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Abstract Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.

Correct 3’end processing of mRNAs is one of the regulatory cornerstones of gene expression. In a parasite that must adapt to the regulatory requirements of its multi-host life style, there is a need to adopt additional means to partition the distinct transcriptional signatures of the closely and tandemly arranged stage-specific genes. In this study, we report our findings in T. gondii of an m6A-dependent 3’end polyadenylation serving as a transcriptional barrier at these loci. We identify the core polyadenylation complex within T. gondii and establish CPSF4 as a reader for m6A-modified mRNAs, via a YTH domain within its C-terminus, a feature which is shared with plants. We bring evidence of the specificity of this interaction both biochemically, and by determining the crystal structure at high resolution of the T. gondii CPSF4-YTH in complex with an m6A-modified RNA. We show that the loss of m6A, both at the level of its deposition or its recognition is associated with an increase in aberrantly elongated chimeric mRNAs emanating from impaired transcriptional termination, a phenotype previously noticed in the plant model Arabidopsis thaliana. Nanopore direct RNA sequencing shows the occurrence of transcriptional read-through breaching into downstream repressed stage-specific genes, in the absence of either CPSF4 or the m6A RNA methylase components in both T. gondii and A. thaliana. Taken together, our results shed light on an essential regulatory mechanism coupling the pathways of m6A metabolism directly to the cleavage and polyadenylation processes, one that interestingly seem to serve, in both T. gondii and A. thaliana, as a guardian against aberrant transcriptional read-throughs.

Introduction: Organised screening reduces the incidence and late-stage diagnosis of cancer. However, participation in screening is not consistent across populations. Variations can be measured using demographic factors on place of residence, race/ethnicity, occupation, gender/sex, religion, education, socio-economic position (SEP), and social capital (PROGRESS-Plus stratifiers). The Republic of Ireland has screening programmes for colorectal, breast, and cervical cancer but assessment of screening participation and cancer incidence is inconsistent. The review aimed to evaluate the use of stratifiers in breast, cervical and colorectal cancer incidence and screening literature, and assess variations in incidence and screening participation across subgroups in Ireland. Methods: PubMed was searched systematically and grey literature was identified via Google, Google Scholar, Lenus (Irish Health Research repository), and The Irish Longitudinal Study of Aging (TILDA) in June 2022. Studies were included if they captured stratifiers alongside incidence or screening participation data of the three cancers. Results: Thirty-six studies and reports were included. Place of residence, SEP, sex, and age were most frequently captured. Incidence and screening participation varied by age, place of residence, SEP, and sex. Discussion: PROGRESS-Plus is a useful equity lens to review health literature. Cancer incidence and screening participation studies lacked a comprehensive equity lens resulting in difficulties in identifying inequities and non-attenders. Place of residence, SEP and ethnicity should be prioritised in monitoring inequities. Integrating unique health identifiers should improve monitoring and enable evidence-based population-specific interventions to promote screening. Collaboration with community organisations would support engagement with vulnerable populations when data is limited.

Introduction Key populations (KP) living with HIV are underserved and often face social and health system barriers to HIV care. To optimise access to quality HIV services among KP, the WHO recommended community-based approaches to HIV service delivery for KP. However, to inform the successful rollout and scale-up of community-based antiretroviral therapy service delivery models for KP (KP-CBART), there is a need to study the programme implementation. This study aims to evaluate the outcomes of KP-CBART in Benue State Nigeria using a realist impact evaluation approach. Our evaluation question is: what are the mechanisms and context conditions that drive successful community-based implementation and how do these lead to better retention in care, treatment adherence and viral suppression among which categories of KP?Methods and analysis This study will be conducted in three phases, relying on a mixed-method design and following the realist evaluation cycle. The first phase is the development of the initial programme theory grounded in a scoping review, programme and policy document review and in-depth interviews with key stakeholders. In phase 2, findings from case studies of KP-CBART programme implementation in one Nigerian state are used to test the initial programme theory and to refine it. The quantitative part is a retrospective cohort study. All HIV-positive KP clients enrolled into the KP-CBART between 2016 and 2020 will be included in the study. While maximum variation and data saturation will inform sample size for the qualitative part, an estimated 90 purposively selected study participants will be interviewed. In phase 3, findings will be synthesised into a middle-range theory through cross-case analysis. The heuristic intervention, context, agents, mechanisms and outcomes (ICAMO) tool will be used to refine the initial programme theory.Ethics and dissemination The study protocol was approved by the Institutional Review Boards of APIN Public Health Initiatives (IRB022-FR), Institute of Tropical Medicine Antwerp (1503/21), and the Benue State Ministry of Health and Human Services (MOH/STA/204/VOL1/154). Written informed consent will be obtained from all study participants. Study results will be disseminated through stakeholders meeting, peer-reviewed journals and conferences.

