Search

Background Knowledge of the window of SARS-CoV-2 infectiousness is crucial in developing policies to curb transmission. Mathematical modelling based on scarce empirical evidence and key assumptions has driven isolation and testing policy, but real-world data are needed. We aimed to characterise infectiousness across the full course of infection in a real-world community setting. Methods The Assessment of Transmission and Contagiousness of COVID-19 in Contacts (ATACCC) study was a UK prospective, longitudinal, community cohort of contacts of newly diagnosed, PCR-confirmed SARS-CoV-2 index cases. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. The primary objective was to define the window of SARS-CoV-2 infectiousness and its temporal correlation with symptom onset. We quantified viral RNA load by RT-PCR and infectious viral shedding by enumerating cultivable virus daily across the course of infection. Participants completed a daily diary to track the emergence of symptoms. Outcomes were assessed with empirical data and a phenomenological Bayesian hierarchical model. Findings Between Sept 13, 2020, and March 31, 2021, we enrolled 393 contacts from 327 households (the SARS-CoV-2 pre-alpha and alpha variant waves); and between May 24, 2021, and Oct 28, 2021, we enrolled 345 contacts from 215 households (the delta variant wave). 173 of these 738 contacts were PCR positive for more than one timepoint, 57 of which were at the start of infection and comprised the final study population. The onset and end of infectious viral shedding were captured in 42 cases and the median duration of infectiousness was 5 (IQR 3–7) days. Although 24 (63%) of 38 cases had PCR-detectable virus before symptom onset, only seven (20%) of 35 shed infectious virus presymptomatically. Symptom onset was a median of 3 days before both peak viral RNA and peak infectious viral load (viral RNA IQR 3–5 days, n=38; plaque-forming units IQR 3–6 days, n=35). Notably, 22 (65%) of 34 cases and eight (24%) of 34 cases continued to shed infectious virus 5 days and 7 days post-symptom onset, respectively (survival probabilities 67% and 35%). Correlation of lateral flow device (LFD) results with infectious viral shedding was poor during the viral growth phase (sensitivity 67% [95% CI 59–75]), but high during the decline phase (92% [86–96]). Infectious virus kinetic modelling suggested that the initial rate of viral replication determines the course of infection and infectiousness. Interpretation Less than a quarter of COVID-19 cases shed infectious virus before symptom onset; under a crude 5-day self-isolation period from symptom onset, two-thirds of cases released into the community would still be infectious, but with reduced infectious viral shedding. Our findings support a role for LFDs to safely accelerate deisolation but not for early diagnosis, unless used daily. These high-resolution, community-based data provide evidence to inform infection control guidance. Funding National Institute for Health and Care Research.

SARS-CoV-2 immune-escape variants have only been observed to arise in immunosuppressed COVID-19 cases, during prolonged viral shedding. Through daily longitudinal RT-qPCR, quantitative viral culture and sequencing, we observe for the first time the evolution of transmissible variants harbouring mutations consistent with immune-escape in mild community cases within 2 weeks of infection.

BACKGROUND: Despite circumstantial evidence for aerosol and fomite spread of SARS-CoV-2, empirical data linking either pathway with transmission are scarce. Here we aimed to assess whether the presence of SARS-CoV-2 on frequently-touched surfaces and residents' hands was a predictor of SARS-CoV-2 household transmission. METHODS: In this longitudinal cohort study, during the pre-alpha (September to December, 2020) and alpha (B.1.1.7; December, 2020, to April, 2021) SARS-CoV-2 variant waves, we prospectively recruited contacts from households exposed to newly diagnosed COVID-19 primary cases, in London, UK. To maximally capture transmission events, contacts were recruited regardless of symptom status and serially tested for SARS-CoV-2 infection by RT-PCR on upper respiratory tract (URT) samples and, in a subcohort, by serial serology. Contacts' hands, primary cases' hands, and frequently-touched surface-samples from communal areas were tested for SARS-CoV-2 RNA. SARS-CoV-2 URT isolates from 25 primary case-contact pairs underwent whole-genome sequencing (WGS). FINDINGS: From Aug 1, 2020, until March 31, 2021, 620 contacts of PCR-confirmed SARS-CoV-2-infected primary cases were recruited. 414 household contacts (from 279 households) with available serial URT PCR results were analysed in the full household contacts' cohort, and of those, 134 contacts with available longitudinal serology data and not vaccinated pre-enrolment were analysed in the serology subcohort. Household infection rate was 28·4% (95% CI 20·8-37·5) for pre-alpha-exposed contacts and 51·8% (42·5-61·0) for alpha-exposed contacts (p=0·0047). Primary cases' URT RNA viral load did not correlate with transmission, but was associated with detection of SARS-CoV-2 RNA on their hands (p=0·031). SARS-CoV-2 detected on primary cases' hands, in turn, predicted contacts' risk of infection (adjusted relative risk [aRR]=1·70 [95% CI 1·24-2·31]), as did SARS-CoV-2 RNA presence on household surfaces (aRR=1·66 [1·09-2·55]) and contacts' hands (aRR=2·06 [1·57-2·69]). In six contacts with an initial negative URT PCR result, hand-swab (n=3) and household surface-swab (n=3) PCR positivity preceded URT PCR positivity. WGS corroborated household transmission. INTERPRETATION: Presence of SARS-CoV-2 RNA on primary cases' and contacts' hands and on frequently-touched household surfaces associates with transmission, identifying these as potential vectors for spread in households. FUNDING: National Institute for Health Research Health Protection Research Unit in Respiratory Infections, Medical Research Council.

