Plasmodium malariae and Plasmodium ovale infections and their association with common red blood cell polymorphisms in a highly endemic area of Uganda.

BACKGROUND: Plasmodium ovale and Plasmodium malariae infections are scarcely studied in sub-Saharan Africa, where the Plasmodium falciparum species predominates. The objective of this study is to investigate the prevalence of P. ovale and P. malariae infections and their relationship with common red blood cell polymorphisms in a cohort of 509 individuals from Uganda. METHODS: Three cross-sectional surveys were conducted in individuals of 1-10 and >20 y of age from the Apac district at baseline and 6 and 16 weeks after drug treatment. Malaria infections were assessed by polymerase chain reaction and genotyping was performed for the sickle-cell allele, α-thalassaemia and glucose-6-phosphate dehydrogenase. RESULTS: At baseline, the prevalence of infection was 7.5%, 12.6% and 57.4% for P. ovale, P. malariae and P. falciparum species, respectively. Co-infections were present in 14.1% of individuals, all including P. falciparum parasites. In children 1-5 y of age, the prevalence of P. ovale mono-infections increased significantly from 1.7% to 7.3% over time (p=0.004) while the prevalence of P. malariae and P. falciparum infections declined significantly during this study. After adjusting for confounding and multiple testing, only α-thalassaemia had a statistically significant increase in the odds of P. falciparum infections (odds ratio 1.93 [95% confidence interval 1.26 to 2.94]). CONCLUSIONS: Common red blood cell polymorphisms do not show strong effects on mild Plasmodium infections in this Ugandan population. To understand the extent of this result, similar studies should be carried out in other populations using larger cohorts

Towards the development of a SARS-CoV-2 variant risk assessment tool:expert consultation on the assessment of scientific evidence on emerging variants

A systematic approach is required for the development of an evidence-based risk assessment tool to robustly estimate the risks and implications of SARS-CoV-2 variants. We conducted a survey among experts involved in technical advisory roles for WHO to capture their assessment of the robustness of different study types that provide evidence for potential changes in transmissibility, antigenicity, virulence, treatability, and detectability of SARS-CoV-2 variants. The views of 62 experts indicated that studies could be grouped on the basis of robustness and reliability for the different risk indicators mentioned. Several study types that experts scored as providing reliable evidence and that can be performed in a timely manner were identified. Although experts from different technical areas had varying responses, there was agreement on the highest and lowest scoring study types. These findings can help to prioritise, harmonise, and optimise study designs for the further development of a systematic, evidence-based, SARS-CoV-2 variant risk assessment tool.</p

Assessment of a health facility based active case finding system for Ebola virus disease in Mbandaka, Democratic Republic of the Congo, June-July 2018.

BACKGROUND: The ninth outbreak of Ebola Virus Disease (EVD) in the Democratic Republic of the Congo occurred in Équateur Province from 8 May-24 July 2018. A system of health facility (HF)-based active case finding (ACF) was implemented in Mbandaka, a regional capital with four confirmed EVD cases, following completion of contact tracing. The goal of this HF-based ACF system was to look for undetected EVD cases among patients that visited HFs beginning one week prior to the system's implementation. METHODS: From 23 June - 24 July 2018, ACF teams visited HFs in Mbandaka and reviewed all medical records as far back as 17 June for any consultations meeting the suspected EVD case definition. The teams then assessed whether to validate these as suspected EVD cases based on factors such as recovery, epidemiological links, and their clinical judgement. ACF teams also assessed HFs' awareness of EVD symptoms and the process for alerting suspected cases. We calculated descriptive statistics regarding the characteristics of reviewed consultations, alert cases, and visited HFs. We also used univariate and multivariate random effects logistic regression models to evaluate the impact of repeated ACF visits to the same HF on the staff's awareness of EVD. RESULTS: ACF teams reviewed 37,746 consultations, of which 690 met the definition of a suspected case of EVD. Two were validated as suspected EVD cases and transferred to the Ebola Treatment Unit for testing; both tested negative. Repeated ACF visits to the same HF were significantly associated with improved EVD awareness (p < 0.001) in univariate and multivariate analyses. CONCLUSION: HF-based ACF during EVD outbreaks may improve EVD awareness and reveal many individuals meeting the suspected case definition. However, many who meet this definition may not have EVD, depending on the population size covered by ACF and amount of ongoing EVD transmission. Given the burdensome procedure of testing suspected EVD cases, future HF-based ACF systems would benefit from improved clarity on which patients require further testing

Sex practices and awareness of Ebola virus disease among male survivors and their partners in Guinea.

