Diminished physical function in older HIV-infected adults in the Southeastern U.S. despite successful antiretroviral therapy

As antiretroviral therapy efficacy improves, HIV is gradually being recognized more as a chronic disease within the aging HIV-infected population. While these individuals are surviving into old age, they may, however, be experiencing “accelerated aging” with greater declines in physical function than that observed among comparably matched individuals free of HIV. This decline is not well understood and it remains unclear if physical decline correlates with the degree of immunosuppression based on CD4 lymphocyte nadir

Effectiveness of a Positive Youth Development Program for Secondary 1 Students in Macau: A Pilot Study

With the rapid change to society after the opening of the gaming licensure by the government and the potential attraction to youth caused by the casinos, a well-tested and comprehensive adolescent development program previously established in Hong Kong was adopted and modified to be used in Macau. It is expected to help our adolescents achieve positive growth and be better prepared for future challenges. The aim of this study is to examine the effectiveness of the modified positive youth development program for Secondary 1 Students in Macau. Specifically, two research questions will be asked: (1) How does the positive youth development program affect positive growth for youth in Macau?; and (2) Is youth growth related to different factors such as gender, age, family financial condition, and parents' marital status? A mixed research method with a quantitative approach using a pre- and post-test pre-experimental design, and a qualitative approach using a focus group for the participants is carried out. The study sample included 232 Secondary 1 Students in two schools. The objective outcome evaluation showed that, overall, 123 (53%) of the participants had significant improvement on the total scores of the Chinese Positive Youth Development Scale (CPYDS) and the two composite scores. However, there were some increases in the behavioral intention of alcohol drinking and participation in gambling activities. The “happiness of the family life” was found to have significant differences in the score of the CPYDS, which was shown to be the factor related to youth growth. The focus group interviews revealed that both positive and negative feedback was obtained from the discussion; however, the majority of the participants perceived benefits to themselves from the program. With reference to the principle of triangulation, the present study suggests that, based on both quantitative and qualitative evaluation findings, it should be concluded that there is positive evidence supporting the effectiveness of the Tier 1 Program of the Hong Kong Project P.A.T.H.S. (Positive Adolescent Training through Holistic Social Programmes), which was adopted and modified for Macau. In addition, special attention should be paid to the behavioral intention of alcohol drinking and participation in gambling activities in the local context

Multivariate methods and software for association mapping in dose¿response genome¿wide association studies

Abstract Background The large sample sizes, freedom of ethical restrictions and ease of repeated measurements make cytotoxicity assays of immortalized lymphoblastoid cell lines a powerful new in vitro method in pharmacogenomics research. However, previous studies may have over‐simplified the complex differences in dose‐response profiles between genotypes, resulting in a loss of power. Methods The current study investigates four previously studied methods, plus one new method based on a multivariate analysis of variance (MANOVA) design. A simulation study was performed using differences in cancer drug response between genotypes for biologically meaningful loci. These loci also showed significance in separate genome‐wide association studies. This manuscript builds upon a previous study, where differences in dose‐response curves between genotypes were constructed using the hill slope equation. Conclusion Overall, MANOVA was found to be the most powerful method for detecting real signals, and was also the most robust method for detection using alternatives generated with the previous simulation study. This method is also attractive because test statistics follow their expected distributions under the null hypothesis for both simulated and real data. The success of this method inspired the creation of the software program MAGWAS. MAGWAS is a computationally efficient, user‐friendly, open source software tool that works on most platforms and performs GWASs for individuals having multivariate responses using standard file formats

Training community healthcare workers on the use of information and communication technologies: a randomised controlled trial of traditional versus blended learning in Malawi, Africa.

BACKGROUND: Despite the increasing uptake of information and communication technologies (ICT) within healthcare services across developing countries, community healthcare workers (CHWs) have limited knowledge to fully utilise computerised clinical systems and mobile apps. The 'Introduction to Information and Communication Technology and eHealth' course was developed with the aim to provide CHWs in Malawi, Africa, with basic knowledge and computer skills to use digital solutions in healthcare delivery. The course was delivered using a traditional and a blended learning approach. METHODS: Two questionnaires were developed and tested for face validity and reliability in a pilot course with 20 CHWs. Those were designed to measure CHWs' knowledge of and attitudes towards the use of ICT, before and after each course, as well as their satisfaction with each learning approach. Following validation, a randomised controlled trial was conducted to assess the effectiveness of the two learning approaches. A total of 40 CHWs were recruited, stratified by position, gender and computer experience, and allocated to the traditional or blended learning group using block randomisation. Participants completed the baseline and follow-up questionnaires before and after each course to assess the impact of each learning approach on their knowledge, attitudes, and satisfaction. Per-item, pre-post and between-group, mean differences for each approach were calculated using paired and unpaired t-tests, respectively. Per-item, between-group, satisfaction scores were compared using unpaired t-tests. RESULTS: Scores across all scales improved after attending the traditional and blended learning courses. Self-rated ICT knowledge was significantly improved in both groups with significant differences between groups in seven domains. However, actual ICT knowledge scores were similar across groups. There were no significant differences between groups in attitudinal gains. Satisfaction with the course was generally high in both groups. However, participants in the blended learning group found it more difficult to follow the content of the course. CONCLUSIONS: This study shows that there is no difference between blended and traditional learning in the acquisition of actual ICT knowledge among community healthcare workers in developing countries. Given the human resource constraints in remote resource-poor areas, the blended learning approach may present an advantageous alternative to traditional learning

Comprehensive evidence implies a higher social cost of CO2

The social cost of carbon dioxide (SC-CO2) measures the monetized value of the damages to society caused by an incremental metric tonne of CO2 emissions and is a key metric informing climate policy. Used by governments and other decision-makers in beneft–cost analysis for over a decade, SC-CO2 estimates draw on climate science, economics, demography and other disciplines. However, a 2017 report by the US National Academies of Sciences, Engineering, and Medicine1 (NASEM) highlighted that current SC-CO2 estimates no longer refect the latest research. The report provided a series of recommendations for improving the scientifc basis, transparency and uncertainty characterization of SC-CO2 estimates. Here we show that improved probabilistic socioeconomic projections, climate models, damage functions, and discounting methods that collectively refect theoretically consistent valuation of risk, substantially increase estimates of the SC-CO2. Our preferred mean SC-CO2 estimate is $185 per tonne of CO2 ($44–$413 per tCO2: 5$51 per tCO2. Our estimates incorporate updated scientifc understanding throughout all components of SC-CO2 estimation in the new open-source Greenhouse Gas Impact Value Estimator (GIVE) model, in a manner fully responsive to the near-term NASEM recommendations. Our higher SC-CO2 values, compared with estimates currently used in policy evaluation, substantially increase the estimated benefts of greenhouse gas mitigation and thereby increase the expected net benefts of more stringent climate policies

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030