Allochthonous transfers are ubiquitous features of marine ecosystems. While these transfers typically subsidise recipient ecosystems and increase donor control, mismatches in allochthony and biotic recipients can also occur. However, driving processes are not well understood, particularly in the context of biotic determinants in coastal ecosystems. Using a 2 yr dataset, we show that allochthonous inputs related to seasonal offshore upwelling on the west coast of South Africa do not lead to strengthening of bottom-up regulation in intertidal lagoonal sandflat ecosystems. Despite an increase in mean phytoplankton biomass by 46.4% at benthic study sites during summer upwelling seasons, benthic primary producer (microphytobenthos) biomass did not increase proportionally, and neither did consumer (macro- and meiofauna) population metrics. Unexpectedly, levels of these response variables were greater during winter downwelling periods than upwelling phases. Correlation analyses indicated that the bentho-pelagic mismatch documented in relation to upwelling may be related to coincidental increases in densities of endobenthic burrowing sandprawns Kraussillichirus kraussi, which are key ecosystem engineers, principally due to rapid sediment reworking and destabilisation. The predominantly negative correlations recorded between benthic response variables and sandprawn density align with our past experimental work, suggesting that the suppressive effect of sandprawns on benthic primary producers and consumers evident in small-scale experiments also manifests over large temporal scales, thereby overriding potential subsidising effects of upwelling. Our findings indicate that in sandflat ecosystems, endobenthic ecosystem engineers that are rapid benthic destabilisers may be important in determining responses to marine allochthonous inputs and the degree of donor control in recipient ecosystems.

Diamond mining on the southern Namibian coastline has created multiple large coastal ponds of up to 380 000 m2 adjacent to the coastline, as the sea overtops erected seawalls or seeps into excavated areas. These ponds span ages of 1–38 years. We investigated whether the ponds offer an environment for the establishment, growth and dispersal of saltmarsh vegetation along the coast, which is otherwise devoid of natural wetlands apart from at the Orange River estuary and Lüderitz Bay. Most ponds supported saltmarshes, but they comprised only a single species, Salicornia natalensis. The abundance of this succulent, mat-forming, salt-tolerant plant was greatest around old ponds, but its health decreased with increasing age and hence salinity of the ponds. The orientation of saltmarshes around the ponds was correlated with prevailing wind direction, suggesting that wind determines dispersal of this plant along the coast. However, any saltmarsh communities that have developed will be disturbed by possible future mining activities. In addition, once mining ends, the saltmarshes will become stressed owing to rising salinities as ponds age. Nevertheless, the ponds are capable of supporting saltmarshes for up to 15 years,and new ponds will be created as mining progresses; this offers an ongoing opportunity for the ponds to serve as ‘stepping stones’ in the dispersal and establishment of S. natalensis along the coast.

Rickettsia africae is a re-emerging tick-borne pathogen causing African tick bite fever (ATBF) in humans. Amblyomma variegatum is the principal vector in most sub-Sahara African countries, whereas in South Africa it is A. hebraeum. Reports of high genetic heterogeneity among R. africae isolates in southern Africa have prompted the need for molecular investigations of isolates form South Africa. Therefore, this study aimed to determine the prevalence and genetic diversity of R. africae in A. hebraeum collected from cattle, grazing pasture, as well as from blood of cattle in the Eastern Cape Province of South Africa. Amblyomma hebraeum and blood from cattle were screened by PCR and the gltA, ompA, ompB, sca4, and 17kDa genes were sequenced for R. africae from samples collected from Caquba in Port St. Johns along the coastal region in the Eastern Cape province of South Africa. The overall proportion of adult A. hebraeum that were positive for the gltA and ompA genes was 0.63 (108/180). The overall proportion of nymphs positive for the gltA and ompA genes was 0.62 (23/37) and 0.22 (20/90) from cattle blood. A positive R. africae infection was inferred by analysis of 26 sequences of the ompA, gltA, ompB, 17kDa and sca4 genes. Neighbour-joining and Maximum Likelihood analysis revealed that the study isolates were closely related to R. africae isolates from South Africa deposited in GenBank, forming a clade that was separate from north, east and west African strains. This study provides new information on the epidemiology and phylogeny of R. africae isolated from A. hebraeum ticks in the Eastern Cape province of South Africa. The heterogeneity observed between R. africae isolates from South Africa deposited in GenBank and R. africae isolates from Africa retrieved from Genbank highlight the importance of differentiation and tracking of the genetic movement among R. africae isolates in southern Africa for the better characterisation of ATBF cases, especially in rural communities and travellers visiting the region.

