The genetics of non-syndromic hearing impairment in South Africa

Hearing impairment (HI) is a sensory disorder resulting in the partial or complete disability to perceive sound in the better-hearing ear. It is defined as the inability to hear better than 25dB in the better-hearing ear. Subsequently, it is considered disabling when a child cannot perceive sound better the 30dB, in the better hearing ear, and an adult cannot perceive sound better than 40dB, in the better hearing ear. Hearing impairment may result from genetic, environmental, or unknown factors. The connexin gene, GJB2, is the prevalent gene resulting in congenital HI in most children with European, North American, and East Asian ancestry. Apart from the founder mutations present in GJB2 in Morocco, Ghana and Senegal, the prevalent causative genes resulting in congenital HI in African populations are yet to be fully elucidated. Congenital Hearing impairment in South Africa (RSA), has been estimated to have an incidence rate of 5.5 per 1000 live births, which is 5 times higher than the birth incidence in high-income countries (approximately 1 to 2 per 1000 live births). Patients are generally diagnosed late with HI, at approximately 3 years old, and the most prevalent environmental factors associated with HI in RSA are middle ear infections, with several reports implicating ototoxicity as a cause of HI. Variants in connexin genes i.e. GJB2 associated with HI have been shown to be irrelevant in the Black South African populations, and the limited genetic studies have identified private mutations in selected families. However, the full extent of prevalent genes associated with HI in the South African populations is still to be investigated. Methods and results Through a systematic review, we investigated the state of HI research in South Africa was established. Though studies have been performed since the 1960s, the results showed that genetics of HI in South Africa was not well explored. Universal new-born hearing screening is ideal in detecting congenital HI, but it is currently not standard practice in the country. However, with the advent of modern technology, HI screening may be more accessible to patients through community health workers. Patients who fail the repeated screenings may then be referred for further audiometry testing. This may positively impact the identification of patients with HI and assist with the necessary interventions. We also collaboratively worked to establish the first disease ontology for HI to further allow standardised and harmonised language surrounding HI. This provides the scalability and interoperability of research going forward. It will allow for all stakeholders in HI research to use the same terminology when discussing HI. In order to address the dearth of genetics research regarding non-syndromic HI, patients presenting with putative genetic HI were recruited from schools of the deaf across South Africa and two hospitals in Cape Town. The patients were recruited along with their family members, both with and without HI, and their DNA was extracted from whole blood. Twenty-seven families segregating non-syndromic HI, consisting of 65 affected and 35 unaffected individuals were subjected to whole exome sequencing (WES). The HI was resolved in 20 families (74%), and pathogenic variants were identified in the genes: WFS1 (c.A2141), MITF (cT918A), ADGRV1(c.G564T, c.A17450G, c.A11298C), PDSS1(c.C641T, NEU1(c.C1069T, c.G754C), c.G727A), TBC1D24(c.G1514A), MYO15A(c.C1378T, TMPRSS3(c.205+6t>A), c.9303+5G>A, c.G6634A), USH2A(c.T9437A, c.G2990T, c.G101A), STRC(c.G225A, c.C4057T, c.G4655C, c.C4351T, c.G4403A), P2RX2(c.G1064A, c.C1187G), OTOG(c.C2525A, c.G3143A, c.G916A), LHFPL5(c.621delC), TRIOBP(c.C3133T, c.C4298T), SLC26A4(c.T94C, c.T716A), GJB2(c.35delG), REST(c.G1244C), CRYM(c.*6_*2delACAAA), CDH23(c.T1585C, c.G8230A), FGFR2(c.1297+10G>C), MYO7A(c.6255delC). The pathogenic variants presented 8 autosomal dominant alleles and 12 autosomal recessive alleles Five families presented with pathogenic or likely pathogenic variations associated with Usher Syndrome and the remaining 14 families presented with pathogenic variations associated with non-syndromic HI. One family presented with putative pathogenic variations in NEU1, which is a gene associated with Sialidosis. We specifically investigated, in greater detail, a dominant novel variation in REST, present in one family, which encodes a transcription factor, that was identified using whole exome sequencing. This gene was previously suspected to be associated with hearing impairment only once, in an American family. The variation was absent in the unaffected South African family members, unrelated patients, and unaffected controls. In vitro cell-based studies indicated that the variation results in the loss of nuclear exclusivity of REST. Luciferase assays indicated that the mutant was unable to repress the expression of one of its target genes, whereas the wild-type effectively inhibited the expression of the target. Conclusions This thesis successfully performed the following investigations: 1) development of the first Hearing Impairment Ontology worldwide, 2) review the genetic profile of HI in South Africa, 3) used WES to find known and novel variants in established HI genes, and 4) confirmed REST as a novel HI gene. Future work will focus on sequencing all the remaining samples and identifying their putative causative mutations. Further work includes feedbacking the results of the genetic testing to the patients and their families. The data will contribute to improving the HI-genes pairs' curation in Africa, and globally

Effectiveness of a Problem-Based Learning Approach in Clinical Teaching of The Undergraduate Nursing Students: An Integrative Literature Review

