Simulating Genetic Mixing in Strongly Structured Populations of the Threatened Southern Brown Bandicoot ().

Genetic mixing aims to increase the genetic diversity of small or isolated populations, by mitigating genetic drift and inbreeding depression, either by maximally increasing genetic diversity, or minimising the prevalence of recessive, deleterious alleles. However, few studies investigate this beyond a single generation of mixing. Here, we model genetic mixing using captive, low-diversity recipient population of the threatened Southern brown bandicoot () over 50 generations and compare wild populations across south-eastern Australia as candidate source populations.

Genotype and Phenotype Correlation of the TPMT∗8 Allele in Thiopurine Metabolism.

Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). TPMT genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur.

A far-ultraviolet-driven photoevaporation flow observed in a protoplanetary disk.

Most low-mass stars form in stellar clusters that also contain massive stars, which are sources of far-ultraviolet (FUV) radiation. Theoretical models predict that this FUV radiation produces photodissociation regions (PDRs) on the surfaces of protoplanetary disks around low-mass stars, which affects planet formation within the disks. We report James Webb Space Telescope and Atacama Large Millimeter Array observations of a FUV-irradiated protoplanetary disk in the Orion Nebula.

Validation of oxygen saturations measured in the community by emergency medical services as a marker of clinical deterioration in patients with confirmed COVID-19: a retrospective cohort study.

Objectives: To evaluate oxygen saturation and vital signs measured in the community by emergency medical services (EMS) as clinical markers of COVID-19-positive patient deterioration.

Design: A retrospective data analysis.

Setting: Patients were conveyed by EMS to two hospitals in Hampshire, UK, between 1 March 2020 and 31 July 2020.

Heterogeneous patterns of heterozygosity loss in isolated populations of the threatened eastern barred bandicoot (Perameles gunnii).

Identifying and analysing isolated populations is critical for conservation. Isolation can make populations vulnerable to local extinction due to increased genetic drift and inbreeding, both of which should leave imprints of decreased genome-wide heterozygosity. While decreases in heterozygosity among populations are frequently investigated, fewer studies have analysed how heterozygosity varies among individuals, including whether heterozygosity varies geographically along lines of discrete population structure or with continuous patterns analogous to isolation by distance.

Organisation of care for people receiving drug-resistant tuberculosis treatment in South Africa: a mixed methods study.

Objectives: Treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) is increasingly transitioning from hospital-centred to community-based care. A national policy for decentralised programmatic MDR/RR-TB care was adopted in South Africa in 2011. We explored variations in the implementation of care models in response to this change in policy, and the implications of these variations for people affected by MDR/RR-TB.

Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.

Background: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM.

Determination of the Duplicated Allele Using Real-Time PCR Signal: An Alternative Approach.

duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated allele.

Formation of the methyl cation by photochemistry in a protoplanetary disk.

Forty years ago, it was proposed that gas-phase organic chemistry in the interstellar medium can be initiated by the methyl cation CH (refs. ), but so far it has not been observed outside the Solar System. Alternative routes involving processes on grain surfaces have been invoked.

A machine-learning based model for automated recommendation of individualized treatment of rifampicin-resistant tuberculosis.

Background: Rifampicin resistant tuberculosis remains a global health problem with almost half a million new cases annually. In high-income countries patients empirically start a standardized treatment regimen, followed by an individualized regimen guided by drug susceptibility test (DST) results. In most settings, DST information is not available or is limited to isoniazid and fluoroquinolones.

The role of emergent champions in policy implementation for decentralised drug-resistant tuberculosis care in South Africa.

Objective: Champions are recognised as important to driving organisational change in healthcare quality improvement initiatives in high-income settings. In low-income and middle-income countries with a high disease burden and constrained human resources, their role is highly relevant yet understudied. Within a broader study on policy implementation for decentralised drug-resistant tuberculosis care in South Africa, we characterised the role, strategies and organisational context of emergent policy champions.

A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus-Associated Tuberculous Meningitis: The LASER-TBM Trial.

Background: Drug regimens that include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in tuberculous meningitis (TBM). Safety data on their use in combination and in the context of human immunodeficiency virus (HIV) are needed to inform clinical trial design.

Methods: We conducted a phase 2, open-label, parallel-design, randomized, controlled trial to assess the safety of high-dose rifampicin, linezolid, and high-dose aspirin in HIV-associated TBM.

A comprehensive overview of pneumococcal vaccination recommendations for adults in South Africa, 2022.

Pneumococcal infections remain a common global cause of significant morbidity and mortality. The first recommendations for adult pneumococcal vaccination, published in South Africa in 1999, contained information only on the 23-valent polysaccharide vaccine (PPV23). With the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in adults and the perceived uncertainty that most clinicians had regarding use of these vaccines in adults, these vaccine recommendations were updated in 2022.

Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study.

Background: Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines.

Alanine-specific appetite in slow growing chickens is associated with impaired glucose transport and TCA cycle.

Background: The rate of protein accretion and growth affect amino acid requirements in young animals. Differences in amino acid metabolism contribute to individual variations in growth rate. This study aimed at determining how amino acid needs may change with growth rates in broiler chickens.

SARS-CoV-2 infection in public hospital medical doctors in an Eastern Cape metro.

Background: Evidence-based Infection Prevention and Control (IPC) measures are critical in protecting medical doctors from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Concerns surrounding access to personal protective equipment (PPE), compliance with IPC measures and the quality of available PPE have been raised as possible causes for high rates of SARS-CoV-2 infection in medical doctors in high transmission settings. This study aimed to determine the prevalence of SARS-CoV-2 infection and the risk factors for occupational infection in doctors in the hospitals in Nelson Mandela Bay (NMB).

A treatment recommender clinical decision support system for personalized medicine: method development and proof-of-concept for drug resistant tuberculosis.

Background: Personalized medicine tailors care based on the patient's or pathogen's genotypic and phenotypic characteristics. An automated Clinical Decision Support System (CDSS) could help translate the genotypic and phenotypic characteristics into optimal treatment and thus facilitate implementation of individualized treatment by less experienced physicians.

Methods: We developed a hybrid knowledge- and data-driven treatment recommender CDSS.

An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study).

Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e.

Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia: a randomized controlled trial (PROTECT-Patient Trial).

There is a need for effective therapy for COVID-19 pneumonia. Convalescent plasma has antiviral activity and early observational studies suggested benefit in reducing COVID-19 severity. We investigated the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19 in a population with a high HIV prevalence and where few therapeutic options were available.

Targeted Genotyping in Clinical Pharmacogenomics: What Is Missing?

Clinical pharmacogenomic testing typically uses targeted genotyping, which only detects variants included in the test design and may vary among laboratories. To evaluate the potential patient impact of genotyping compared with sequencing, which can detect common and rare variants, an in silico targeted genotyping panel was developed based on the variants most commonly included in clinical tests and applied to a cohort of 10,030 participants who underwent sequencing for CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, DPYD, SLCO1B1, TPMT, UGT1A1, and VKORC1. The results of in silico targeted genotyping were compared with the clinically reported sequencing results.