groups) to explore social norms and community perceptions related to COVID-19, including prevention behaviors, stigma, and vaccines. Researchers collected data in Abidjan, Côte d'Ivoire, in November 2020. In considering whether to accept a future COVID-19 vaccine or not, individuals in the study weighed perceived risk of the vaccine against the severity of the disease. Perceived severity of rumored side effects or safety issues of vaccines were also a factor. Convenience was a secondary, albeit also important, consideration. While concerns about vaccine safety tended to produce an expressed intention to delay vaccination, conspiracy theories about those developing and promoting vaccines and their motives led people to say they would opt out entirely. Behavior change interventions must raise awareness and address misunderstandings about the purpose of vaccines, transparently communicate about vaccine safety and development processes, and engage trusted influencers to build an enabling environment for COVID-19 vaccine roll out., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to evaluate uptake and follow-up using internet-assisted population genetic testing (GT) for BRCA1/2 Ashkenazi Jewish founder pathogenic variants (AJPVs)., Methods: Across 4 cities in the United States, from December 2017 to March 2020, individuals aged ≥25 years with ≥1 Ashkenazi Jewish grandparent were offered enrollment. Participants consented and enrolled online with chatbot and video education, underwent BRCA1/2 AJPV GT, and chose to receive results from their primary care provider (PCP) or study staff. Surveys were conducted at baseline, at 12 weeks, and annually for 5 years., Results: A total of 5193 participants enrolled and 4109 (79.1%) were tested (median age = 54, female = 77.1%). Upon enrollment, 35.1% of participants selected a PCP to disclose results, and 40.5% of PCPs agreed. Of those tested, 138 (3.4%) were AJPV heterozygotes of whom 21 (15.2%) had no significant family history of cancer, whereas 86 (62.3%) had a known familial pathogenic variant. At 12 weeks, 85.5% of participants with AJPVs planned increased cancer screening; only 3.7% with negative results and a significant family history reported further testing., Conclusion: Although continued follow-up is needed, internet-enabled outreach can expand access to targeted GT using a medical model. Observed challenges for population genetic screening efforts include recruitment barriers, improving PCP engagement, and increasing uptake of additional testing when indicated., Competing Interests: Conflict of Interest Kenneth Offit reports being a founder and shareholder of AnaNeo Therapeutics Incorporated, which is not involved in diagnostic testing and played no role in the current study; Susan M. Domchek reports honoraria from AstraZeneca; Nadine Tung reports institutional research funding from AstraZeneca and Myriad Genetics; Judy E. Garber reports research support from Myriad Genetics, Ambry Genetics, and Invitae, leading 2 clinical trials for AstraZeneca, consulting for Helix Genetics, being on the Scientific Advisory Board of Konica Minolta, and receiving speaker’s honorarium from Clinical Care Options, LLC; Mark E. Robson reports research funding from Invitae; Yuri Fesko reports being employed by Quest Diagnostics and having Quest stock; Victoria Howell reports being employed by Quest Diagnostics; Kylin Boehler reports being employed by Quest Diagnostics and having Quest stock; and Jacob Heitler reports having an ownership stake in Lifelink Systems. All other authors declare no conflicts of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: Malaria is endemic to sub-Saharan African countries. Mass and routine distribution, promotion, and use of ITNs are critical components of malaria prevention programmes. Correct and consistent use of insecticide-treated mosquito nets (ITN) is an effective strategy for malaria prevention. To extend bed-net lifespan, the World Health Organization recommends folding or tying up ITNs when they are not in use. This study analyses factors associated with net care practices in three African countries., Methods: Researchers collected household data nationwide in Côte d'Ivoire, from the North and Far North regions of Cameroon, and from Port Loko and Bo districts in Sierra Leone, between 2018 and 2019. The dependent variable was respondents reporting that they fold or tie up their nets. The study adjusted for selected sociodemographic, ideational (psychosocial), and household variables using multilevel models. The analysis was limited to women of reproductive age and their male spouses/partners from households with at least one ITN: 2,940 respondents in Cameroon, 6,105 in Côte d'Ivoire, and 2,730 in Sierra Leone., Results: Among respondents, 50.2% in Cameroon, 52.0% in Côte d'Ivoire and 75.6% in Sierra Leone reported folding or tying up their net when it was not in use. In all three countries, the data showed significant clustering at both household and community levels, indicating the influence of factors operating at these levels on net-care behaviour. The odds of reporting the behaviour varied significantly by geographic unit in each country. Consistent use of nets was strongly correlated with net-care behaviour. Furthermore, five ideational variables were positively associated with the outcome behaviour in all three countries: positive attitude towards net care, perceived susceptibility for malaria, response-efficacy of ITNs, perceived self-efficacy for net use, and the perception that net use was a community norm. Additional significant ideational variables included positive attitudes towards net use (Cameroon and Côte d'Ivoire), perceived severity of malaria (Côte d'Ivoire), and interpersonal communication about malaria (Côte d'Ivoire)., Conclusions: The study identified ideational variables associated with recommended net-care practice. Programme efforts designed to promote net-care practices and extend average lifespan of ITNs may be more effective if they emphasize positive attitudes towards net care, perceived susceptibility of malaria infection, response-efficacy of ITNs, perceived self-efficacy for net use, and promote net-care behaviour as a positive community norm., (© 2022. The Author(s).)