Aims: To explore the effectiveness of the PBL approach in the clinical teaching of undergraduate nursing students Methods: An integrative literature review was used to evaluate the effectiveness of PBL in integrating theory and practice among nursing students in clinical practice. The review searched research articles published in English from 2013 to 2023. Medical Subject Headings (MeSH) guidelines were used to identify relevant search terms, which included PBL. Articles that met the inclusion criteria entailed research articles published in peer-reviewed journals, written in English and the population of undergraduate nursing students. A matrix was developed that outlined (1)  characteristics of the study population and (2) challenges affecting the implementation and effectiveness of PBL in clinical teaching. Results: The literature search revealed twenty-one (n=21) studies conducted in various countries. The studies highlighted positive experiences on the effectiveness of the PBL approach in the clinical teaching of undergraduate nursing students. Skills such as critical thinking, problem-solving, and patient diagnosis were attributed to using PBL in the simulation. Conclusion: This paper contributes to the body of knowledge on the effectiveness of the PBL approach in the clinical teaching of undergraduate nursing students. It also contributes to the body of knowledge on PBL in nursing education, particularly in South Africa.

Whole exome sequencing reveals pathogenic variants in MYO3A, MYO15A and COL9A3 and differential frequencies in ancestral alleles in hearing impairment genes among individuals from Cameroon

There is scarcity of known gene variants of hearing impairment (HI) in African populations. This knowledge deficit is ultimately affecting the development of genetic diagnoses. We used whole exome sequencing to investigate gene variants, pathways of interactive genes and the fractions of ancestral overderived alleles for 159 HI genes among 18 Cameroonian patients with non-syndromic HI (NSHI) and 129 ethnically matched controls. Pathogenic and likely pathogenic (PLP) variants were found in MYO3A, MYO15A and COL9A3, with a resolution rate of 50% (9/18 patients). The study identified significant genetic differentiation in novel population-specific gene variants at FOXD4L2, DHRS2L6, RPL3L and VTN between HI patients and controls. These gene variants are found in functional/co-expressed interactive networks with other known HI-associated genes and in the same pathways with VTN being a hub protein, that is, focal adhesion pathway and regulation of the actin cytoskeleton (P-values <0.05). The results suggest that these novel population-specific gene variants are possible modifiers of the HI phenotypes. We found a high proportion of ancestral allele versus derived at low HI patients-specific minor allele frequency in the range of 0.0–0.1. The results showed a relatively low pickup rate of PLP variants in known genes in this group of Cameroonian patients with NSHI. In addition, findings may signal an evolutionary enrichment of some variants of HI genes in patients, as the result of polygenic adaptation, and suggest the possibility of multigenic influence on the phenotype of congenital HI, which deserves further investigations

A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family

Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in REST substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant REST in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target AF1q. The data demonstrates that the identified mutation compromises the function of REST and support its implication in HI. This study is the second report, worldwide, to implicate REST in HI and suggests that it should be included in diagnostic HI panels

Hospital adoption of antimicrobial stewardship programmes in Gulf Cooperation Council countries: A review of existing evidence

© 2018 International Society for Chemotherapy of Infection and Cancer Antimicrobial resistance is increasing at an alarming rate in the Gulf Cooperation Council (GCC) owing to the overuse and misuse of antimicrobials. Novel and rare multidrug-resistant strains can spread globally since the region is host to the largest expatriate population in the world as well as a pilgrimage destination for more than 4 million people annually. Adoption of antimicrobial stewardship programmes (ASPs) could improve the use of antimicrobials and reduce antimicrobial resistance in the region. However, despite the established benefits of these interventions, little is known about the level of their adoption in the region and the impact of these programmes on antimicrobial use and resistance. This study aimed to review existing evidence on the level of adoption of ASPs, the facilitators and barriers to their adoption, and outcomes of their adoption in GCC hospitals

Retraction.

This is a retraction of 'Gradual emergence followed by exponential spread of the SARS-CoV-2 Omicron variant in Africa' 10.1126/science.add873

Emergence and spread of the SARS-CoV-2 omicron (BA.1) variant across Africa: an observational study.