We aim to carry out a radio study of the SoUthern Cluster sCale Extended Source Survey (SUCCESS) sample consisting of twenty massive (M$_{500} > 5\times10^{14}$ M$_{\odot}$), nearby (redshift $, 20 pages, 17 figures, accepted for publication in MNRAS

Background: Malpositioned central venous access devices (CVADs) can lead to significant patient injury including central vein thrombosis and dysrhythmias. Intra-cavitary electrocardiography (IC ECG) has been recommended by peak professional bodies as an accurate alternative for bedside CVAD insertion, to reduce risk of malposition and allowing immediate use of the device. Our objective was to compare the effect of IC ECG on CVAD malposition compared to traditional institutional practice for CVAD placement. Methods: Randomised controlled trial of IC ECG CVAD insertion verses traditional CVAD insertion (surface landmark measurement with post insertion x ray). Patient recruitment was from December 2016 to July 2018. The setting was a 900-bed tertiary referral hospital based in South Western Sydney, Australia. Three hundred and forty-four adult patients requiring CVAD insertion for intravenous therapy, were enrolled and randomly allocated (1:1 ratio) to either IC-ECG (n = 172) or traditional (n = 172) CVAD insertion. Our primary outcome of interest was the rate of catheters not requiring repositioning after insertion (ready for use). Secondary outcomes were comparison of procedure time and cost. Results: Of the 172 patients allocated to the IC ECG method, 170 (99%) were ready for use immediately compared to 139 of the 172 (81%) in the traditional insertion group (difference, 95% confidence interval (CI): 18%, 11.9–24.1%). The total procedure time was mean 15 min (SD 8 min) for IC ECG and mean 36 min (SD 17 min) for traditional CVAD insertion (difference–19.9 min (95% CI–14.6 to −34.4). IC ECG guided CVAD insertion had a cost reduction of AUD $62.00 per procedure. Conclusions: Using IC-ECG resulted in nearly no requirement for post-insertion repositioning of CVADs resulting in savings in time and cost and virtually eliminating the need for radiographic confirmation. Trial registration: This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12620000919910. © The Author(s) 2022.

BackgroundThe success of case isolation and contact tracing for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS), i.e. fever, cough and loss or change in smell or taste, could improve case definitions and accelerate case identification in SARS-CoV-2 contacts.MethodsTwo prospective longitudinal London (UK)-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and area under the receiver operating characteristic curve. Improvements in sensitivity and time to detection were compared with penalties in terms of specificity and number needed to test.ResultsOf 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion “≥1 of the CS, or ≥2 of the EP” identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than “≥1 of the CS”, with only modest reduction in specificity (5.7%).ConclusionsBroadening symptom criteria to include individuals with at least two of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time to detection, providing greater opportunities to prevent SARS-CoV-2 transmission.

African tick bite fever (ATBF) is one of the most important rickettsial infections in international travellers to sub-Saharan Africa. The heterogeneity of Rickettsia africae infection rates among tick vector species has been studied. However, this information has not been systematised to allow for comparative estimates. Quantifying the trends and heterogeneity in R. africae infection rates among the different tick vector species is paramount in understanding the role in transmission to humans. A systematic search was conducted in PubMed, Web of Knowledge, Google Scholar, and SCOPUS from 2005 to 2020. The selection criteria included all studies in sub-Saharan Africa reporting R. africae infection rates in tick adults, nymphs, and larvae. A quality effects model was used in the meta-analysis due to the observed heterogeneity with an assessment of publication bias using funnel plots. The prevalence estimates were conducted by geographic region and tick genus from 32 studies reporting R. africae infection rates in ticks from sub-Saharan Africa. A total of 12,301 ticks comprising of adults (96.19%, n=11, 832), nymphs (3.6%, n=443) and larvae (0.2%, n=26) and 1214 pooled samples were evaluated for R. africae infection. The overall prevalence of R. africae was higher in Amblyomma spp. (48%, 95% CI: 26-70%) compared to Rhipicephalus spp. (1%, 95% CI: 0-5%), Hyalomma spp. (1%, 95% CI: 0-3%) and other tick genera (1%, 95% CI: 0-4%) throughout all regions. The highest prevalence in Amblyomma spp. was recorded in western Africa (53%, 95% CI: 14-90%) and in Rhipicephalus spp. in southern Africa (2%, 95% CI: 0-5%). Cattle were the most frequently sampled hosts across all tick vectors (62.98%, n=5492), followed by goats (19.07%, n= 1663) and sheep (9.1%, n= 793). To our knowledge, this is the first systematic and quantitative analysis of R. africae infection in tick vectors collected from mammalian hosts in sub-Saharan Africa. The results highlight a marked heterogeneity between species in different regions of sub-Saharan Africa and provide initial estimates of infection rates.

Background The SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community. Methods Between Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status. Findings The SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was similar to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs. Although peak viral load did not differ by vaccination status or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log10 viral load per mL between those aged 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log10 copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·13 to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]). Interpretation Vaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory. Funding National Institute for Health Research.

BACKGROUND: Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.METHODS: The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROC), sensitivities, and specificities.FINDINGS: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.INTERPRETATION: In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.FUNDING: National Institute for Health Research.

