Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis.

During the preparation of this article, owing to an administrative oversight between the collaborating institutions, we omitted Dr Dermot Maher from the author list. Dr Maher was involved in the early phases of the General Population Cohort (GPC) Study, data from which were used in the individual-level participant data analyses in this manuscript. His role included contributing to the GPC study protocol development, management of initial research ethics application for the GPC, and organisation of initial field programmes at MRC/UVRI Uganda Research Unit on AIDS. As a result, we request that Dr Maher is included in the author list

Electronic data capture in a rural African setting: evaluating experiences with different systems in Malawi

Background As hardware for electronic data capture (EDC), such as smartphones or tablets, becomes cheaper and more widely available, the potential for using such hardware as data capture tools in routine healthcare and research is increasing. Objective We aim to highlight the advantages and disadvantages of four EDC systems being used simultaneously in rural Malawi: two for Android devices (CommCare and ODK Collect), one for PALM and Windows OS (Pendragon), and a custom-built application for Android (Mobile InterVA – MIVA). Design We report on the personal field and development experience of fieldworkers, project managers, and EDC system developers. Results Fieldworkers preferred using EDC to paper-based systems, although some struggled with the technology at first. Highlighted features include in-built skip patterns for all systems, and specifically the ‘case’ function that CommCare offers. MIVA as a standalone app required considerably more time and expertise than the other systems to create and could not be customised for our specific research needs; however, it facilitates standardised routine data collection. CommCare and ODK Collect both have user-friendly web-interfaces for form development and good technical support. CommCare requires Internet to build an application and download it to a device, whereas all steps can be done offline with ODK Collect, a desirable feature in low connectivity settings. Pendragon required more complex programming of logic, using a Microsoft Access application, and generally had less technical support. Start-up costs varied between systems, and all were considered more expensive than setting up a paper-based system; however running costs were generally low and therefore thought to be cost-effective over the course of our projects. Conclusions EDC offers many opportunities for efficient data collection, but brings some issues requiring consideration when designing a study; the decision of which hardware and software to use should be informed by the aim of data collection, budget, and local circumstances

Design and Synthesis of a Quintessential Self-Transmissible IncX1 Plasmid, pX1.0

DNA exchange in bacteria via conjugative plasmids is believed to be among the most important contributing factors to the rapid evolution- and diversification rates observed in bacterial species. The IncX1 plasmids are particularly interesting in relation to enteric bacteria, and typically carry genetic loads like antibiotic resistance genes and virulence factors. So far, however, a “pure” version of these molecular parasites, without genetic loads, has yet to be isolated from the environment. Here we report the construction of pX1.0, a fully synthesized IncX1 plasmid capable of horizontal transfer between different enteric bacteria. The designed pX1.0 sequence was derived from the consensus gene content of five IncX1 plasmids and three other, more divergent, members of the same phylogenetic group. The pX1.0 plasmid was shown to replicate stably in E. coli with a plasmid DNA per total DNA ratio corresponding to approximately 3–9 plasmids per chromosome depending on the growth phase of the host. Through conjugation, pX1.0 was able to self-transfer horizontally into an isogenic strain of E. coli as well as into two additional species belonging to the family Enterobacteriaceae. Our results demonstrate the immediate applicability of recent advances made within the field of synthetic biology for designing and constructing DNA systems, previously existing only in silica

Automated versus manual post-processing of perfusion-CT data in patients with acute cerebral ischemia: influence on interobserver variability

The purpose of this study is to compare the variability of PCT results obtained by automatic selection of the arterial input function (AIF), venous output function (VOF) and symmetry axis versus manual selection. Imaging data from 30 PCT studies obtained as part of standard clinical stroke care at our institution in patients with suspected acute hemispheric ischemic stroke were retrospectively reviewed. Two observers performed the post-processing of 30 CTP datasets. Each observer processed the data twice, the first time employing manual selection of AIF, VOF and symmetry axis, and a second time using automated selection of these same parameters, with the user being allowed to adjust them whenever deemed appropriate. The volumes of infarct core and of total perfusion defect were recorded. The cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and blood-brain barrier permeability (BBBP) values in standardized regions of interest were recorded. Interobserver variability was quantified using the Bland and Altman's approach. Automated post-processing yielded lower coefficients of variation for the volume of the infarct core and the volume of the total perfusion defect (15.7% and 5.8%, respectively) compared to manual post-processing (31.0% and 12.2%, respectively). Automated post-processing yielded lower coefficients of variation for PCT values (11.3% for CBV, 9.7% for CBF, and 9.5% for MTT) compared to manual post-processing (23.7% for CBV, 32.8% for CBF, and 16.7% for MTT). Automated post-processing of PCT data improves interobserver agreement in measurements of CBV, CBF and MTT, as well as volume of infarct core and penumbra

Ecological Study of HIV Infection and Hypertension in Sub-Saharan Africa: Is There a Double Burden of Disease?