Background: There are limited existing approaches to generate estimates from Routine Health Information Systems (RHIS) data, despite the growing interest to these data. We calculated and assessed the consistency of maternal and child health service coverage estimates from RHIS data, using census-based and health service-based denominators in Sierra Leone., Methods: We used Sierra Leone 2016 RHIS data to calculate coverage of first antenatal care contact (ANC1), institutional delivery and diphtheria-pertussis-tetanus 3 (DPT3) immunization service provision. For each indicator, national and district level coverages were calculated using denominators derived from two census-based and three health service-based methods. We compared the coverage estimates from RHIS data to estimates from MICS 2017. We considered the agreement adequate when estimates from RHIS fell within the 95% confidence interval of the survey estimate., Results: We found an overall poor consistency of the coverage estimates calculated from the census-based methods. ANC1 and institutional delivery coverage estimates from these methods were greater than 100% in about half of the fourteen districts, and only 3 of the 14 districts had estimates consistent with the survey data. Health service-based methods generated better estimates. For institutional delivery coverage, five districts met the agreement criteria using BCG service-based method. We found better agreement for DPT3 coverage estimates using DPT1 service-based method as national coverage was close to survey data, and estimates were consistent for 8 out of 14 districts. DPT3 estimates were consistent in almost half of the districts (6/14) using ANC1 service-based method., Conclusion: The study highlighted the challenge in determining an appropriate denominator for RHIS-based coverage estimates. Systematic and transparent data quality check and correction, as well as rigorous approaches to determining denominators are key considerations to generate accurate coverage statistics using RHIS data., (© 2021. The Author(s).)

Background: In Sierra Leone (SL), a low-income country in West Africa, dental care is very limited, largely private, and with services focused in the capital Freetown. There is no formal dental education. Ten dentists supported by a similar number of dental care professionals (DCPs) serve a population of over 7.5 million people. The objective of this research was to estimate needs-led requirements for dental care and human resources for oral health to inform capacity building, based on a national survey of oral health in SL., Methods: A dedicated operational research (OR) decision tool was constructed in Microsoft Excel to support this project. First, total treatment needs were estimated from our national epidemiological survey data for three key ages (6, 12 and 15 years), collected using the 'International Caries Classification and Management System (ICCMS)' tool. Second, oral health needs were extrapolated to whole population levels for each year-group, based on census demographic data. Third, full time equivalent (FTE) workforce capacity needs were estimated for mid-level providers in the form of Dental Therapists (DTs) and non-dental personnel based on current oral disease management approaches and clinical timings for treatment procedures. Fourth, informed by an expert panel, three oral disease management scenarios were explored for the national population: (1) Conventional care (CC): comprising oral health promotion (including prevention), restorations and tooth extraction; (2) Surgical and Preventive care (S 5&6 P and S 6 P): comprising oral health promotion (inc. prevention) and tooth extraction (D5 and D6 together, & at D6 level only); and (3) Prevention only (P): consisting of oral health promotion (inc. prevention). Fifth, the findings were extrapolated to the whole population based on demography, assuming similar levels of treatment need., Results: To meet the needs of a single year-group of childrens' needs, an average of 163 DTs (range: 133-188) would be required to deliver Conventional care (CC); 39 DTs (range: 30-45) to deliver basic Surgical and Preventive care (S 6 P); 54 DTs for more extended Surgical and Preventive care (S 5&6 P) (range 38-68); and 27 DTs (range: 25-32) to deliver Prevention only (P). When scaled up to the total population, an estimated 6,147 DTs (range: 5,565-6,870) would be required to deliver Conventional care (CC); 1,413 DTs (range: 1255-1438 DTs) to deliver basic Surgical and Preventive care (S 6 P); 2,000 DTs (range 1590-2236) for more extended Surgical and Preventive care (S 5&6 P) (range 1590-2236); and 1,028 DTs to deliver Prevention only (P) (range: 1016-1046). Furthermore, if oral health promotion activities, including individualised prevention, could be delivered by non-dental personnel, then the remaining surgical care could be delivered by 385 DTs (range: 251-488) for the S 6 P scenario which was deemed as the minimum basic baseline service involving extracting all teeth with extensive caries into dentine. More realistically, 972 DTs (range: 586-1179) would be needed for the S 5&6 P scenario in which all teeth with distinctive and extensive caries into dentine are extracted., Conclusion: The study demonstrates the huge dental workforce needs required to deliver even minimal oral health care to the Sierra Leone population. The gap between the current workforce and the oral health needs of the population is stark and requires urgent action. The study also demonstrates the potential for contemporary epidemiological tools to predict dental treatment needs and inform workforce capacity building in a low-income country, exploring a range of solutions involving mid-level providers and non-dental personnel., (© 2021. The Author(s).)