Objectives The wide spectrum of clinical outcomes to SARSCoV-2 exposure suggests that early immune responses play a pivotal role 1 We aim to describe early, longitudinal, local (nasal mucosal lining fluid) and systemic (peripheral blood) cytokine and cellular immune responses to SARS-CoV-2 in a symptomatic index case and their household contacts with detailed clinical and virological phenotyping We hypothesise that immune responses at symptom onset would correlate with outcomes Methods Participants from the London area are referred to INSTINCT study by general practitioners as suspected, or Public Health England as laboratory-confirmed, cases (ethical review details: IRAS 282820, approved 24 04 2020) Households are visited the day after identification and again on days 7, 15 and 28 Clinical and exposure questionnaires, samples of environment (surface swabs and air);oropharynx (swabs);nasal mucosa (synthetic absorptive matrix) and blood, and daily symptom diaries are collected Samples are analysed by PCR, serology, 20-plex cytokine assay and flow cytometry in institutional laboratories Results The index case was the first SARS-CoV-2 PCR-positive recruit of INSTINCT, confirmed on oropharyngeal swab 5 days after symptom onset Contacts 1 and 2, the spouse and daughter, became symptomatic 2 days after the index case and were confirmed PCR-positive 3 days after symptom onset The three PCR-positive individuals seroconverted during follow-up Contact 3, the son, remained asymptomatic, PCRand serology-negative throughout (figure 1a-b) None required hospitalisation Swabs of the kettle and fridge handles were positive for virus, while other household surfaces and air samples were negative Induction, peak and decline of interferonl-1 and IP-10 levels were captured in nasal mucosa, with lower serum levels (figures 1c-f) Conclusion These data demonstrate the ability of the INSTINCT household contact study to capture early immune responses in mild SARS-CoV-2 infection, not captured by COVID-19 hospital cohort studies Early nasal mucosal cytokine responses to SARS-CoV-2 infection are not reflected in serum The correlations observed provide cogent hypotheses that will be tested in the larger INSTINCT cohort, with implications for COVID-19 risk stratification, therapeutics, prophylaxis and vaccinology

Background: The SARS-CoV-2 Delta variant is highly transmissible and spreading globally but a detailed understanding of community transmission risks in highly vaccinated populations is lacking. Methods: Between September 2020 and August 2021, we recruited 510 community contacts of 422 UK COVID-19 cases to a cohort study. A total of 7194 upper respiratory tract (URT) samples were tested from sequential daily sampling of participants for up to 20 days. We analysed transmission risk by vaccination status for 139 contacts exposed to the Delta variant. We compared viral load (VL) trajectories from fully-vaccinated cases of Delta infection (n=19) with unvaccinated Delta (n=10), Alpha (n=39) and pre-Alpha (n=49) infections. Findings: The household secondary attack rate for fully-vaccinated contacts exposed to Delta was 19.7% (95%CI:11.6-31.3%), compared with 35.7% (95%CI:16.4-61.2%) in the unvaccinated. One third of infections in Delta-exposed contacts arose from fully-vaccinated index cases and one half of infected contacts were also fully-vaccinated. Seven transmission events between fully vaccinated index-contact pairs occurred. Genomic analysis confirmed transmission pathways between fully-vaccinated individuals within three households. Peak VL was similar in vaccinated and unvaccinated individuals with Delta variant infection but vaccinated Delta cases saw significantly faster VL decline than unvaccinated Alpha or Delta cases. Within infected individuals, faster VL growth was correlated with higher peak VL and slower decline. Interpretation: Although vaccination reduces the risk of Delta infection and causes some changes to viral kinetics, fully-vaccinated individuals with breakthrough infections have peak URT VL similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Funding: National Institute for Health Research (Award:NIHR200927) Declaration of Interest: The authors declare no relevant conflicts. Ethical Approval: The study was approved by the Health Research Authority (Research Ethics Committee reference: 20/NW/0231).

Supplemental Digital Content is available in the text., Importance: Management of severe coronavirus disease 2019 relies on advanced respiratory support modalities including invasive mechanical ventilation, continuous positive airway pressure, and noninvasive ventilation, all of which are associated with the development of subcutaneous emphysema, pneumomediastinum, and pneumothorax (herein collectively termed barotrauma). Objectives: To assess the occurrence rate of barotrauma in severe coronavirus disease 2019 and to explore possible associated factors. Design, Setting, and Participants: A retrospective, single-center cohort study with nested case series, conducted at University Hospital Lewisham: a 450-bed general hospital in London, United Kingdom. All patients with confirmed coronavirus disease 2019 admitted to the critical care department from March 12, to April 12, 2020, were included. Main Outcomes and Measures: Patients were retrospectively screened for radiological evidence of barotrauma. Admission characteristics, modalities of respiratory support, and outcomes were compared between barotrauma and nonbarotrauma groups. Respiratory parameters in the period preceding barotrauma identification were recorded. Results: Of 83 admissions with coronavirus disease 2019, eight suffered barotrauma (occurrence rate 9.6%; 95% CI 4.3%–18.1%). Barotrauma cases had longer illness duration prior to critical care admission (10 vs 7 d; interquartile range, 8–14 and 6–10, respectively; p = 0.073) and were more often treated with continuous positive airway pressure or noninvasive ventilation as the initial modality of advanced respiratory support (87.5% vs 36.0%; p = 0.007). Patients managed with continuous positive airway pressure or noninvasive ventilation prior to the development of barotrauma had median minute ventilation of 16.2–19.9 and 21.3–22.7 L/min, respectively. Compared with the nonbarotrauma group, a higher proportion of patients with barotrauma had died (62.5% vs 43.2%), and a lower proportion of patients had been discharged (25.0% vs 53.3%) at 3-month follow-up. Conclusions and Relevance: Barotrauma appears to be a common complication of severe coronavirus disease 2019. Determining whether high minute ventilation while using continuous positive airway pressure or noninvasive ventilation predisposes patients to barotrauma requires further investigation.

