Trends in the burden of HIV mortality after roll-out of antiretroviral therapy in KwaZulu-Natal, South Africa: an observational community cohort study.

Antiretroviral therapy (ART) substantially decreases morbidity and mortality in people living with HIV. In this study, we describe population-level trends in the adult life expectancy and trends in the residual burden of HIV mortality after the roll-out of a public sector ART programme in KwaZulu-Natal, South Africa, one of the populations with the most severe HIV epidemics in the world. Data come from the Africa Centre Demographic Information System (ACDIS), an observational community cohort study in the uMkhanyakude district in northern KwaZulu-Natal, South Africa. We used non-parametric survival analysis methods to estimate gains in the population-wide life expectancy at age 15 years since the introduction of ART, and the shortfall of the population-wide adult life expectancy compared with that of the HIV-negative population (ie, the life expectancy deficit). Life expectancy gains and deficits were further disaggregated by age and cause of death with demographic decomposition methods. Covering the calendar years 2001 through to 2014, we obtained information on 93 903 adults who jointly contribute 535 42 8 person-years of observation to the analyses and 9992 deaths. Since the roll-out of ART in 2004, adult life expectancy increased by 15·2 years for men (95% CI 12·4-17·8) and 17·2 years for women (14·5-20·2). Reductions in pulmonary tuberculosis and HIV-related mortality account for 79·7% of the total life expectancy gains in men (8·4 adult life-years), and 90·7% in women (12·8 adult life-years). For men, 9·5% is the result of a decline in external injuries. By 2014, the life expectancy deficit had decreased to 1·2 years for men (-2·9 to 5·8) and to 5·3 years for women (2·6-7·8). In 2011-14, pulmonary tuberculosis and HIV were responsible for 84·9% of the life expectancy deficit in men and 80·8% in women. The burden of HIV on adult mortality in this population is rapidly shrinking, but remains large for women, despite their better engagement with HIV-care services. Gains in adult life-years lived as well as the present life expectancy deficit are almost exclusively due to differences in mortality attributed to HIV and pulmonary tuberculosis. Wellcome Trust, the Bill & Melinda Gates Foundation, and the National Institutes of Health

The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA):Data on mortality, by HIV status and stage on the HIV care continuum, among the general population in seven longitudinal studies between 1989 and 2014

Timely progression of people living with HIV (PLHIV) from the point of infection through the pathway from diagnosis to treatment is important in ensuring effective care and treatment of HIV and preventing HIV-related deaths and onwards transmission of infection. Reliable, population-based estimates of new infections are difficult to obtain for the generalised epidemics in sub-Saharan Africa. Mortality data indicate disease burden and, if disaggregated along the continuum from diagnosis to treatment, can also reflect the coverage and quality of different HIV services. Neither routine statistics nor observational clinical studies can estimate mortality prior to linkage to care nor following disengagement from care. For this, population-based data are required.The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa brings together studies in Kenya, Malawi, South Africa, Tanzania, Uganda, and Zimbabwe. Eight studies have the necessary data to estimate mortality by HIV status, and seven can estimate mortality at different stages of the HIV care continuum. This data note describes a harmonised dataset containing anonymised individual-level information on survival by HIV status for adults aged 15 and above. Among PLHIV, the dataset provides information on survival during different periods: prior to diagnosis of infection; following diagnosis but before linkage to care; in pre-antiretroviral treatment (ART) care; in the first six months after ART initiation; among people continuously on ART for 6+ months; and among people who have ever interrupted ART

Accessibility and suitability of residential alcohol treatment for older adults: a mixed method study