Global misinformation and information overload have characterized the coronavirus disease (COVID-19) pandemic. Rumors are unverified pieces of information spreading online or person-to-person that reduce trust in health authorities and create barriers to protective practices. Risk communication and community engagement can increase transparency, build trust, and stop the spread of rumors. Building on previous work on Ebola and Zika viruses using Global Health Security Agenda systems strengthening support, the U.S. Agency for International Development-funded Breakthrough ACTION project developed a process and technology for systematically collecting, analyzing, and addressing COVID-19 rumors in real-time in Côte d'Ivoire. Rumors were submitted through community-based contributors and collected from callers to the national hotlines and then processed on a cloud-hosted database built on the open-source software District Health Information System 2 (DHIS2). Hotline teleoperators and data managers coded rumors in near-real-time according to behavioral theory frameworks within DHIS2 and visualized the findings on custom dashboards. The analysis and response were done in full collaboration with the Government of Côte d'Ivoire and implementing partners to ensure a timely and coordinated response. The system captured both widespread rumors consistent with misinformation in other settings, such as suspicions about case counts and the belief that masks were deliberately contaminated, as well as very localized beliefs related to specific influencers. The qualitative findings provided rapid insights on circulating beliefs, enabling risk communicators to nuance and tailor messaging around COVID-19., (© Tibbels et al.)

Several studies show altered heart rate variability (HRV) in autism spectrum disorder (ASD), but findings are neither universal nor specific to ASD. We apply a set of linear and nonlinear HRV measures-including phase rectified signal averaging-to segments of resting ECG data collected from school-age children with ASD, age-matched typically developing controls, and children with other psychiatric conditions characterized by altered HRV (conduct disorder, depression). We use machine learning to identify time, frequency, and geometric signal-analytical domains that are specific to ASD (receiver operating curve area = 0.89). This is the first study to differentiate children with ASD from other disorders characterized by altered HRV. Despite a small cohort and lack of external validation, results warrant larger prospective studies.

Objective: Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective strategy to prevent pelvic serous carcinoma for women at high risk of developing ovarian cancer; however, it results in premature menopause. Data is lacking to adequately counsel these women about potential effects of premature menopause on cognition and quality of life., Methods: A prospective study in premenopausal women at high risk of ovarian cancer to determine changes in cognition over time after RRSO and the impact of hormone therapy (HT) on cognition. Participants were surveyed before and after surgery using the Functional Assessment of Cancer Therapy-Cognitive questionnaire and questions regarding domains of wellbeing at 6, 12 and 18 months. Data was tested for changes across time using mixed model regression and logistic regression., Results: Fifty-seven women were included. Sixty-three percent of participants used HT. At 6 months postoperatively, perceived cognitive impairment declined by 5.5 points overall (4.4 in non-HT users and 6 in HT users), P = 0.003. The other domains of cognition assessed did not change significantly over time and the use of HT did not impact scores. Sleep disruption was common in this cohort and was not mitigated by HT. Self-reported depression improved after RRSO (P = 0.004)., Conclusion: Women at high risk of ovarian cancer who choose RRSO may experience declines in cognition within the first 6 months of surgical menopause. HT may cause small declines in perceived cognitive impairment at 6 months after RRSO. Women can expect more sleep disruption after menopause, which is not mitigated by HT., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2020 by The North American Menopause Society.)

Sleep problems are common among children with neurodevelopmental disorders (NDDs). We review sleep disturbance in three major NDDs: autism spectrum disorder, Down syndrome, and fetal alcohol spectrum disorder (FASD). We review associations with functional impairment, discuss how patterns of sleep disturbance inform understanding of etiology, and theorize about mechanisms of impairment. Sleep disturbance is a transdiagnostic feature of NDDs. Caregivers report high rates of sleep problems, including difficulty falling or staying asleep. Polysomnography data reveal differences in sleep architecture and increased rates of sleep disorders. Sleep disturbance is associated with functional impairment and stress among families. Further research is needed to elucidate mechanisms of impairment and develop more effective interventions. Despite significant sleep disturbance in FASD, limited research is available., Competing Interests: Conflict of Interest: The authors declare they have no conflict of interest.

Background: Evidence is needed regarding effective incentive strategies to increase clinician survey response rates. Cash cards are increasingly used as survey incentives; they are appealing because of their convenience and because in some cases their value can be reclaimed by investigators if not used. However, their effectiveness in clinician surveys is not known. In this study within the BRCA Founder OutReach (BFOR) study, a clinical trial of population-based BRCA1/2 mutation screening, we compared the use of upfront cash cards requiring email activation versus checks as clinician survey incentives., Methods: Participants receiving BRCA1/2 testing in the BFOR study could elect to receive their results from their primary care provider (PCP, named by the patient) or from a geneticist associated with the study. In order to understand PCPs' knowledge, attitudes, experiences and willingness to disclose results we mailed paper surveys to the first 501 primary care providers (PCPs) in New York, Boston, Los Angeles and Philadelphia who were nominated by study participants to disclose their BRCA1/2 mutation results obtained through the study. We used alternating assignment stratified by city to assign the first 303 clinicians to receive a $50 up-front incentive as a cash card (N = 155) or check (N = 148). The cash card required PCPs to send an activation email in order to be used. We compared response rates by incentive type, adjusting for PCP characteristics and study site., Results: In unadjusted analyses, PCPs who received checks were more likely to respond to the survey than those who received cash cards (54.1% versus 41.9%, p = 0.046); this remained true when we adjusted for provider characteristics (OR for checks 1.61, 95% CI 1.01, 2.59). No other clinician characteristics had a statistically significant association with response rates in adjusted analyses. When we included an interaction term for incentive type and city, the favorable impact of checks on response rates was evident only in Los Angeles and Philadelphia., Conclusions: An up-front cash card incentive requiring email activation may be less effective in eliciting clinician responses than up-front checks. However, the benefit of checks for clinician response rates may depend on clinicians' geographic location., Trial Registration: ClinicalTrials.gov ( NCT03351803 ), November 24, 2017.