Introduction Tuberculosis (TB) has become an occupational health hazard in South African hospitals where healthcare workers (HCWs) are additionally confronted daily with HIV and its associated stigma, causing a syndemic. Early TB diagnosis and treatment are vital, but the uptake of these services through occupational healthcare units (OHUs) is low. The current study hypothesises that (1) the link between HIV and TB and (2) the perceived HIV stigmatisation by colleagues create (3) a double HIV–TB stigma which increases (4) internalised TB stigma and leads to (5) a lower willingness to use OHU services for TB screening and treatment.Design A cross-sectional study using the baseline data from the HIV and TB Stigma among Healthcare workers Study (HaTSaH Study).Setting Six hospitals in the Free State province of South Africa.Participants 820 HCWs of the six selected hospitals.Results The study results demonstrate that the co-epidemic (β=0.399 (screening model) and β=0.345 (treatment model)) combined (interaction effect: β=0.133 (screening) and β=0.132 (treatment)) with the persistent stigmatisation of HIV is altering the attitudes towards TB (β=0.345 (screening) and β=0.400 (treatment)), where the stigmatising views of HIV are transferred to TB—illustrating the syndemic impact. Our model demonstrated that this syndemic not only leads to higher levels of internal TB stigma (β=0.421 (screening) and β=0.426 (treatment)), but also to a lower willingness to use the OHU for TB screening (probit coefficient=−0.216) and treatment (probit coefficient=−0.160). Confidentiality consistently emerged as a contextual correlate of OHU use.Conclusions Theoretically, our results confirm HIV as a ‘syndemic generator’ which changes the social meaning of TB in the hospital context. Practically, the study demonstrated that the syndemic of TB and HIV in a highly endemic context with stigma impacts the intended use of occupational TB services.Trial registration number Pre-results of the trial registered at the South African National Clinical Trials Register, registration ID: DOH-27-1115-5204.

Introduction The process of adapting to a life with a chronic illness, is a well-researched phenomenon for a number of common chronic illnesses. The construct, adaptation, embeds the notions of integration of the chronic illness into identity and self-management. Integration precedes self-management and is key to living positively with a chronic illness. Adaptation is an important concept in understanding trajectory and outcomes of living with a chronic illness. Applicability of these concepts to HIV as a chronic illness; when suppressive adherence has been achieved, however, is unknown. Specifically, the adaptation process to living with HIV as a chronic illness, the integration of HIV into identity and the resulting self-management behaviours by adults living with HIV are relatively unexplored. We describe a protocol for a scoping review of adaptation to living with HIV, we structure the enquiry around integration of HIV into identity and self-management and interrogate theories, models and frameworks that have been proposed and studied and we evaluate them for relevance and usefulness in the care and management of HIV.Methods and analysis Methods proposed by the Johanna Briggs Institute will be followed. The protocol was drafted using the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for Scoping Reviews and was registered with the Open Science Framework. MEDLINE, SCOPUS, Cochrane Library, CINHAL and SocINDEX databases will be searched. A search in Social Science Research Network eLibrary and Open Access Theses and Dissertations will gather grey literature and reference lists of included sources will be screened. Study selection process will involve a title and abstract review and full text review, guided by clearly defined inclusion and exclusion criteria.Ethics and dissemination Ethical approval is not required because this is a proposed review and collection of data on publicly available materials. The results will be published in a topic relevant journal and presented at related scientific events.

IntroductionThis study produces an estimate of the proportion of eligible PrEP users among people of Sub-Saharan African background based on the Belgian PrEP eligibility criteria and examines associations with socio-economic and demographic characteristics.MethodsWe performed logistic regression analysis on data of a representative community-based survey conducted among Sub-Saharan African communities (n = 685) living in Antwerp.ResultsAlmost a third (30.3%) of the respondents were eligible to use PrEP. Those who were male, single, lower educated, undocumented, and had experienced forced sex were more likely to be eligible for PrEP use. The findings highlight the importance of taking intra-, interpersonal and structural HIV risk factors into account.ConclusionsThe study shows high unmet PrEP needs in this population, especially among those with high vulnerability for HIV acquisition. A better understanding of barriers to PrEP use in this population group is needed to allow for equitable access.