Rickettsia africae is a re-emerging tick-borne pathogen causing African tick bite fever (ATBF) in humans. Amblyomma variegatum is the principal vector in most sub-Sahara African countries, whereas in South Africa it is A. hebraeum. Reports of high genetic heterogeneity among R. africae isolates in southern Africa have prompted the need for molecular investigations of isolates form South Africa. Therefore, this study aimed to determine the prevalence and genetic diversity of R. africae in A. hebraeum collected from cattle, grazing pasture, as well as from blood of cattle in the Eastern Cape Province of South Africa. Amblyomma hebraeum and blood from cattle were screened by PCR and the gltA, ompA, ompB, sca4, and 17kDa genes were sequenced for R. africae from samples collected from Caquba in Port St. Johns along the coastal region in the Eastern Cape province of South Africa. The overall proportion of adult A. hebraeum that were positive for the gltA and ompA genes was 0.63 (108/180). The overall proportion of nymphs positive for the gltA and ompA genes was 0.62 (23/37) and 0.22 (20/90) from cattle blood. A positive R. africae infection was inferred by analysis of 26 sequences of the ompA, gltA, ompB, 17kDa and sca4 genes. Neighbour-joining and Maximum Likelihood analysis revealed that the study isolates were closely related to R. africae isolates from South Africa deposited in GenBank, forming a clade that was separate from north, east and west African strains. This study provides new information on the epidemiology and phylogeny of R. africae isolated from A. hebraeum ticks in the Eastern Cape province of South Africa. The heterogeneity observed between R. africae isolates from South Africa deposited in GenBank and R. africae isolates from Africa retrieved from Genbank highlight the importance of differentiation and tracking of the genetic movement among R. africae isolates in southern Africa for the better characterisation of ATBF cases, especially in rural communities and travellers visiting the region.

Background Hand, foot and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) is associated with acute neurological disease in children. This study aimed to estimate the burden of long-term sequelae and death following severe HFMD. Methods This systematic review and meta-analysis pooled all reports from English and Chinese databases including MEDLINE and Wangfang on outbreaks of clinically diagnosed HFMD and/or laboratory-confirmed EV-A71 with at least 7 days' follow-up published between 1st January 1966 and 19th October 2015. Two independent reviewers assessed the literature. We used a random effects meta-analysis to estimate cumulative incidence of neurological sequelae or death. Studies were assessed for methodological and reporting quality. PROSPERO registration number: 10.15124/CRD42015021981. Findings 43 studies were included in the review, and 599 children from 9 studies were included in the primary analysis. Estimated cumulative incidence of death or neurological sequelae at maximum follow up was 19.8% (95% CI:10.2%, 31.3%). Heterogeneity (I^2) was 88.57%, partly accounted for by year of data collection and reporting quality of studies. Incidence by acute disease severity was 0.00% (0.00, 0.00) for grade IIa; 17.0% (7.9, 28.2) for grade IIb/III; 81.6% (65.1, 94.5) for grade IV (p ¼ 0.00) disease. Conclusions HFMD with neurological involvement is associated with a substantial burden of long-term neurological sequelae. Grade of acute disease severity was a strong predictor of outcome. Strengths of this study include its bilingual approach and clinical applicability. Future prospective and interventional studies must use rigorous methodology to assess long-term outcomes in survivors.

Ideal control of diabetes mellitus (DM) remains a global goal, which has not yet been reached. As part of an integrated public healthcare strategy, data with subsequent analysis of diabetes control achieved in patients living with DM (PLWD) need to be available. Diabetes control data from KwaZulu-Natal (KZN) Province, South Africa, are scarce. Smaller studies conducted in public and private healthcare sectors of KZN have shown suboptimal DM control.To identify the percentage of glycated haemoglobin (HbA1c) tests done in KZN public healthcare facilities, and to provide a glimpse into diabetes control being achieved in each KZN district municipality.Data regarding the number of HbA1c tests performed, number of patients with an HbA1c ≤7% and number of diabetes visits were accessed from the KZN Department of Health Information Systems and analysed.The majority of HbA1c tests were performed in the metro municipality of eThekwini (plt;0.001). Approximately two-thirds (64.5%) of PLWD in whom HbA1c tests had been performed, were suboptimally controlled. In 5 of the 11 KZN district municipalities more than two-thirds of PLWD had an HbA1cgt;7%. Most of the patients in 9 of the 11 district municipalities showed suboptimal control of their DM. The total number of HbA1c tests performed in KZN represents approximately one-tenth of the total number of diabetes treatment visits. This trend was prevalent in all 11 district municipalities, where the incidence of DM was on an upward trajectory.Our study demonstrated that the majority of PLWD visiting public healthcare facilities in KZN have suboptimal glycaemic control. They are at increased risk of developing diabetes-related complications, further burdening the healthcare fiscus of low- to middle-income countries. We also showed that the number of HbA1c tests being performed, in the presence of suboptimal control, was well below par. This finding serves to emphasise the need for strategies to be implemented to increase awareness of HbA1c testing for the monitoring of glycaemic control, and for making point-of-care HbA1c testing readily available in these healthcare facilities.