Background: Historically, men in sub-Saharan Africa have worse outcomes along the HIV care continuum than women. Brothers for Life (BFL) is a community-based behavior change intervention for men, adapted for Côte d'Ivoire, involving group discussions that address salient gender norms and promote HIV prevention, testing, and linkage to care with support from peer navigators. The goal of this study was to describe the BFL program as implemented in Côte d'Ivoire, evaluate program implementation, and report uptake of HIV testing and treatment among BFL participants., Setting: Three urban and periurban sites in Côte d'Ivoire., Methods: The implementation evaluation assessed the fidelity and acceptability of the BFL program and the reach of program completion, testing and peer navigation using qualitative and quantitative approaches., Results: BFL facilitation fidelity and content fidelity were high. Semistructured interviews with BFL participants indicated that men appreciated the format and content and that the BFL program helped some participants overcome their fears and adopt more positive attitudes and behaviors around testing and treatment. Assessments of reach showed that, of the 7187 BFL participants, 81% tested for HIV as part of BFL and 2.3% (135) tested HIV-positive. Of those, 76% (102) accepted peer navigator support, and 97% (131) initiated treatment. After 6 months, 100% of the 131 men who initiated treatment remained in care., Conclusion: The implementation of BFL in Côte d'Ivoire successfully achieved the goals of engaging participants in discussions around HIV prevention, encouraging HIV testing, and achieving linkage to care, treatment initiation, and retention.

This qualitative research study explored the role of masculinity in men's engagement in the HIV care continuum in Côte d'Ivoire. The researchers conducted 73 in-depth interviews and 28 focus group discussions with 227 Ivoirian men between November and December 2016 across three urban sites. Participants in the study expressed that fear was the primary barrier to HIV testing and treatment. These men described five value domains-health, sexuality, work and financial success, family, and social status. Men saw HIV as a direct threat to their agency and strength with respect to each of these value domains, thus shedding light on their reluctance to discover their HIV status through HIV testing. With this data, the researchers created the Masculine Values Framework, a descriptive framework of masculine values that can be applied to better understand the behavior men exhibit in Côte d'Ivoire in the face of HIV. The Masculine Values Framework offers practical guidance for developing gender-sensitive HIV-focused social and behavior change programming in Côte d'Ivoire and similar contexts to reach the UNAIDS 90-90-90 targets., Competing Interests: The authors have declared that no competing interests exist.

Men diagnosed with HIV face gender-related barriers to initiating and adhering to antiretroviral therapy (ART). This qualitative study (73 in-depth interviews; 28 focus group discussions), conducted with men in three urban sites in Côte d'Ivoire in 2016, examined perceptions of ART, including benefits and challenges, to explore how ART mitigates HIV's threats to men's sexuality, economic success, family roles, social status, and health. Participants perceived that adhering to ART would reduce risk of transmitting HIV to others, minimize job loss and lost productivity, and help maintain men's roles as decision makers and providers. ART adherence was thought to help reduce the threat of HIV-related stigma, despite concerns about unintentional disclosure. While ART was perceived to improve health directly, it restricted men's schedules. Side effects were also a major challenge. Social and behavior change approaches building on these insights may improve male engagement across the HIV care continuum.

Background: Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV)., Methods: HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype., Findings: 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60-1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29-5.50] and 2.24 [1.77-2.84] respectively) and older age (1.28 [1.17-1.39] and 1.19 [1.12-1.25]). Male gender (1.62 [1.14-2.31] and 0.60 [0.35-0.91]), previous cardiovascular events (4.03 [2.91-5.57] and 1.44 [0.66-3.16]) and smoking (1.90 [1.41-2.56] and 1.08 [0.68-1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72-2.40] and 0.46 [0.30-0.70]) and estimated glomerular filtration rate < 60 mL/min/1.72 m 3 (4.80 [2.47-9.36] and 1.04 [0.67-1.60]) were stronger predictors of hemorrhagic than ischemic strokes. A CD4 count < 200 cells/μL was associated with an increased risk of hemorrhagic stroke only., Interpretation: Risk factors for stroke may differ by subtype in PLWHIV, emphasizing the importance of further research to increase the precision of stroke risk estimation., Competing Interests: PR has served as a scientific adviser to Bristol-Myers Squibb, Gilead Sciences, Grupo Ferrer Internacional, GlaxoSmithKline, Janssen Pharmaceutica, Merck, and ViiV Healthcare; has served on data and safety monitoring boards and endpoint adjudication committees for Janssen Pharmaceutica; reports honoraria to his institution for speaking engagements at scientific conferences from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline; and reports research support from Gilead Sciences, ViiV Healthcare, Merck, Janssen Pharmaceutica, Bristol-Myers Squibb, Abbott Laboratories, and Boehringer Ingelheim. ML reports grants from Boehringer Ingelheim, Gilead Sciences, Merck Sharp & Dohme, Bristol-Myers Squibb, Janssen-Cilag, and ViiV HealthCare and personal fees from Gilead Sciences and Sirtex Pty Ltd, outside the submitted work. CS reports grants from The D:A:D Oversight Committee, during the conduct of the study, personal fees from Gilead Sciences, personal fees from ViiV Healthcare, and personal fees from Janssen-Cilag, outside the submitted work. FB reports personal fees and non-financial support from ViiV Healthcare, Gilead, BMS, Janssen, and MSD and grants from Gilead and Janssen, outside the submitted work; CP reports personal fees from Gilead, outside the submitted work; AM reports personal fees from ViiV and Gilead, outside the submitted work. HK has received travel grants from Gilead and her institution received consultancy fees from Gilead and MSD; OK reports personal fees from Gilead, personal fees from MSD, personal fees from ViiV, non-financial support from Gilead, personal fees from Gilead, personal fees from Janssen, non-financial support from ViiV, and non-financial support from BMS, outside the submitted work; SDW. CIH, LR, DK, AP, WE-S, ADM, SDW and JDL have no disclosures to declare.