BackgroundKey populations (KP) are disproportionately infected with HIV and experience barriers to HIV care. KP include men who have sex with men (MSM), female sex workers (FSW), persons who inject drugs (PWID) and transgender people (TG). We implemented three different approaches to the delivery of community-based antiretroviral therapy for KP (KP-CBART) in Benue State Nigeria, including One Stop Shop clinics (OSS), community drop-in-centres (DIC), and outreach venues. OSS are community-based health facilities serving KP only. DIC are small facilities led by lay healthcare providers and supported by an outreach team. Outreach venues are places in the community served by the outreach team. We studied long-term attrition of KP and virological non-suppression.MethodThis is a retrospective cohort study of KP living with HIV (KPLHIV) starting ART between 2016 and 2019 in 3 0SS, 2 DIC and 8 outreach venues. Attrition included lost to follow-up (LTFU) and death. A viral load >1000 copies/mL showed viral non-suppression. Survival analysis was used to assess retention on ART. Cox regression and Firth logistic regression were used to assess risk factors for attrition and virological non-suppression respectively.ResultOf 3495 KPLHIV initiated on ART in KP-CBART, 51.8% (n = 1812) were enrolled in OSS, 28.1% (n = 982) in DIC, and 20.1% (n = 701) through outreach venues. The majority of participants were FSW-54.2% (n = 1896), while 29.8% (n = 1040), 15.8% (n = 551) and 0.2% (n = 8) were MSM, PWID, and TG respectively. The overall retention in the programme was 63.5%, 55.4%, 51.2%, and 46.7% at 1 year, 2 years, 3 years, and 4 years on ART. Of 1650 with attrition, 2.5% (n = 41) died and others were LTFU. Once adjusted for other factors (age, sex, place of residence, year of ART enrollment, WHO clinical stage, type of KP group, and KP-CBART approach), KP-CBART approach did not predict attrition. MSM were at a higher risk of attrition (vs FSW; adjusted hazard ratio (aHR) 1.27; 95%CI: 1.14-1.42). Of 3495 patients, 48.4% (n = 1691) had a viral load test. Of those, 97.8% (n = 1654) were virally suppressed.ConclusionAlthough long-term retention in care is low, the virological suppression was optimal for KP on ART and retained in community-based ART care. However, viral load testing coverage was sub-optimal. Future research should explore the perspectives of clients on reasons for LTFU and how to adapt approach to CBART to meet individual client needs.

Understanding the clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and prognosis in children is a major issue. Children often present mild symptoms, and some severe forms require paediatric intensive care, with in some cases a fatal prognosis. Our aim was to identify the epidemiological characteristics, clinical presentation, and prognosis of children with coronavirus disease 2019 (Covid-19) hospitalized in Paris suburb hospitals. In this prospective, observational, multicentre study, we included children hospitalized in paediatric departments of Paris suburb hospitals from 23 March 2020 to 10 May 2020, during the national lockdown in France with confirmed SARS-CoV-2 infection (positive RNA test on a nasopharyngeal swab) or highly suspected infection (clinical, biological, and/or radiological data features suggestive for SARS-CoV-2 infection). A total of 192 children were included for confirmed (n = 157) or highly suspected (n = 35) SARS-CoV-2 infection. The median age was one year old (interquartile range 0.125–11) with a sex ratio 1.3:1. Fever was recorded in 147 (76.6%) children and considered poorly tolerated in 29 (15.1%). The symptoms ranged from rhinorrhoea (34.4%) and gastrointestinal (35.5%) to respiratory distress (25%). Only 10 (5.2%) children had anosmia and five (2.6%) had chest pain. An underlying condition was identified in almost 30% of the children in our study. Overall, 24 (12.5%) children were admitted to paediatric intensive care units, 12 required mechanical ventilation, and three died. For children in Paris suburbs, most cases of Covid-19 showed mild or moderate clinical expression. However, one-eighth of children were admitted to paediatric intensive care units and three died.