INTRODUCTION: Towards the end of the 2013-2016 West African outbreak, sexually-transmitted Ebola virus re-emerged from Ebola virus disease (EVD) survivors in all three hardest hit countries. We explore sex practices and awareness of the risk of Ebola virus transmission among EVD survivors and their partners. METHODS: In this cross-sectional study, we recruited a convenience sample of study participants aged >15 years who were male EVD survivors, their sexual partners and a comparison group. We administered a questionnaire to all respondents, estimated self-reported sexual practices and risk awareness and conducted in-depth interviews. RESULTS: We recruited 234 EVD survivors, 256 sexual partners of survivors and 65 individuals in the comparison group from five prefectures in Guinea. The prevalence of safe sexual behaviour (regular condom use or sexual abstinence >12 months) and regular condom use in EVD survivors was 38% (95% CI 31% to 44%) and 21% (95% CI 16% to 27%), respectively. Among partners, these prevalences were lower (11%, 95% CI 7% to 15% and 9%, 95% CI 5% to 12%, respectively). EVD survivors were more than five times as likely to engage in safe sexual behaviour compared with the comparison group (aOR 5.59, 95% CI 2.36 to 13.2). One-hundred and thirty one EVD survivors (57%) and 94 partners (37%) were aware of the risk of Ebola virus re-emergence associated with having unsafe sex. Partners who reported not being informed by their husband/boyfriend (EVD survivor) were more likely to be unaware of this risk (aOR 20.5, 95% CI 8.92 to 47.4). CONCLUSIONS: We disclose here a need to improve knowledge of the disease and close the gap between knowledge and practice found in EVD survivors and their partners. Current and future survivors' follow-up programmes should include partners and be more effective at communicating sex-related risks. Community-level fears and attitudes that enable stigmatisation should be addressed. Safe sex interventions targeting EVD survivors and their partners should be prioritised

Subsequent mortality in survivors of Ebola virus disease in Guinea: a nationwide retrospective cohort study.

BACKGROUND: A record number of people survived Ebola virus infection in the 2013-16 outbreak in west Africa, and the number of survivors has increased after subsequent outbreaks. A range of post-Ebola sequelae have been reported in survivors, but little is known about subsequent mortality. We aimed to investigate subsequent mortality among people discharged from Ebola treatment units. METHODS: From Dec 8, 2015, Surveillance Active en ceinture, the Guinean national survivors' monitoring programme, attempted to contact and follow-up all survivors of Ebola virus disease who were discharged from Ebola treatment units. Survivors were followed up until Sept 30, 2016, and deaths up to this timepoint were recorded. Verbal autopsies were done to gain information about survivors of Ebola virus disease who subsequently died from their closest family members. We calculated the age-standardised mortality ratio compared with the general Guinean population, and assessed risk factors for mortality using survival analysis and a Cox proportional hazards regression model. FINDINGS: Of the 1270 survivors of Ebola virus disease who were discharged from Ebola treatment units in Guinea, information was retrieved for 1130 (89%). Compared with the general Guinean population, survivors of Ebola virus disease had a more than five-times increased risk of mortality up to Dec 31, 2015 (age-standardised mortality ratio 5·2 [95% CI 4·0-6·8]), a mean of 1 year of follow-up after discharge. Thereafter (ie, from Jan 1-Sept 30, 2016), mortality did not differ between survivors of Ebola virus disease and the general population. (0·6 [95% CI 0·2-1·4]). Overall, 59 deaths were reported, and the cause of death was tentatively attributed to renal failure in 37 cases, mostly on the basis of reported anuria. Longer stays (ie, equal to or longer than the median stay) in Ebola treatment units were associated with an increased risk of late death compared with shorter stays (adjusted hazard ratio 2·62 [95% CI 1·43-4·79]). INTERPRETATION: Mortality was high in people who recovered from Ebola virus disease and were discharged from Ebola treatment units in Guinea. The finding that survivors who were hospitalised for longer during primary infection had an increased risk of death, could help to guide current and future survivors' programmes and in the prioritisation of funds in resource-constrained settings. The role of renal failure in late deaths after recovery from Ebola virus disease should be investigated. FUNDING: WHO, International Medical Corps, and the Guinean Red Cross

Monitoring of human coronaviruses in Belgian primary care and hospitals, 2015-20: a surveillance study.