As early as infancy, caregivers' facial expressions shape children's behaviors, help them regulate their emotions, and encourage or dissuade their interpersonal agency. In childhood and adolescence, proficiencies in producing and decoding facial expressions promote social competence, whereas deficiencies characterize several forms of psychopathology. To date, however, studying facial expressions has been hampered by the labor-intensive, time-consuming nature of human coding. We describe a partial solution: automated facial expression coding (AFEC), which combines computer vision and machine learning to code facial expressions in real time. Although AFEC cannot capture the full complexity of human emotion, it codes positive affect, negative affect, and arousal-core Research Domain Criteria constructs-as accurately as humans, and it characterizes emotion dysregulation with greater specificity than other objective measures such as autonomic responding. We provide an example in which we use AFEC to evaluate emotion dynamics in mother-daughter dyads engaged in conflict. Among other findings, AFEC (a) shows convergent validity with a validated human coding scheme, (b) distinguishes among risk groups, and (c) detects developmental increases in positive dyadic affect correspondence as teen daughters age. Although more research is needed to realize the full potential of AFEC, findings demonstrate its current utility in research on emotion dysregulation.

Men in sub-Saharan Africa have lower rates of HIV testing and are less likely to initiate treatment compared to women. Service delivery dimensions are a key factor in facilitating engagement along the HIV treatment continuum for men and women, yet male specific overall perceptions of the service delivery environment have received little attention in West Africa. This study draws on qualitative data collected in Côte d'Ivoire to explore provider-level and structural factors affecting men's engagement in HIV testing and treatment through interviews and focus group discussions conducted with health workers and men living with HIV (some on ART) or whose HIV status was unknown. Factors influencing decisions to test or initiate treatment were considered in terms of perceived benefits and costs. Men described costs at the interpersonal (client-provider) level, such as unwanted disclosure or stigma, which were weighed against the potential for social support and clinical guidance. Likewise, fear of unwanted disclosure operated at the facility level, as the layout of facilities sometimes grouped clients living with HIV together. Notably, the benefits men described from engaging in HIV testing and care all operated at the interpersonal level and none at the facility level. In light of the fact that provider- and facility-level factors influenced the perceptions and experiences of men along the treatment continuum, we offer recommendations to reduce barriers to testing and engagement in care related to service delivery., Competing Interests: The authors have declared that no competing interests exist.

In cancer genetic counseling (CGC), communication across language and culture challenges the model of practice based on shared decision-making. To date, little research has examined the decision-making process of low-income, limited English proficiency (LEP) patients in CGC. This study identified communication patterns in CGC sessions with this population and assessed how these patterns facilitate or inhibit the decision-making process during the sessions. We analyzed 24 audio recordings of CGC sessions conducted in Spanish via telephone interpreters at two public hospitals. Patients were referred for risk of hereditary breast and ovarian cancer; all were offered genetic testing. Audio files were coded by two bilingual English-Spanish researchers and analyzed using conventional content analysis through an iterative process. The 24 sessions included 13 patients, 6 counselors, and 18 interpreters. Qualitative data analyses identified three key domains - Challenges Posed by Hypothetical Explanations, Misinterpretation by the Medical Interpreter, and Communication Facilitators - that reflect communication patterns and their impact on the counselor's ability to facilitate shared decision-making. Overall, we found an absence of patient participation in the decision-making process. Our data suggest that when counseling LEP Latina patients via medical interpreter, prioritizing information with direct utility for the patient and organizing information into short- and long-term goals may reduce information overload and improve comprehension for patient and interpreter. Further research is needed to test the proposed counseling strategies with this population and to assess how applicable our findings are to other populations.