In the context of severe human resource shortages in HIV care, task-shifting and especially community-based support are increasingly being cited as potential means of providing durable care to chronic HIV patients. Socio-ecological theory clearly stipulates that-in all social interventions-the interrelatedness and interdependency between individuals and their immediate social contexts should be taken into account. People living with HIV/AIDS (PLWHA) seldom live in isolation, yet community-based interventions for supporting chronic HIV patients have largely ignored the social contexts in which they are implemented. Research is thus required to investigate such community-based support within its context. The aim of this study is to address this research gap by examining the way in which HIV/AIDS competence in the household hampers or facilitates community-based treatment adherence support. The data was analyzed carefully in accordance with the Grounded Theory procedures, using Nvivo 10. More specifically, we analyzed field notes from participatory observations conducted during 48 community-based treatment adherence support sessions in townships on the outskirts of Cape Town, transcripts of 32 audio-recorded in-depth interviews with PLWHA and transcripts of 4 focus group discussions with 36 community health workers (CHWs). Despite the fact that the CHWs try to present themselves as not being openly associated with HIV/AIDS services, results show that the presence of a CHW is often seen as a marker of the disease. Depending on the HIV/AIDS competence in the household, this association can challenge the patient's hybrid identity management and his/her attempt to regulate the interference of the household in the disease management. The results deepen our understanding of how the degree of HIV/AIDS competence present in a PLWHA's household affects the manner in which the CHW can perform his or her job and the associated benefits for the patient and his/her household members. In this respect, a household with a high level of HIV/AIDS competence will be more receptive to treatment adherence support, as the patient is more likely to allow interaction between the CHW and the household. In contrast, in a household which exhibits limited characteristics of HIV/AIDS competence, interaction with the treatment adherence supporter may be difficult in the beginning. In such a situation, visits from the CHW threaten the hybrid identity management. If the CHW handles this situation cautiously and the patient-acting as a gate keeper-allows interaction, the CHW may be able to help the household develop towards HIV/AIDS competence. This would have a more added value compared to a household which was more HIV/AIDS competent from the outset. This study indicates that pre-existing dynamics in a patient's social environment, such as the HIV/AIDS competence of the household, should be taken into account when designing community-based treatment adherence programs in order to provide long-term quality care, treatment and support in the context of human resource shortages.

Reviews of impact evaluations of community-based health workers and peer support groups highlight the considerable variability in the effectiveness of such support in improving antiretroviral treatment (ART) outcomes. Evidence indicates that community-based support interventions targeting patients known to be at risk will probably display better results than generic interventions aimed at the entire population of people living with HIV. It is however difficult to identify these at-risk populations, rendering knowledge on the characteristics of patients groups who are in need of community-based support a clear research priority. The current study aims to address the knowledge gap by exploring the predictors of the willingness to (1) receive the support from a community-based health worker or (2) to participate in a support group in public sector ART programme of the Free State Province of South Africa. Based on the Individual-Family-Community framework for HIV research, the study employs a comprehensive approach by not only testing classical individual-level but also family-level predictors of the willingness to receive community-based support. In addition to individual-level predictors-such as age, health status and coping styles-our analysis demonstrated the importance of family characteristics. The results indicated that discrepancies in the family's changeability level were an important predictor of the demand for community-based support services. Conversely, the findings indicated that patients living in a family more flexible than deemed ideal are more likely to require the support of a community health worker. The current study expands theory by indicating the need to acknowledge all social ecological levels in the study of chronic HIV care. The detection of both individual level and family level determinants of the expressed need for community-based support can inform health policy to devise strategies to target scarce resources to those vulnerable patients who report the greatest need for this support. In this way, the study results are a first step in an attempt to move away from generic, broad based community-based interventions towards community support that is tailored to the patient needs at both the individual and family level.

Background and objectivesAccess to antiretroviral treatment among adolescents living with HIV (ALH) is increasing. Health-related quality of life (HRQOL) is relevant for monitoring the impact of the disease on both well-being and treatment outcomes. However, adequate screening tools to assess HRQOL in low-resource settings are scarce. This study aims to fill this research gap, by 1) assessing the psychometric properties and reliability of an Eastern African English version of a European HRQOL scale for adolescents (KIDSCREEN) and 2) determining which version of the KIDSCREEN (52-, 27- and 10-item version) is most suitable for low-resource settings.MethodsThe KIDSCREEN was translated into Eastern African English, Luganda (Uganda) and Dholuo (Kenya) according to standard procedures. The reconciled version was administered in 2011 to ALH aged 13-17 in Kenya (n = 283) and Uganda (n = 299). All three KIDSCREEN versions were fitted to the data with confirmatory factor analysis (CFA). After comparison, the most suitable version was adapted based on the CFA outcomes utilizing the results of previous formative research. In order to develop a general HRQOL factor, a second-order measurement model was fitted to the data.ResultsThe CFA results showed that without adjustments, the KIDSCREEN cannot be used for measuring the HRQOL of HIV-positive adolescents. After comparison, the most suitable version for low-resource settings--the 27-item version--was adapted further. The introduction of a negative wording factor was required for the Dholuo model. The Dholuo (CFI: 0.93; RMSEA: 0.039) and the Luganda model (CFI: 0.90; RMSEA: 0.052) showed a good fit. All cronbach's alphas of the factors were 0.70 or above. The alpha value of the Dholuo and Lugandan HRQOL second-order factor was respectively 0.84 and 0.87.ConclusionsThe study showed that the adapted KIDSCREEN-27 is an adequate tool for measuring HRQOL in low-resource settings with high HIV prevalence.