An ecological correlation study of the prevalence of hypertension with human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa was conducted to determine the extent to which these conditions coincide at country level. Data on prevalence of hypertension were derived from a systematic search of literature published between 1975 and 2014 with corresponding national estimates on HIV prevalence and antiretroviral therapy (ART) coverage from the Demographic and Health Surveys and the joint United Nations Programme on HIV/AIDS databases. National estimates on gross national income (GNI) and under-five mortality were obtained from the World Bank database. Linear regression analyses using robust standard errors (allowing for clustering at country level) were carried out for associations of age-standardised hypertension prevalence ratios (standardized to rural Uganda’s hypertension prevalence data) with HIV prevalence, adjusted for national indicators, year of study and sex of the study population. In total, 140 estimates of prevalence of hypertension representing 25 nations were sex-and area-matched with corresponding HIV prevalence. A two-fold increase in HIV prevalence was associated with a 9.29% increase in age, sex and study year-adjusted prevalence ratio for hypertension (95% CI 2.0 to 16.5, p = 0.01), which increased to 16.3% (95% CI 9.3 to 21.1) after adjusting for under-five mortality, GNI per capita and ART coverage. Countries with a pronounced burden of HIV may also have an increased burden of non-communicable diseases such as hypertension with potential economic and health systems implications

HIV treatment is associated with a twofold higher probability of raised triglycerides: pooled analyses in 21 023 individuals in sub-Saharan Africa

Background Anti-retroviral therapy (ART) regimes for HIV are associated with raised levels of circulating triglycerides (TGs) in western populations. However, there are limited data on the impact of ART on cardiometabolic risk in sub-Saharan African (SSA) populations. Methods Pooled analyses of 14 studies comprising 21 023 individuals, on whom relevant cardiometabolic risk factors (including TG), HIV and ART status were assessed between 2003 and 2014, in SSA. The association between ART and raised TG (>2.3 mmol/L) was analysed using regression models. Findings Among 10 615 individuals, ART was associated with a two-fold higher probability of raised TG (RR 2.05, 95% CI 1.51–2.77, I2 = 45.2%). The associations between ART and raised blood pressure, glucose, HbA1c, and other lipids were inconsistent across studies. Interpretation Evidence from this study confirms the association of ART with raised TG in SSA populations. Given the possible causal effect of raised TG on cardiovascular disease (CVD), the evidence highlights the need for prospective studies to clarify the impact of long term ART on CVD outcomes in SS

Improved Outcome Prediction Using CT Angiography in Addition to Standard Ischemic Stroke Assessment: Results from the STOPStroke Study

Purpose: To improve ischemic stroke outcome prediction using imaging information from a prospective cohort who received admission CT angiography (CTA). Methods: In a prospectively designed study, 649 stroke patients diagnosed with acute ischemic stroke had admission NIH stroke scale scores, noncontrast CT (NCCT), CTA, and 6-month outcome assessed using the modified Rankin scale (mRS) scores. Poor outcome was defined as mRS.2. Strokes were classified as ‘‘major’ ’ by the (1) Alberta Stroke Program Early CT Score (ASPECTS+) if NCCT ASPECTS was#7; (2) Boston Acute Stroke Imaging Scale (BASIS+) if they were ASPECTS+ or CTA showed occlusion of the distal internal carotid, proximal middle cerebral, or basilar arteries; and (3) NIHSS for scores.10. Results: Of 649 patients, 253 (39.0%) had poor outcomes. NIHSS, BASIS, and age, but not ASPECTS, were independent predictors of outcome. BASIS and NIHSS had similar sensitivities, both superior to ASPECTS (p,0.0001). Combining NIHSS with BASIS was highly predictive: 77.6 % (114/147) classified as NIHSS.10/BASIS+ had poor outcomes, versus 21.5 % (77/358) with NIHSS#10/BASIS2 (p,0.0001), regardless of treatment. The odds ratios for poor outcome is 12.6 (95 % CI: 7.9 to 20.0

Differential requirements for Tousled-like kinases 1 and 2 in mammalian development

The regulation of chromatin structure is critical for a wide range of essential cellular processes. The Tousled-like kinases, TLK1 and TLK2, regulate ASF1, a histone H3/H4 chaperone, and likely other substrates, and their activity has been implicated in transcription, DNA replication, DNA repair, RNA interference, cell cycle progression, viral latency, chromosome segregation and mitosis. However, little is known about the functions of TLK activity in vivo or the relative functions of the highly similar TLK1 and TLK2 in any cell type. To begin to address this, we have generated Tlk1- and Tlk2-deficient mice. We found that while TLK1 was dispensable for murine viability, TLK2 loss led to late embryonic lethality because of placental failure. TLK2 was required for normal trophoblast differentiation and the phosphorylation of ASF1 was reduced in placentas lacking TLK2. Conditional bypass of the placental phenotype allowed the generation of apparently healthy Tlk2-deficient mice, while only the depletion of both TLK1 and TLK2 led to extensive genomic instability, indicating that both activities contribute to genome maintenance. Our data identifies a specific role for TLK2 in placental function during mammalian development and suggests that TLK1 and TLK2 have largely redundant roles in genome maintenance