Innovative approaches are required to further enhance leprosy control, reduce the number of people developing leprosy, and curb transmission. Early case detection, contact screening, and chemoprophylaxis currently is the most promising approach to achieve this goal. The Leprosy Post-Exposure Prophylaxis (LPEP) programme generates evidence on the feasibility of integrating contact tracing and single-dose rifampicin (SDR) administration into routine leprosy control activities in different settings. The LPEP programme is implemented within the leprosy control programmes of Brazil, Cambodia, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania. Focus is on three key interventions: tracing the contacts of newly diagnosed leprosy patients; screening the contacts for leprosy; and administering SDR to eligible contacts. Country-specific protocol adaptations refer to contact definition, minimal age for SDR, and staff involved. Central coordination, detailed documentation and rigorous supervision ensure quality evidence. Around 2 years of field work had been completed in seven countries by July 2017. The 5,941 enrolled index patients (89·4% of the registered) identified a total of 123,311 contacts, of which 99·1% were traced and screened. Among them, 406 new leprosy patients were identified (329/100,000), and 10,883 (8·9%) were excluded from SDR for various reasons. Also, 785 contacts (0·7%) refused the prophylactic treatment with SDR. Overall, SDR was administered to 89·0% of the listed contacts. Post-exposure prophylaxis with SDR is safe; can be integrated into the routines of different leprosy control programmes; and is generally well accepted by index patients, their contacts and the health workforce. The programme has also invigorated local leprosy control., Competing Interests: Conflicts of interest Novartis Foundation provided technical input in the design phase of the LPEP programme and ensures overall programme coordination. All authors are either staff of the Novartis Foundation, work as paid consultants for the programme described here, act as national programme coordinators or serve on the Steering Committee of the programme. The funder had no role in the interpretation of findings or decision to publish this manuscript.

Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention., (Copyright © 2017. Published by Elsevier Inc.)

Background: In Bo district, rural Sierra Leone, we assessed the burden of the 2014 Ebola outbreak on under-five consultations at a primary health center and the quality of care for under-15 children at a Médecins Sans Frontières (MSF) referral hospital., Methods: Retrospective cohort study, comparing a period before (May-October 2013) and during the same period of the Ebola outbreak (2014). Health worker infections occurred at the outbreak peak (October 2014), resulting in hospital closure due to fear of occupational-risk of contracting Ebola. Standardized hospital exit outcomes and case fatality were used to assess quality of care until closure., Results: A total of 13,658 children under-five, were seen at the primary health center during 2013 compared to 8761 in 2014; a consultation decline of 36%. Of 6497 children seen in the hospital emergency room, during the outbreak, patients coming from within hospital catchment area declined with 38% and there were significantly more self-referrals (80% vs. 61%, P < 0.001). During Ebola, 23 children were dead on arrival and the proportion of children in severe clinical status (requiring urgent attention) was higher (74% during Ebola vs. 65% before, P < 0.001). Of 5,223 children with available hospital outcomes, unfavorable outcomes (combination of deaths and abandoned) were less than 15% during both periods, which is within the maximum acceptable in-house threshold set by MSF. Case fatality for severe malaria and lower respiratory tract infections (n = 3752) were similar (≤15%)., Conclusions: Valuable and good quality pediatric care was being provided in the pediatric hospital during the 2014 Ebola outbreak, but could not be sustained because of hospital closure. Health facility and health worker safety should be tackled as a universal requirement to try to avoid a déjà-vu.

Both high sugar and fat diets can induce prosteatotic genes, leading to obesity and obesity-associated diseases, including hepatic steatosis. Unsaturated fat/fatty acid (USFA) reduces high sugar-induced hepatic steatosis by inhibiting the induced prosteatotic genes. In contrast, it is still unclear how USFA ameliorates saturated fat/fatty acid (SFA)-induced hepatic steatosis. As sugar and fat have different transport and metabolic pathways, we hypothesized that USFA suppressed SFA-induced hepatic steatosis via a different set of prosteatotic genes. To test this, we implemented high SFA vs USFA diets and a control diet in C57BL/6 mice for 16 weeks. Severe hepatic steatosis was induced in mice fed the SFA diet. Among a nearly complete set of prosteatotic genes, only the stearoyl-coenzyme a desaturase 1 (Scd1), cluster of differentiation 36 (Cd36), and peroxisome proliferator-activated receptor γ (Pparγ) genes that were differentially expressed in the liver could contribute to SFA-induced steatosis or the alleviative effect of USFA. That is, the SFA diet induced the expression of Cd36 and Pparγ but not Scd1, and the USFA diet suppressed Scd1 expression and the induction of Cd36 and Pparγ. These findings were mainly recapitulated in cultured hepatocytes. The essential roles of SCD1 and CD36 were confirmed by the observation that the suppression of SCD1 and CD36 with small interfering RNA or drug treatment ameliorated SFA-induced lipid accumulation in hepatocytes. We thus concluded that SCD1, CD36, and PPARγ were essential to the suppression of SFA-induced hepatic steatosis by main dietary USFA, which may provide different therapeutic targets for reducing high-fat vs sugar-induced hepatic steatosis., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To consider associations between the latest/nadir CD4 cell count, and time spent with CD4 cell count less than 200 cells/μl (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals., Design: Longitudinal cohort study., Methods: Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included stroke-like events and rejected strokes into the stroke endpoint., Results: Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4 cell counts after adjustment [current CD4 <100 cells/μl: relative rate (95% confidence interval) 0.96 (0.62-1.50) for MI, 0.89 (0.30-2.36) for CHD; nadir CD4 <100 cells/μl: 1.36 (0.57-3.23) for MI, 0.98 (0.45-2.16) for CHD], stroke and CVD rates were higher in those with a latest CD4 cell count less than 100 cells/μl [2.26 (1.29-3.94) and 1.14 (0.84-1.56), respectively]. All events occurred less frequently in those who had not experienced immune depression, although evidence for a linear association with duration of immune depression was weak. The association between stroke risk and the latest CD4 cell count strengthened as stroke-like and rejected strokes were included; conversely, associations with established stroke risk factors weakened., Conclusion: We do not find strong evidence that HIV-positive individuals with a low CD4 cell count are more likely to experience MI/CHD. Although strokes appear to occur more commonly at low CD4 cell counts, this may be partly explained by misclassification or other biases.