Background . Anecdotally, 2015 was declared the year of the selfie. The theme of selfies is used as an opportunity to engage neuroanatomy students by drawing from it as a newly created art form by means of models and video clips. Objectives. To provide a synopsis of student perceptions of a team project to inform further project development and refinement. Methods. Topics were allocated to teams of 5 - 6 students, constituting a class of 27. Teams were required to prepare a model that would demonstrate a topic, which would be used to produce a video clip presented as a teaching tool. Three focus groups comprising 6 - 8 students subsequently held discussions to determine student perspectives of the project. Results. Students viewed the project as a means of facilitating teamwork and peer learning and of enhancing presentation skills. While all the teams enjoyed the project and found it to be beneficial, students preferred making the model rather than producing the video clip. Nonetheless, students felt particularly accomplished on seeing the completed video clip. A dominant view was that the project provided enhancement of the subject content, pertaining largely to the team’s project, while the knowledge gained of other topics was limited. Some students preferred conventional teaching and found the synopsis provided by the lecturer at the end of each presentation to be particularly useful. Conclusion. This case study provides evidence to support simple strategies of integrating discipline-specific content (‘hard skills’) with general education (‘soft skills’), as required of higher education.

Background. Allogeneic haemopoietic stem cell transplant (Allo-HSCT) is a specialised and costly intervention, associated with significant morbidity and mortality. It is used to treat a broad range of paediatric conditions. South Africa (SA) is an upper middle-income country with limitations on healthcare spending. The role of paediatric Allo-HSCT in this setting is reviewed. Objectives. To review paediatric patients who underwent Allo-HSCT at the Groote Schuur Hospital/University of Cape Town Private Academic Hospital transplant unit in Cape Town, South Africa, and received post-transplant care at Red Cross War Memorial Children’s Hospital, over the period January 2006 - December 2014 in respect of indications for the transplant, donor sources, conditioning regimens, treatment-related morbidity and overall survival (OS). Methods. A retrospective analysis of patient records was performed and a database was created in Microsoft Access. Descriptive analyses of relevant demographic, clinical and laboratory data were performed. Summary statistics of demographic and clinical parameters were derived with Excel. OS was calculated from the date of transplant to the date of an event (death) or last follow-up using the Kaplan-Meier method in Statistica. Results. A total of 48 children received Allo-HSCT: 24 for haematological malignancies, 20 for non-oncological haematological conditions, 3 for immune disorders and 1 for adrenoleukodystrophy. There were 28 boys (median age 7.5 years) and 20 girls (8.5 years). There were 31 sibling matched peripheral-blood stem cell (PBSC) transplants and 1 maternal haploidentical PBSC transplant. Stem cells were mobilised from bone marrow into peripheral blood by administering granulocyte-colony stimulating factor to donors. PBSCs were harvested by apheresis. Eight patients received 10/10 HLA-matched grafts from unrelated donors. Six were PBSC grafts and 2 were bone marrow grafts. Three of the unrelated PBSC grafts were from SA donors. Eight transplants used umbilical cord blood from international registries. OS for patients with non-oncological disorders was 91.3% (median follow-up 3.9 years), while that for oncology patients was 56.8% (1.9 years). Two of the survivors developed chronic graft-versus-host disease. Conclusions. OS for non-oncological conditions was excellent, while outcomes for oncological disorders were on par with those in high-income settings. Transplantation offers many patients the opportunity for long-term survival and has been shown to be both feasible and rewarding in a less well-resourced environment servicing an economically diverse population.