Background Whilst alcohol misuse is decreasing amongst younger adults in many countries, it is increasing in older adults. Residential rehabilitation (rehab) is a vital component of the alcohol treatment system, particularly for those with relatively complex needs and entrenched alcohol problems. In this study, we sought to find out to what extent rehabs in England have upper age limits that exclude older adults, whether rehabs are responsive to older adults’ age-related needs and how older adults experience these services. Method This is a mixed method study. A search was carried out of Public Health England’s online directory of rehabs to identify upper age thresholds. Semi-structured qualitative interviews were carried out with 16 individuals who had attended one of five residential rehabs in England and Wales since their 50th birthday. A researcher with experience of a later life alcohol problem conducted the interviews. Results Of the 118 services listed on Public Health England’s online directory of rehabs, 75% stated that they had an upper age limit that would exclude older adults. Perceived differences in values, attitudes and behaviour between younger and older residents had an impact on older residents’ experience of rehab. Activities organised by the rehabs were often based on physical activity that some older adults found it difficult to take part in and this could create a sense of isolation. Some older adults felt unsafe in rehab and were bullied, intimidated and subjected to ageist language and attitudes. Conclusion This study identified direct and indirect age discrimination in rehabs contrary to the law. Further research is required to find out if age discrimination exists in rehabs in other countries. Rehabs should remove arbitrary age limits and ensure that they are responsive to the needs of older adults

Towards personalised allele-specific CRISPR gene editing to treat autosomal dominant disorders

Abstract CRISPR/Cas9 holds immense potential to treat a range of genetic disorders. Allele-specific gene disruption induced by non-homologous end-joining (NHEJ) DNA repair offers a potential treatment option for autosomal dominant disease. Here, we successfully delivered a plasmid encoding S. pyogenes Cas9 and sgRNA to the corneal epithelium by intrastromal injection and acheived long-term knockdown of a corneal epithelial reporter gene, demonstrating gene disruption via NHEJ in vivo. In addition, we used TGFBI corneal dystrophies as a model of autosomal dominant disease to assess the use of CRISPR/Cas9 in two allele-specific systems, comparing cleavage using a SNP-derived PAM to a guide specific approach. In vitro, cleavage via a SNP-derived PAM was found to confer stringent allele-specific cleavage, while a guide-specific approach lacked the ability to distinguish between the wild-type and mutant alleles. The failings of the guide-specific approach highlights the necessity for meticulous guide design and assessment, as various degrees of allele-specificity are achieved depending on the guide sequence employed. A major concern for the use of CRISPR/Cas9 is its tendency to cleave DNA non-specifically at “off-target” sites. Confirmation that S. pyogenes Cas9 lacks the specificity to discriminate between alleles differing by a single base-pair regardless of the position in the guide is demonstrated

Conditional Gene Knockout in Human Cells with Inducible CRISPR/Cas9.

The advent of the easily programmable and efficient CRISPR/Cas9 nuclease system has revolutionized genetic engineering. While conventional gene knockout experiments using CRISPR/Cas9 are very valuable, these are not well suited to study stage-specific gene function in dynamic situations such as development or disease. Here we describe a CRISPR/Cas9-based OPTimized inducible gene KnockOut method (OPTiKO) for conditional loss-of-function studies in human cells. This approach relies on an improved tetracycline-inducible system for conditional expression of single guide RNAs (sgRNAs) that drive Cas9 activity. In order to ensure homogeneous and stable expression, the necessary transgenes are expressed following rapid and efficient single-step genetic engineering of the AAVS1 genomic safe harbor. When implemented in human pluripotent stem cells (hPSCs), the approach can be then efficiently applied to virtually any hPSC-derived human cell type at various stages of development or disease

Data resource profile: network for analysing longitudinal population-based HIV/AIDS data on Africa (ALPHA Network)

The Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA Network, http://alpha.lshtm.ac.uk/) brings together ten population-based HIV surveillance sites in eastern and southern Africa, and is coordinated by the London School of Hygiene and Tropical Medicine (LSHTM). It was established in 2005 and aims to (i) broaden the evidence base on HIV epidemiology for informing policy, (ii) strengthen the analytical capacity for HIV research, and (iii) foster collaboration between network members. All study sites, some starting in the late 1980s and early 1990s, conduct demographic surveillance in populations that range from approximately 20 to 220 thousand individuals. In addition, they conduct population-based surveys with HIV testing, and verbal autopsy interviews with relatives of deceased residents. ALPHA Network datasets have been used for studying HIV incidence, sexual behaviour and the effects of HIV on mortality, fertility, and household composition. One of the network’s substantive focus areas is the monitoring of AIDS mortality and HIV services coverage in the era of antiretroviral therapy. Service use data are retrospectively recorded in interviews and supplemented by information from record linkage with medical facilities in the surveillance areas. Data access is at the discretion of each of the participating sites, but can be coordinated by the network

