Efficacy of Short-Course AZT Plus 3TC to Reduce Nevirapine Resistance in the Prevention of Mother-to-Child HIV Transmission: A Randomized Clinical Trial

Neil Martinson and colleagues report a randomized trial of adding short-course zidovudine+lamivudine to reduce drug resistance from single-dose nevirapine used to prevent mother-to-child transmission of HIV

Influenza- and respiratory syncytial virus-associated adult mortality in Soweto

Background: Influenza and respiratory syncytial virus (RSV) infections cause seasonal excess mortality and hospitalisation in adults, particularly the elderly, in high-income countries. Little information exists on the impact of these infections on African adults. Objectives: To estimate influenza- and RSV -related adult mortality, stratified by age, and hospitalisation in Soweto, South Africa. Study design: A retrospective hospital-based study in Soweto from 1997-1999 to estimate influenza- and RSV -related excess all-cause deaths and hospitalisation using a rate-difference method. It was based on influenza seasons of varying severity provided by surveillance data. Results: Influenza seasons were significantly associated with excess mortality in adults across all 3 years, except for 18-64 year olds in 1998. Excess mortality was highest in those ≥65 years of age, 82.8 /100 000 population in the mild 1997 season and 220.9 / 100 000 in the severe 1998 season. Influenza significantly increased adult medical hospitalisation in the severe 1998 season alone. RSV did not significantly affect mortality or hospitalisation. Conclusions: Influenza-related mortality was substantial and disproportionately affected the elderly. Influenza vaccination for the elderly needs consideration. The RSV -related burden was not significantly increased but merits observation over a longer period.

Impact of Isotype on the Mechanism of Action of Agonist Anti-OX40 Antibodies in Cancer: Implications for Therapeutic Combinations

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer. METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed. RESULTS: Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion. CONCLUSIONS: These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

A digital soil map of Victoria-VicDSMv1

This paper describes the production of the first version of a digital soil map for Victoria (VicDSMv1) which has combined existing soil point and polygon data. Four soil properties: pH, EC (electrical conductivity), clay percentage and Soil Organic Carbon (SOC) at the 6 depths specified by GlobalSoilMap.net have been mapped. The mapping has utilised data from 5,233 legacy sites collated from soil and land surveys conducted across Victoria since the 1930s and stored in the Victorian Soil Information System (VSIS). These sites were prepared by allocating property values to each of the 6 depths using equal area splines or depth weighted values. A land unit map for Victoria was derived from an overlay of map units from 32 surveys mapped at 100,000 scale or better. A dominant soil type at Suborder level in the Australian Soil Classification system (ASC) was assigned to each land unit. For each polygon a hierarchical grouping of sites from the VSIS was created using soil classification and location in relation to the polygon. A set of statistics for each soil property value at each set depth were calculated from the best available site cluster for each polygon. Metadata relating to property calculations have been collected. Creation of the VicDSMv1 has involved the preparation and entry of a large volume of legacy soil information into the VSIS. Consultation with current and retired soil surveyors during the process has enabled valuable expert knowledge to be captured into digital soil mapping. © 2014 Taylor & Francis Group, London, UK

A digital soil map of Victoria—VicDSMv1

This paper describes the production of the first version of a digital soil map for Victoria (VicDSMv1) which has combined existing soil point and polygon data. Four soil properties: pH, EC (electrical conductivity), clay percentage and Soil Organic Carbon (SOC) at the 6 depths specified by GlobalSoilMap.net have been mapped. The mapping has utilised data from 5,233 legacy sites collated from soil and land surveys conducted across Victoria since the 1930s and stored in the Victorian Soil Information System (VSIS). These sites were prepared by allocating property values to each of the 6 depths using equal area splines or depth weighted values. A land unit map for Victoria was derived from an overlay of map units from 32 surveys mapped at 100,000 scale or better. A dominant soil type at Suborder level in the Australian Soil Classification system (ASC) was assigned to each land unit. For each polygon a hierarchical grouping of sites from the VSIS was created using soil classification and location in relation to the polygon. A set of statistics for each soil property value at each set depth were calculated from the best available site cluster for each polygon. Metadata relating to property calculations have been collected. Creation of the VicDSMv1 has involved the preparation and entry of a large volume of legacy soil information into the VSIS. Consultation with current and retired soil surveyors during the process has enabled valuable expert knowledge to be captured into digital soil mapping. © 2014 Taylor & Francis Group, London, UK

Multi-source data integration and identification of uncertainties affecting production of a digital soil map

Production of a digital soil map for the state of Victoria in Australia is subject to various errors arising from the use of legacy data (as is often the case around the globe). Potential sources of uncertainty for inputs and methods undertaken in the creation of a Victorian DSM version 1.0 (VicDSMv1) are identified. These sources of uncertainty are recognised and issues discussed including their potential contribution to error propagation. Examples include possible errors associated with legacy soil maps, soil sites, laboratory analysis and predictive modelling by regression or spline approaches. Experiences in processing of legacy data in Victoria are described and some aspects of incorporating uncertainty in data discussed. As part of this initial DSM exercise these uncertainties and contextual information will be captured as associated metadata. A framework, as a five component process model for integrated assessment of uncertainty, is suggested based on uncertainty in the mapping process. © 2014 Taylor & Francis Group, London, UK

Climate-averaging of terrestrial faunas: an example from the Plio-Pleistocene of South Africa

Fundamental to the interpretation of bone-bearing faunal deposits is an understanding of the taphonomic processes that have modified the once living fossil community. An often neglected source of bias is that of climate-averaging, which occurs when the duration of bone accumulation exceeds the duration of an individual climatic episode. Tropical and subtropical climate change is dominated by precessional cyclicity (~21,000 year cycle), which controls monsoon rainfall intensity and thus plant communities over time. Under a climate-averaging scenario, the paleoecological characteristics of a faunal deposit represent an amalgamation of more than one phase of the precessional cycle. We investigate the degree of climate-averaging in Plio-Pleistocene bone breccias from South Africa by comparing stable isotope measurements of fossil enamel with the evidence from high-resolution speleothem paleoclimate proxies. We conclude that each of the four faunal assemblages studied are climate-averaged, having formed over a time period in excess of one-third of a precessional cycle (~7000 years). This has implications for the reconstruction of hominin paleoenvironments and estimates of Plio-Pleistocene biodiversity. We hypothesize that climate-averaging may be a common feature of tropical terrestrial vertebrate assemblages throughout the Cenozoic and Mesozoic