OBJECTIVES Transmission of drug-resistant HIV-1 has decreased in the UK since the early 2000s. This analysis reports recent trends and characteristics of transmitted drug resistance (TDR) in the UK from 2010 to 2013. METHODS Resistance tests conducted in antiretroviral treatment (ART)-naive individuals between 2010 and 2013 were analysed for the presence of transmitted drug resistance mutations (TDRMs), defined as any mutations from a modified 2009 World Health Organization surveillance list, or a modified 2013 International Antiviral Society-USA list for integrase tests. Logistic regression was used to examine associations between demographics and the prevalence of TDRMs. RESULTS TDRMs were observed in 1223 (7.5%) of 16 425 individuals; prevalence declined from 8.1% in 2010 to 6.6% in 2013 (P = 0.02). The prevalence of TDRMs was higher among men who have sex with men (MSM) compared with heterosexual men and women (8.7% versus 6.4%, respectively) with a trend for decreasing TDRMs among MSM (P = 0.008) driven by a reduction in nucleoside reverse transcriptase inhibitor (NRTI)-related mutations. The most frequently detected TDRMs were K103N (2.2%), T215 revertants (1.6%), M41L (0.9%) and L90M (0.7%). Predicted phenotypic resistance to first-line ART was highest to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) rilpivirine and efavirenz (6.2% and 3.4%, respectively) but minimal to NRTIs, including tenofovir, and protease inhibitors (PIs). No major integrase TDRMs were detected among 101 individuals tested while ART-naive. CONCLUSIONS We observed a decrease in TDRMs in recent years. However, this was confined to the MSM population and rates remained stable in those with heterosexually acquired HIV infection. Resistance to currently recommended first-line ART, including integrase inhibitors, remained reassuringly low.

Background. The administration of intravenous contrast media (IVCM) is one of the key areas currently under investigation for inclusion in the South African (SA) radiographers’ scope of practice. However, for the radiographers to legally administer IVCM, training guidelines must first be identified, developed and accredited by the Health Professions Council of SA. Objective. To investigate the radiologists’ perspective of the knowledge, skills and medicolegal training required of radiographers for the administration of IVCM to provide input for the development of national training guidelines. Methods. A quantitative, cross-sectional research study using an online survey, administered by SurveyMonkey, was conducted. The target population included all radiologists residing and practising in the province of KwaZulu-Natal, SA. Results. Fifty-nine participants (60.8%) completed the online survey. Twelve were excluded owing to incomplete surveys, resulting in a final response rate of 48.5% ( n =47). The study revealed that various theoretical, clinical/practical and medicolegal study units should be included in the training, i.e. the study of the pharmacology of contrast media, practical training on cardiopulmonary resuscitation and basic life support, as well as the rights and responsibilities of a healthcare professional. In addition, both theory and practical/clinical assessments need to be included. Conclusion. Key data have been provided for the development of national training guidelines for radiographers to administer IVCM, based on scientific evidence that is relevant to the SA context. The study may be of value to other related health professions where scopes of practice are expanded through transforming the education and training curricula.

Objective To compare all-cause and cause-specific mortality among 3 distinct groups: within-country, rural-to-urban migrants, and rural and urban dwellers in a longitudinal cohort in Peru. Methods The PERU MIGRANT Study, a longitudinal cohort study, used an age-stratified and sex-stratified random sample of urban dwellers in a shanty town community in the capital city of Peru, rural dwellers in the Andes, and migrants from the Andes to the shanty town community. Participants underwent a questionnaire and anthropomorphic measurements at a baseline evaluation in 2007–2008 and at a follow-up visit in 2012–2013. Mortality was determined by death certificate or family interview. Results Of the 989 participants evaluated at baseline, 928 (94%) were evaluated at follow-up (mean age 48 years; 53% female). The mean follow-up time was 5.1 years, totalling 4732.8 person-years. In a multivariable survival model, and relative to urban dwellers, rural participants had lower all-cause mortality (HR=0.27; 95% CI 0.07 to 0.98), and both the rural (HR=0.07; 95% CI 0.01 to 0.87) and migrant (HR=0.13; 95% CI 0.02 to 0.81) groups had lower cardiovascular mortality. Conclusions Cardiovascular mortality of migrants remains similar to that of the rural group, suggesting that rural-to-urban migrants do not appear to catch up with urban mortality in spite of having a more urban cardiovascular risk factor profile.

ObjectiveTo determine the effect of increasing fruit visibility, adding information and lowering price on fruit purchasing at a university cafeteria in Lima, Peru.DesignQuasi-experimental pilot study of a three-phase stepped intervention. In Phase 1, fruit was displayed >3 m from the point of purchase with no additional information. Phase 2 consisted in displaying the fruit near the point of purchase with added health and price information. Phase 3 added a 33 % price reduction. The duration of each phase was 3 weeks and phases were separated by 2-week breaks. Primary outcomes were total pieces of fruit and number of meals sold daily.SettingA university cafeteria in Lima, Peru.SubjectsApproximately 150 people, students and non-student adults, who purchased food daily. Twelve students participated in post-intervention interviews.ResultsFruit purchasing doubled from Phase 1 to Phase 3 (PPPPPConclusionsPromoting fruit consumption by product placement close to the point of purchase, adding health information and price reduction had a positive effect on fruit purchasing in a university cafeteria, especially in males and non-student adults.