How have ART treatment programmes changed the patterns of excess mortality in people living with HIV? Estimates from four countries in East and Southern Africa

Background: Substantial falls in the mortality of people living with HIV (PLWH) have been observed since the introduction of antiretroviral therapy (ART) in sub-Saharan Africa. However, access and uptake of ART have been variable in many countries. We report the excess deaths observed in PLWH before and after the introduction of ART. We use data from five longitudinal studies in Malawi, South Africa, Tanzania, and Uganda, members of the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA). Methods: Individual data from five demographic surveillance sites that conduct HIV testing were used to estimate mortality attributable to HIV, calculated as the difference between the mortality rates in PLWH and HIV-negative people. Excess deaths in PLWH were standardized for age and sex differences and summarized over periods before and after ART became generally available. An exponential regression model was used to explore differences in the impact of ART over the different sites. Results: 127,585 adults across the five sites contributed a total of 487,242 person years. Before the introduction of ART, HIV-attributable mortality ranged from 45 to 88 deaths per 1,000 person years. Following ART availability, this reduced to 14–46 deaths per 1,000 person years. Exponential regression modeling showed a reduction of more than 50% (HR =0.43, 95% CI: 0.32–0.58), compared to the period before ART was available, in mortality at ages 15–54 across all five sites. Discussion: Excess mortality in adults living with HIV has reduced by over 50% in five communities in sub-Saharan Africa since the advent of ART. However, mortality rates in adults living with HIV are still 10 times higher than in HIV-negative people, indicating that substantial improvements can be made to reduce mortality further. This analysis shows differences in the impact across the sites, and contrasts with developed countries where mortality among PLWH on ART can be similar to that of the general population. Further research is urgently needed to establish why the different impacts on mortality were observed and how the care and treatment programmes in these countries can be more effective in reducing mortality further

Role of salicylic acid in acclimation to low temperature

Low temperature is one of the most important limiting factors for plant growth throughout the world. Exposure to low temperature may cause various phenotypic and physiological symptoms, and may result in oxidative stress, leading to loss of membrane integrity and to the impairment of photosynthesis and general metabolic processes. Salicylic acid (SA),phenolic compound produced by a wide range of plant species, a may participate in many physiological and metabolic reactions in plants. It has been shown that exogenous SA may provide protection against low temperature injury in various plant species, while various stress factors may also modify the synthesis and metabolism of SA. In the present review, recent results on the effects of SA and related compounds in processes leading to acclimation to low temperatures will be discussed

High-latitude dust in the Earth system

Natural dust is often associated with hot, subtropical deserts, but significant dust events have been reported from cold, high latitudes. This review synthesizes current understanding of high-latitude (≥50°N and ≥40°S) dust source geography and dynamics and provides a prospectus for future research on the topic. Although the fundamental processes controlling aeolian dust emissions in high latitudes are essentially the same as in temperate regions, there are additional processes specific to or enhanced in cold regions. These include low temperatures, humidity, strong winds, permafrost and niveo-aeolian processes all of which can affect the efficiency of dust emission and distribution of sediments. Dust deposition at high latitudes can provide nutrients to the marine system, specifically by contributing iron to high-nutrient, low-chlorophyll oceans; it also affects ice albedo and melt rates. There have been no attempts to quantify systematically the expanse, characteristics, or dynamics of high-latitude dust sources. To address this, we identify and compare the main sources and drivers of dust emissions in the Northern (Alaska, Canada, Greenland, and Iceland) and Southern (Antarctica, New Zealand, and Patagonia) Hemispheres. The scarcity of year-round observations and limitations of satellite remote sensing data at high latitudes are discussed. It is estimated that under contemporary conditions high-latitude sources cover >500,000 km2 and contribute at least 80–100 Tg yr−1 of dust to the Earth system (~5% of the global dust budget); both are projected to increase under future climate change scenarios