Background: An inverse association between serum alanine aminotransferase (ALT) levels and the risk of myocardial infarction (MI) has been reported in the general population. We investigated associations between ALT levels and the risk of various cardiovascular and cerebrovascular outcomes in a large cohort study of HIV-positive individuals., Methods: Using Poisson regression, we investigated associations between the latest ALT level and MI, coronary heart disease (CHD), and stroke, after adjusting for known confounders and cumulative/recent exposure to antiretroviral drugs. Analyses were also performed for the end points of all-cause/liver-related mortality and new-onset diabetes mellitus., Results: By February 2011, participants had experienced 541 MIs, 804 CHD, and 258 stroke events. The MI rate decreased from 3.1/1000 person-years among those with ALT ≤18 U/L to 2.1/1000 person-years among those with ALT >60 U/L. After adjustment for confounders, each 2-fold increment in ALT was associated with a 19% drop in the MI rate {relative rate, 0.81 [95% confidence interval (CI): 0.74 to 0.89], P = 0.0001}. A weaker inverse association was seen for CHD with no indication of a linear association between ALT levels and stroke (P = 0.72). Adjusted relative rates were 0.88 (95% CI: 0.81 to 0.97) and 0.70 (95% CI: 0.54 to 0.92) in those who were hepatitis C virus negative and hepatitis C virus positive, respectively, and 0.72 (95% CI: 0.58 to 0.89) and 0.84 (0.77 to 0.93) in injection drug users and non-injection drug users, respectively. Liver-related mortality and diabetes both demonstrated a positive association with ALT levels, whereas all-cause mortality showed a U-shaped relationship., Conclusions: Higher ALT levels are associated with lower MI risk in HIV-positive individuals, but with higher risks of liver-related mortality and diabetes mellitus.

Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

Objective: A previously published randomized clinical trial indicated that a developmental behavioral intervention, the Early Start Denver Model (ESDM), resulted in gains in IQ, language, and adaptive behavior of children with autism spectrum disorder. This report describes a secondary outcome measurement from this trial, EEG activity., Method: Forty-eight 18- to 30-month-old children with autism spectrum disorder were randomized to receive the ESDM or referral to community intervention for 2 years. After the intervention (age 48 to 77 months), EEG activity (event-related potentials and spectral power) was measured during the presentation of faces versus objects. Age-matched typical children were also assessed., Results: The ESDM group exhibited greater improvements in autism symptoms, IQ, language, and adaptive and social behaviors than the community intervention group. The ESDM group and typical children showed a shorter Nc latency and increased cortical activation (decreased α power and increased θ power) when viewing faces, whereas the community intervention group showed the opposite pattern (shorter latency event-related potential [ERP] and greater cortical activation when viewing objects). Greater cortical activation while viewing faces was associated with improved social behavior., Conclusions: This was the first trial to demonstrate that early behavioral intervention is associated with normalized patterns of brain activity, which is associated with improvements in social behavior, in young children with autism spectrum disorder., (Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

This article describes Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) recent use of specially trained African giant pouched rats as detectors of pulmonary tuberculosis in people living in Tanzania. It summarizes the achievements and challenges encountered over the years and outlines future prospects. Since 2008, second-line screening by the rats has identified more than 2000 tuberculosis-positive patients who were missed by microscopy at Direct Observation of Treatment--Short Course centres in Tanzania. Moreover, data that are reviewed herein have been collected with respect to the rats' sensitivity and specificity in detecting tuberculosis. Findings strongly suggest that scent-detecting rats offer a quick and practical tool for detecting pulmonary tuberculosis and within the year APOPO's tuberculosis-detection project will be extended to Mozambique. As part of its local capacity building effort, APOPO hires and trains Tanzanians to play many important roles in its TB detection project and provides research and training opportunities for Tanzanian students.

The effect of expertise training with faces was studied in adults with ASD who showed initial impairment in face recognition. Participants were randomly assigned to a computerized training program involving either faces or houses. Pre- and post-testing included standardized and experimental measures of behavior and event-related brain potentials (ERPs), as well as interviews after training. After training, all participants met behavioral criteria for expertise with the specific stimuli on which they received training. Scores on standardized measures improved after training for both groups, but only the face training group showed an increased face inversion effect behaviorally and electrophysiological changes to faces in the P100 component. These findings suggest that individuals with ASD can gain expertise in face processing through training.