BACKGROUND: Seasonal human coronaviruses (hCoVs) broadly circulate in humans. Their epidemiology and effect on the spread of emerging coronaviruses has been neglected thus far. We aimed to elucidate the epidemiology and burden of disease of seasonal hCoVs OC43, NL63, and 229E in patients in primary care and hospitals in Belgium between 2015 and 2020. METHODS: We retrospectively analysed data from the national influenza surveillance networks in Belgium during the winter seasons of 2015-20. Respiratory specimens were collected through the severe acute respiratory infection (SARI) and the influenza-like illness networks from patients with acute respiratory illness with onset within the previous 10 days, with measured or reported fever of 38°C or greater, cough, or dyspnoea; and for patients admitted to hospital for at least one night. Potential risk factors were recorded and patients who were admitted to hospital were followed up for the occurrence of complications or death for the length of their hospital stay. All samples were analysed by multiplex quantitative RT-PCRs for respiratory viruses, including seasonal hCoVs OC43, NL63, and 229E. We estimated the prevalence and incidence of seasonal hCoV infection, with or without co-infection with other respiratory viruses. We evaluated the association between co-infections and potential risk factors with complications or death in patients admitted to hospital with seasonal hCoV infections by age group. Samples received from week 8, 2020, were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). FINDINGS: 2573 primary care and 6494 hospital samples were included in the study. 161 (6·3%) of 2573 patients in primary care and 371 (5·7%) of 6494 patients admitted to hospital were infected with a seasonal hCoV. OC43 was the seasonal hCoV with the highest prevalence across age groups and highest incidence in children admitted to hospital who were younger than 5 years (incidence 9·0 [95% CI 7·2-11·2] per 100 000 person-months) and adults older than 65 years (2·6 [2·1-3·2] per 100 000 person-months). Among 262 patients admitted to hospital with seasonal hCoV infection and with complete information on potential risk factors, 66 (73·3%) of 90 patients who had complications or died also had at least one potential risk factor (p=0·0064). Complications in children younger than 5 years were associated with co-infection (24 [36·4%] of 66; p=0·017), and in teenagers and adults (≥15 years), more complications arose in patients with a single hCoV infection (49 [45·0%] of 109; p=0·0097). In early 2020, the Belgian SARI surveillance detected the first SARS-CoV-2-positive sample concomitantly with the first confirmed COVID-19 case with no travel history to China. INTERPRETATION: The main burden of severe seasonal hCoV infection lies with children younger than 5 years with co-infections and adults aged 65 years and older with pre-existing comorbidities. These age and patient groups should be targeted for enhanced observation when in medical care and in possible future vaccination strategies, and co-infections in children younger than 5 years should be considered during diagnosis and treatment. Our findings support the use of national influenza surveillance systems for seasonal hCoV monitoring and early detection, and monitoring of emerging coronaviruses such as SARS-CoV-2. FUNDING: Belgian Federal Public Service Health, Food Chain Safety, and Environment; Belgian National Insurance Health Care (Institut national d'assurance maladie-invalidité/Rijksinstituut voor ziekte-en invaliditeitsverzekering); and Regional Health Authorities (Flanders Agentschap zorg en gezondheid, Brussels Commission communautaire commune, Wallonia Agence pour une vie de qualité)

Evolution of seroprevalence to SARS-CoV-2 in blood donors in Sarajevo Canton, Federation of Bosnia and Herzegovina: Cross-sectional and longitudinal studies

Background: Sarajevo Canton in the Federation of Bosnia and Herzegovina has recorded several waves of high SARS-CoV-2 transmission and has struggled to reach adequate vaccination coverage. We describe the evolution of infection- and vaccine- induced SARS-CoV-2 antibody response and persistence. Methods: We conducted repeated cross-sectional analyses of blood donors aged 18–65 years in Sarajevo Canton in November–December 2020 and 2021. We ana- lyzed serum samples for anti-nucleocapsid (anti-N) and anti-spike (anti-S) antibodies. To assess immune durability, we conducted longitudinal analyses of seropositive participants at 6 and 12 months. Results: One thousand fifteen participants were included in Phase 1 (November– December 2020) and 1152 in Phase 2 (November–December 2021). Seropreva- lence increased significantly from 19.2% (95% CI: 17.2%–21.4%) in Phase 1 to 91.6% (95% CI: 89.8%–93.1%) in Phase 2. Anti-S IgG titers were significantly higher among vaccinated (58.5%) than unvaccinated infected participants across vaccine products (p < 0.001), though highest among those who received an mRNA vaccine. At 6 months, 78/82 (95.1%) participants maintained anti-spike seroposi- tivity; at 12 months, 58/58 (100.0%) participants were seropositive, and 33 (56.9%) had completed the primary vaccine series within 6 months. Among 11 unvaccinated participants who were not re-infected at 12 months, anti-S IgG declined from median 770.1 (IQR 615.0–1321.7) to 290.8 (IQR 175.7–400.3). Anti-N IgG antibodies waned earlier, from 35.4% seropositive at 6 months to 24.1% at 12 months

