A novel mutation in the calcium-sensing receptor gene in an Irish pedigree showing familial hypocalciuric hypercalcemia: a case report

Abstract Introduction Familial hypocalciuric hypercalcemia is a rare autosomal dominant disorder characterized by asymptomatic and non-progressive hypercalcemia due to mutations of the calcium-sensing receptor gene. Disorders of calcium metabolism are very common in the elderly, and they can coexist with familial hypocalciuric hypercalcemia in affected families. Case presentation We describe an Irish family with hypercalcemia and hypocalciuria. The proband, an 80-year-old Irish woman, presented with hypercalcemia, relative hypocalciuria, and an elevated parathormone level. She also had chronic kidney disease stage 3 and vitamin D deficiency. Two of her sons were also found to be hypercalcemic and hypocalciuric. DNA sequencing identified a novel missense inactivating mutation in the calcium sensing-receptor gene of the proband and her two hypercalcemic sons. Conclusion Familial hypocalciuric hypercalcemia due to a novel mutation in the calcium-sensing receptor gene was diagnosed in the proband and her two sons. Disorders of calcium metabolism can be multifarious in the elderly. We suggest that testing first degree relatives for calcium levels and DNA sequencing may have a role in the assessment of elderly patients with parathormone-related hypercalcemia.</p

Recent acquisition of Helicobacter pylori by Baka Pygmies

Both anatomically modern humans and the gastric pathogen Helicobacter pylori originated in Africa, and both species have been associated for at least 100,000 years. Seven geographically distinct H. pylori populations exist, three of which are indigenous to Africa: hpAfrica1, hpAfrica2, and hpNEAfrica. The oldest and most divergent population, hpAfrica2, evolved within San hunter-gatherers, who represent one of the deepest branches of the human population tree. Anticipating the presence of ancient H. pylori lineages within all hunter-gatherer populations, we investigated the prevalence and population structure of H. pylori within Baka Pygmies in Cameroon. Gastric biopsies were obtained by esophagogastroduodenoscopy from 77 Baka from two geographically separated populations, and from 101 non-Baka individuals from neighboring agriculturalist populations, and subsequently cultured for H. pylori. Unexpectedly, Baka Pygmies showed a significantly lower H. pylori infection rate (20.8%) than non-Baka (80.2%). We generated multilocus haplotypes for each H. pylori isolate by DNA sequencing, but were not able to identify Baka-specific lineages, and most isolates in our sample were assigned to hpNEAfrica or hpAfrica1. The population hpNEAfrica, a marker for the expansion of the Nilo-Saharan language family, was divided into East African and Central West African subpopulations. Similarly, a new hpAfrica1 subpopulation, identified mainly among Cameroonians, supports eastern and western expansions of Bantu languages. An age-structured transmission model shows that the low H. pylori prevalence among Baka Pygmies is achievable within the timeframe of a few hundred years and suggests that demographic factors such as small population size and unusually low life expectancy can lead to the eradication of H. pylori from individual human populations. The Baka were thus either H. pylori-free or lost their ancient lineages during past demographic fluctuations. Using coalescent simulations and phylogenetic inference, we show that Baka almost certainly acquired their extant H. pylori through secondary contact with their agriculturalist neighbors

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

A systematic review and meta-analysis of the efficacy and safety of N-acetylcysteine in preventing aminoglycoside-induced ototoxicity: implications for the treatment of multidrug-resistant TB.

BACKGROUND: Ototoxicity is a severe side effect of aminoglycoside antibiotics. Aminoglycosides are recommended for the treatment of multidrug-resistant TB (MDR-TB). N-Acetylcysteine (NAC) appears to protect against drug- and noise-induced hearing loss. This review aimed to determine if coadministering NAC with aminoglycoside affected ototoxicity development, and to assess the safety and tolerability of prolonged NAC administration. METHODS: Eligible studies reported on the efficacy of concomitant NAC and aminoglycoside administration for ototoxicity prevention or long-term (≥ 6 weeks) administration of NAC regardless of indication. Pooled estimates were calculated using a fixed-effects model. Heterogeneity was assessed using the I(2) statistic. RESULTS: Three studies reported that NAC reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides. Pooled relative risk for otoprotection at 4-6 weeks was 0.14 (95% CI 0.05 to 0.45), and the risk difference was -33.3% (95% CI 45.5% to 21.2%). Eighty-three studies (N=9988) described the administration of NAC for >6 weeks. Abdominal pain, nausea and vomiting, diarrhoea and arthralgia were increased 1.4-2.2 times. DISCUSSION: This review provides evidence for the safety and otoprotective effect of NAC when coadministered with aminoglycoside. It represents a strong justification for a clinical trial to investigate the effect of concomitant NAC treatment in patients receiving aminoglycosides as part of MDR-TB treatment

Base scenario model parameters determined empirically for Baka Pygmies and Cameroon.

1<p>WHO, 2012.</p><p>WHO Global Observatory Health Data Repository. World Health Organization, Geneva, Switzerland. <a href="http://apps.who.int/gho/data/" target="_blank">http://apps.who.int/gho/data/</a>. Last accessed on 11/02/2012.</p><p>N: For the Cameroon-wide simulation to validate the model, a population of 200,000 was adopted, following Rupnow <i>et al.</i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003775#pgen.1003775-Rupnow1" target="_blank">[41]</a>.</p><p>Le: For the Baka, the Migliano <i>et al.</i> estimate for the Aka was used <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003775#pgen.1003775-Migliano1" target="_blank">[52]</a>.</p><p>S₅: Fraction of individuals that reach five years of age. For the Baka, no estimate was available, so the base scenario assumes that half of mortality that will occur by age 15 takes place by age 5, in keeping with typically high infant mortality in developing-world contexts.</p><p>S₁₅: Fraction of individuals that reach fifteen years of age. For the Baka, the Migliano <i>et al.</i> estimate for the Aka was used <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003775#pgen.1003775-Migliano1" target="_blank">[52]</a>.</p><p>NS: Fraction born non-susceptible, i.e., the fraction of individuals that cannot become infected “for physiologic, physical, or immunologic reasons” <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003775#pgen.1003775-Rupnow1" target="_blank">[41]</a>. Estimated from observed maximum prevalences in the developing world.</p><p>β_XY: = Transmission coefficients, with X and Y in {C,Y, A}, where these stand for child, youth and adult age classes, respectively, yielding nine coefficients in all. This represents the probability of transmission from class X to class Y, and is derived from Rupnow <i>et al.</i><a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003775#pgen.1003775-Rupnow1" target="_blank">[41]</a>, as described in the text.</p

Population demographic parameters for <i>H. pylori</i> from Baka Pygmies and non-Baka agriculturalists derived using an isolation-with-migration model and assuming two demographically explicit scenarios.

<p>Population parameter theta (<i>θ</i>) = 4<i>N₁μ</i>, where <i>N₁</i> is the effective population size of the reference population (non-Baka) and <i>μ</i> is the mutation rate. <i>t</i> is the timing parameter in coalescent units, and <i>T</i> the time to split between Baka and non-Baka (). <i>m</i> is the fraction of the population replaced by migrants per generation: of population 1 (non-Baka) are replaced per generation and of population 2 (Baka) are replaced per generation. The <i>θ</i> estimated by the software refers only to population 1. c.i., confidence interval; L, lower; U, upper.</p

Assignment of Cameroonian <i>H. pylori</i> isolates to populations and subpopulations.

1<p>Seven of the ten identical haplotypes were isolated from individuals of different ethnicity and count more than once, thus, the total number of isolates in this table is 121 instead of 113.</p