Background: Several FIDELIS projects (Fund for Innovative DOTS Expansion through Local Initiatives to Stop TB) in Tanzania were conducted by the National Tuberculosis and Leprosy Programme (NTLP) during the years 2004-2008 to strengthen diagnostic and treatment services. These projects collected information on treatment delay and some of it was available for research purposes. With this database our objective was to assess the duration and determinants of treatment delay among new smear positive pulmonary tuberculosis (TB) patients in FIDELIS projects, and to compare delay according to provider visited prior to diagnosis., Methods: Treatment delay among new smear positive TB patients was recorded for each patient at treatment initiation and this information was available and fairly complete in 6 out of 57 districts with FIDELIS projects enrolling patients between 2004 and 2007; other districts had discarded their forms at the time of analysis. It was analysed as a cross sectional study., Results: We included 1161 cases, 10% of all patients recruited in the FIDELIS projects in Tanzania. Median delay was 12 weeks. The median duration of cough, weight loss and haemoptysis was 12, 8 and 3 weeks, respectively. Compared to Hai district Handeni had patients with longer delays and Mbozi had patients with shorter delays. Urban and rural patients reported similar delays. Patients aged 15-24 years and patients of 65 years or older had longer delays. Patients reporting contact with traditional healers before diagnosis had a median delay of 15 weeks compared to 12 weeks among those who did not. Patients with dyspnoea and with diarrhoea had longer delays., Conclusion: In this patient sample in Tanzania half of the new smear positive pulmonary tuberculosis patients had a treatment delay longer than 12 weeks. Delay was similar in men and women and among urban and rural patients, but longer in the young and older age groups. Patients using traditional healers had a 25% longer median delay.

Background: The combination of rapamycin and R1507, a fully human IgG1 monoclonal antibody targeting the IGF-1 receptor (IGF-1R), in osteosarcoma xenograft tumors in vivo is evaluated in this report., Procedure: Six osteosarcoma xenograft tumor models were evaluated for growth inhibition after monotherapy with R1507, rapamycin, and the combination of both drugs. Phosphorylation of proteins involved in IGF-1R signaling is evaluated at various time points by immunoblotting., Results: IGF-1R was expressed in five of the six human osteosarcoma tumor lines. Objective responses to R1507 were seen in four of the six tumor lines (OS1, OS2, OS9, and OS17) including one complete response in OS1. IGF-1R protein levels did not predict degree of response to R1507 in the sensitive tumors. However, in one of the two R1507-resistant tumors (OS33), there was a minimal expression of IGF-1R. An increase in AKT phosphorylation was observed in all the osteosarcoma tumors treated with rapamycin. However, phosphorylation of AKT was inhibited when rapamycin was used in combination with R1507. In three of the xenograft tumor lines, there was an improvement in response when R1507 was used in combination with rapamycin., Conclusions: IGF-1R inhibition by R1507 induced tumor growth delays and improvement in event-free survival in four of six osteosarcoma xenograft tumor lines. R1507 negates increased signaling through AKT in response to mammalian target of rapamycin inhibition, suggesting that the combination is worthy of further evaluation in patients. As R1507 and other IGF-1R inhibitors advance in clinical trials, it will be important to understand biomarkers of response and pathways of resistance.

The RNA-binding protein HuR regulates the stability and translation of numerous mRNAs encoding stress-response and proliferative proteins. Although its post-transcriptional influence has been linked primarily to its cytoplasmic translocation, here we report that moderate heat shock (HS) potently reduces HuR levels, thereby altering the expression of HuR target mRNAs. HS did not change HuR mRNA levels or de novo translation, but instead reduced HuR protein stability. Supporting the involvement of the ubiquitin-proteasome system in this process were results showing that (1) HuR was ubiquitinated in vitro and in intact cells, (2) proteasome inhibition increased HuR abundance after HS, and (3) the HuR kinase checkpoint kinase 2 protected against the loss of HuR by HS. Within a central, HS-labile approximately 110-amino-acid region, K182 was found to be essential for HuR ubiquitination and proteolysis as mutant HuR(K182R) was left virtually unubiquitinated and was refractory to HS-triggered degradation. Our findings reveal that HS transiently lowers HuR by proteolysis linked to K182 ubiquitination and that HuR reduction enhances cell survival following HS.

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Determining variation in genes is fundamental to understanding their function in the disease state. Cardiac troponin T (cTnT) and phospholamban (PLN) genes have been implicated in dilated cardiomyopathy (DCM) in human and model species. To investigate the role of these 2 candidate genes in DCM in the turkey Meleagris gallopavo, understanding sequence variants and map position distribution is necessary. To this end, a total of 1854 and 1771 bp of cTnT and PLN gene sequences, respectively, were scanned for single nucleotide polymorphisms (SNPs) in a randomly bred population. A total of 15 SNPs was identified in the cTnT and PLN genomic sequences. Nine haplotypes, 5 in cTnT and 4 in PLN, were identified. Observed heterozygosities (0.02-0.39) in the turkey population were low for both genes. Within each gene, 1 SNP corresponding to a restriction enzyme site was identified and used to develop a PCR-restriction fragment length polymorphism (RFLP) genotyping assay. The PLN gene was genetically mapped to turkey chromosome 2, equivalent to Gallus gallus chromosome 3, and cTnT mapped to a turkey microchromosome. Although limited because of the relatively small sample size of 55 birds, the data from this SNP analysis of PLN and cTnT provide a foundation from which to evaluate the function of cTnT and PLN in the turkey. Information about the distribution of the SNPs and haplotypes will facilitate future association and linkage studies.