Unusual Ebola Virus Chain of Transmission, Conakry, Guinea, 2014-2015

In October 2015, a new case of Ebola virus disease in Guinea was detected. Case investigation, serology, and whole-genome sequencing indicated possible transmission of the virus from an Ebola virus disease survivor to another person and then to the case-patient reported here. This transmission chain over 11 months suggests slow Ebola virus evolution

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Biochemical insights into SARS-CoV replication

Mon travail de thèse s'est focalisé sur la machinerie enzymatique impliquée dans la réplication du génome ARN du Syndrome Respiratoire Aigu Sévère-Coronavirus (SRAS-CoV). J'ai montré in vitro que l'activité ARN polymérase ARN-dépendante (RdRp) portée par nsp12 nécessite le complexe nsp7/nsp8, qui agit comme facteur de processivité. Grâce à ce complexe polymérase hautement actif, j'ai pu en suite étudier le mécanisme de "proofreading" (correction d'épreuve) associé aux coronavirus, pour lequel seulement des preuves indirectes avaient été assemblées. En effet, les coronavirus codent pour une activité exonucléase 3'-5' (nsp14-ExoN) qui lorsqu'elle est absente, entraine 14-fois plus d'erreurs de réplication en contexte cellulaire. In vitro, nous avons pu montrer que nsp14-ExoN est capable d'exciser l'ARN double brin ainsi qu'un nucléotide mésapparié en 3' de l'ARN en cours d'élongation. J'ai pu apporter pour la première fois une preuve directe de l'existence d'un système de réparation des erreurs au cours de la synthèse, mené par le complexe nsp7/nsp8/nsp12/nsp14. En effet, le complexe nsp7/nsp8/nsp12 ralentit jusqu'à 30-fois quand il rajoute une base mésappariée. Par sequençage, nous avons pu montrer la réparation de cette base mésappariée en presence de nsp14. Enfin, grâce à ce système in vitro nous avons une base pour comprendre l'inefficacité de la ribavirine sur des patients atteints du SRAS. En effet, la ribavirine, incorporée par le complexe polymérase, serait également excisée par nsp14, annihilant tout potentiel effet mutagenique. En conclusion, ce système va permettre de guider le développement d'antiviraux de type nucleoside analogues contre les coronavirus.This work focused on the enzymatic machinery involved in Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) RNA replication and transcription. Firstly, I established a robust in vitro polymerase assay with the canonical SARS-CoV RNA-dependent RNA polymerase (RdRp) nsp12. I showed that nsp12, in order to engage processive RNA synthesis, needs two viral proteins, i.e. nsp7 and nsp8. This nsp7/nsp8 complex not only activates nsp12-RdRp, but also acts as a processivity factor. Thus, using this processive polymerase complex, I could investigate SARS-CoV proofreading for which only indirect evidences were reported. Indeed, coronaviruses encode for a 3'-5' exonuclease (nsp14-ExoN), putatively involved in a mechanism that proofreads coronavirus RNA during viral replication. We first showed in vitro that nsp14-ExoN, which is stimulated by nsp10, is able to excise specifically dsRNA as well as all primer/templates bearing a 3' mismatch on the primer. Moreover, we could confirm by sequencing that a RNA 3' mismatch was indeed corrected in vitro by the nsp7/nsp8/nsp12/nsp14 complex. We provide for the first time direct evidence that nsp14-ExoN, in coordination with the polymerase complex, is able to proofread RNA. Interestingly, using this in vitro system we found an element that could possibly explain the inefficacy of ribavirin therapeutic treatment on SARS-patients: ribavirin, which is incorporated by the SARS-CoV polymerase complex, would also be excised by nsp14. In conclusion, this system will drive future development of antivirals, particularly of the nucleoside analogue type, against coronaviruses