Background This longitudinal study aimed to evaluate the impact of a multifaceted educational intervention (Sexual Health in Practice, SHIP) on general practice HIV testing rates in a high prevalence London area. Intervention SHIP offered training in sexual health clinical skills to general practitioners (GPs) and practice nurses (PNs) in Haringey. SHIP training aims to break down stigma in sexual health and provide sexual history and communication tools (e.g. differential diagnosis), and provides resources to practices (including condoms). Design Numbers of GP HIV tests were collected from laboratories for 24 months prior, 19 months during and 5 months after training. Attendance data and practice list sizes were obtained. Results 39 of 51 practices had at least one trained individual. These ‘trained’ practices conducted an average 526 HIV tests p.a. before training began which rose to a projected 1556 p.a. (on the basis of the last 6 months of data). Testing rates of trained and untrained practices increased from 2.29 to 6.66 and 1.54 to 1.90 tests/1000 registered patients/year (p=0.0016 and p=0.5195) respectively. The rate of positive diagnosis was high in the trained group (18.0 and 16.7 positives/1000 tests before and after training began; p=0.7908). This equates to a rise from 9.5 to 22 new diagnoses p.a. Conclusions The training intervention has been found to significantly increase general practice HIV testing rates in the absence of financial incentives. Positivity rates are substantially higher than that found in pilots of screening in London, suggesting that the training nurtured and supplemented complex clinical skills.

Background. Global trends in the delivery of healthcare services have placed tremendous strain on resources, among them human and capital. With this has emerged the need to revisit the job requirements and/or scope of practice of cadres within a profession, to ensure adequate training where needed. The administration of intravenous contrast media (IVCM), a fundamental element of expertise within the radiology field, is an example of such evolution in South Africa (SA). Currently falling within radiologists’ scope of practice, it has become necessary for radiographers to extend their own scope to include this skill, owing to the national shortage of radiologists and subsequent service delivery constraints, as well as the need to close the gap with international trends. Objective. To provide a synopsis of the perspectives of radiologists on the medicolegal responsibilities related to the administration of IVCM by radiographers. Methods. A quantitative, descriptive, cross-sectional research design was conducted, targeting qualified radiologists in KwaZulu-Natal Province (KZN). An online questionnaire was administered through SurveyMonkey that provided information on the medicolegal responsibilities associated with the administration of IVCM. Results. Of a total of 97 qualified radiologists in KZN, a response rate of 48.5% ( n =47) was obtained. The majority of respondents felt that radiographers should be responsible for obtaining informed patient consent (66.0%), and deciding on the site of IVCM administration (72.3%). It was also felt that the radiologists should remain responsible for decisions regarding the type and dose of IVCM (87.2%) and managing the possible complications and adverse reactions due to the administration of IVCM (78.7%). Conclusion. Evidence-based research provides a contextualised approach towards addressing transformation in service delivery and training needs. This study, in demonstrating the importance of appropriate medicolegal responsibilities in the extension of a professional role, forms a basis for informing the future training of radiographers in SA.

P Naidoo, D Pillay, S SamanDepartment of Internal Medicine, Port Shepstone Regional Hospital, University of KwaZulu-Natal, South AfricaAbstract: A 37-year-old female presented confused with a preceding history of severe headache. After clinical examination and investigations, she was diagnosed with disseminated tuberculosis (including central nervous system involvement), and Human immunodeficiency virus/acquired immune deficiency syndrome. Her hospital stay was complicated. She developed stridor and a cerebrovascular accident with left hemiplegia. She died approximately 2 weeks after admission. The potential causes of her stridor included a mediastinal mass or a central mechanism secondary to tuberculosis meningitis. Limited resources precluded definitive imaging of the chest to rule out a mediastinal mass. Further, an autopsy was not done. Despite these limitations, this case is unique because it reports the presence of both stridor and tuberculosis meningitis in an adult patient.Keywords: Human immunodeficiency virus, acquired immune deficiency syndrome, meningitis, stridor, tuberculosis

A positive attitude to patients with mental illness is important in all branches of medicine, as it can impact on the quality of care patients receive from doctors. Attitudes of preclinical medical students is an under researched area. This study aims to (1) assess the attitudes of preclinical and clinical medical students to patients with mental illness and (2) assess the effect of two modules taught using different teaching methods on students’ attitudes to patients with mental illness. During the same academic year all students (N = 394) completing the year 3 preclinical psychiatry module and the final year psychiatry module completed an attitudinal questionnaire at the beginning and following completion of the module. Seventy-two percent of students completed both pre- and post-module questionnaires in full (n = 285). There was no significant difference in attitudes displayed by preclinical and clinical medical students prior to starting their respective modules. An association was found between female gender and more tolerant attitudes (r = 0.20, p = 0.02). Students who knew someone with experience of mental illness were associated with more tolerant attitudes (r = 0.32, p

Governments around the world are struggling to address persistent disparities in health care access. However, this priority competes with many others for support in moving onto and up the political agenda. In this paper, a novel method of agenda-setting analysis is developed by merging and modifying the Hall and Kingdon models. As a case study, this method is used to explore how health financing reform reached the policy agenda in South Africa between the years 2000 and 2010. Certain factors are identified that could have determined the agenda-setting process: a change in government, increase in the cost of private medical schemes, and increase in support for reform from various stakeholders. Further analysis, using a conceptual framework of interacting trends and shocks, identifies the growing middle class, the private sector, and workers unions as powerful actors and outlines further factors that may have contributed to the process: a broad political shift in the second half of the decade and the changing prioritisation of HIV/AIDS. Study findings have relevance to academics and policy makers in South Africa and beyond.