BACKGROUND: In mid-November, 2021, the SARS-CoV-2 omicron variant (B.1.1.529; BA.1 sublineage) was detected in southern Africa, prompting international travel restrictions. We aimed to investigate the spread of omicron BA.1 in Africa. METHODS: In this observational study, samples from patients infected with SARS-CoV-2 from 27 laboratories in 24 African countries, collected between June 1, 2021 and April 14, 2022, were tested for omicron BA.1 and delta (B.1.617.2) variants using real-time RT-PCR. Samples that tested positive for BA.1 by RT-PCR and were collected before estimated BA.1 emergence according to epidemiological properties were excluded from downstream analyses. The diagnostic precision of the assays was evaluated by high-throughput sequencing of samples from four countries. The observed spread of BA.1 was compared with mobility-based mathematical simulations and entries for SARS-CoV-2 in the Global Initiative on Sharing All Influenza Data (GISAID) genomic database. We estimated the effective reproduction number (Rt) at the country level considering the BA.1 fraction and the reported numbers of infections. Phylogeographical analyses were done in a Bayesian framework. FINDINGS: Through testing of 13 294 samples from patients infected with SARS-CoV-2, we established that, by November-December, 2021, omicron BA.1 had replaced the delta variant of SARS-CoV-2 in all African subregions, following a south-north gradient, with a median Rt of 2·60 (95% CI 2·46-2·71). This south-north spread, established on the basis of PCR data, was substantiated by phylogeographical reconstructions, ancestral state reconstructions, and GISAID data. PCR-based reconstructions of country-level BA.1 predominance and the availability of BA.1 genomic sequences in GISAID correlated significantly in time (p=0·0002, r=0·78). The first detections of BA.1 in high-income settings beyond Africa were predicted accurately in time by mobility-based mathematical simulations (p<0·0001). Comparing PCR-based reconstructions with mobility-based mathematical simulations suggested that SARS-CoV-2 infections in Africa were under-reported by approximately ten times. Inbound travellers infected with BA.1, departing from five continents, were identified in six African countries by early December, 2021. INTERPRETATION: Omicron BA.1 was widespread in Africa when travel bans were implemented, limiting their effectiveness. Combined with genomic surveillance and mobility-based mathematical modelling, PCR-based strategies can inform Rt and the geographical spread of emerging pathogens in a cost-effective and timely manner, and can guide evidence-based, non-pharmaceutical interventions such as travel restrictions or physical distancing. FUNDING: Bill & Melinda Gates Foundation. TRANSLATIONS: For the French, Portugese and Spanish translations of the abstract see Supplementary Materials section

Gradual emergence followed by exponential spread of the SARS-CoV-2 Omicron variant in Africa.

The geographic and evolutionary origins of the SARS-CoV-2 Omicron variant (BA.1), which was first detected mid-November 2021 in Southern Africa, remain unknown. We tested 13,097 COVID-19 patients sampled between mid-2021 to early 2022 from 22 African countries for BA.1 by real-time RT-PCR. By November-December 2021, BA.1 had replaced the Delta variant in all African sub-regions following a South-North gradient, with a peak Rt of 4.1. Polymerase chain reaction and near-full genome sequencing data revealed genetically diverse Omicron ancestors already existed across Africa by August 2021. Mutations, altering viral tropism, replication and immune escape, gradually accumulated in the spike gene. Omicron ancestors were therefore present in several African countries months before Omicron dominated transmission. These data also indicate that travel bans are ineffective in the face of undetected and widespread infection

Emergence and spread of the SARS-CoV-2 omicron (BA.1) variant across Africa: an observational study.

In mid-November, 2021, the SARS-CoV-2 omicron variant (B.1.1.529; BA.1 sublineage) was detected in southern Africa, prompting international travel restrictions. We aimed to investigate the spread of omicron BA.1 in Africa. In this observational study, samples from patients infected with SARS-CoV-2 from 27 laboratories in 24 African countries, collected between June 1, 2021 and April 14, 2022, were tested for omicron BA.1 and delta (B.1.617.2) variants using real-time RT-PCR. Samples that tested positive for BA.1 by RT-PCR and were collected before estimated BA.1 emergence according to epidemiological properties were excluded from downstream analyses. The diagnostic precision of the assays was evaluated by high-throughput sequencing of samples from four countries. The observed spread of BA.1 was compared with mobility-based mathematical simulations and entries for SARS-CoV-2 in the Global Initiative on Sharing All Influenza Data (GISAID) genomic database. We estimated the effective reproduction number (R ) at the country level considering the BA.1 fraction and the reported numbers of infections. Phylogeographical analyses were done in a Bayesian framework. Through testing of 13 294 samples from patients infected with SARS-CoV-2, we established that, by November-December, 2021, omicron BA.1 had replaced the delta variant of SARS-CoV-2 in all African subregions, following a south-north gradient, with a median R of 2·60 (95% CI 2·46-2·71). This south-north spread, established on the basis of PCR data, was substantiated by phylogeographical reconstructions, ancestral state reconstructions, and GISAID data. PCR-based reconstructions of country-level BA.1 predominance and the availability of BA.1 genomic sequences in GISAID correlated significantly in time (p=0·0002, r=0·78). The first detections of BA.1 in high-income settings beyond Africa were predicted accurately in time by mobility-based mathematical simulations (p<0·0001). Comparing PCR-based reconstructions with mobility-based mathematical simulations suggested that SARS-CoV-2 infections in Africa were under-reported by approximately ten times. Inbound travellers infected with BA.1, departing from five continents, were identified in six African countries by early December, 2021. Omicron BA.1 was widespread in Africa when travel bans were implemented, limiting their effectiveness. Combined with genomic surveillance and mobility-based mathematical modelling, PCR-based strategies can inform R and the geographical spread of emerging pathogens in a cost-effective and timely manner, and can guide evidence-based, non-pharmaceutical interventions such as travel restrictions or physical distancing. Bill & Melinda Gates Foundation. For the French, Portugese and Spanish translations of the abstract see Supplementary Materials section. [Abstract copyright: Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.