Wellcome Open Research

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ISSN / EISSN : 2398-502X / 2398-502X
Published by: F1000 Research Ltd (10.12688)
Total articles ≅ 1,761
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Eve Nakabembe, Bahaa Abu-Raya, Mary Kyohere, Valerie Tusubira, Alexander Amone, Lydia Nakibuuka, Madeleine Cochet, Annettee Nakimuli, Merryn Voysey, Andrew Gorringe, et al.
Published: 17 May 2022
Wellcome Open Research, Volume 7; https://doi.org/10.12688/wellcomeopenres.17749.1

Abstract:
Background: Globally there are an estimated 24.1 million cases and 160,700 deaths from pertussis annually in children under five years. The disease burden is higher in low- and middle-income countries, especially the African region, which contributes the largest proportions of cases and deaths. Immunization against pertussis in pregnancy is a recommended strategy for the prevention of infant pertussis in many high-income countries. However, vaccine immunogenicity and effectiveness may be different in immunocompromised individuals such as women living with HIV. There is a need to generate data on the impact of HIV infection in pregnancy on maternal and infant immunity to vaccines against pertussis. Methods: This is a phase II, randomized controlled observer blind clinical trial of 100 women living with HIV and 100 uninfected women randomized to either standard vaccines (tetanus diphtheria vaccine, Td) or a tetanus diphtheria-pertussis vaccine (Tdap). Participants aged 18-40 years carrying a low-risk singleton pregnancy with a gestational age between 16 and 26 weeks confirmed on ultrasound scan, with no history of receipt of tetanus or pertussis vaccines in the current pregnancy will be recruited. Women will receive either two doses of Td or a first dose of Td and second dose of Tdap vaccine. Participants will complete 14-day diary cards to monitor reactogenicity. Mother-infant dyads will be followed up until the infant is one year old. The outcomes include: safety for the pregnant woman and infant; anti-pertussis toxin (PT) and anti-filamentous haemagglutinin (FHA) IgG concentrations in maternal, cord and infant blood and breastmilk, compared by maternal HIV status. Discussion: This study will investigate whether vaccines given to women living with HIV have similar immunogenicity and reactogenicity to vaccines given to pregnant women without HIV and monitor the effect of Tdap in pregnancy on infant immune responses. clinicalTrials.gov registration: NCT04589312 (19/10/2020)
, Vishal Diwan, Anil A Kumar, Suman Sarah Varghese, Upasana Sharma, Manju Purohit, Arundhati Das,
Published: 13 May 2022
Wellcome Open Research, Volume 7; https://doi.org/10.12688/wellcomeopenres.17865.1

Abstract:
Background Directly Observed Treatment (DOT) is a requirement in the management of Tuberculosis (TB) globally. With the transition from alternate day treatment to daily treatment in India, monitoring treatment adherence through DOT is a logistic challenge. The pervasiveness of mobile phones in India provides a unique opportunity to address this challenge remotely. This study was designed to compare the acceptability of mobile phones for antitubercular treatment (ATT) support in two distinct regions of India. Methodology This was a cross-sectional exploratory study that enrolled 351 patients with TB, of whom 185 were from Bangalore, South India, and 166 from Ujjain, Central India. Trained research assistants administered a pretested questionnaire comprising demographics, phone usage patterns, and acceptability of mobile phone technology to support treatment adherence to TB medicines. Results The mean age of the 351 participants was 32±13.6 years of whom 140 (40%) were women. Of the participants, 259 (74%) were urban, 221 (63%) had >4 years of education. A significantly greater number of participants were newly diagnosed with TB and were in the intensive phase of treatment. Overall, 218 (62%) preferred vDOT over DOT. There was an overall difference in preference between the two sites which is explained by differences in socio-economic variables. Conclusion Mobile phone adherence support is acceptable to patients on Antitubercular treatment ATT with minor variations in design based on demographic and cultural differences. In India, the preference for voice calls over text messages/SMS while designing mHealth interventions cannot be ignored. Of importance is the preference for DOT over vDOT in central India, unlike South India. However, in time, the expanding use of mobile technology supplemented with counseling, could overcome the barriers of privacy and stigma and promote the transition from in-person DOT to vDOT or mobile phone adherence monitoring and support for ATT in India.
New version
Guadalupe Arteaga-Zarate, Gina Demarini-Olivares, ,
Published: 13 May 2022
Wellcome Open Research, Volume 6; https://doi.org/10.12688/wellcomeopenres.17328.2

Abstract:
Background: Information about the effect of type 2 diabetes mellitus (T2DM) awareness in the prevalence of anxiety disorders is scarce. Moreover, reports from resource-constrained and semiurban settings are usually focused on hospital-based data, instead of population-based surveys. We aimed to evaluate the association between T2DM and anxiety symptoms, with emphasis on T2DM awareness. Methods: A secondary data analysis was conducted using information from a population-based study. The outcome of interest was the presence of anxiety symptoms assessed by the Goldberg anxiety test, while the exposure variable was T2DM, defined using the oral glucose tolerance test. In addition, another definition was used based on self-reported T2DM awareness of previous diagnosis. Prevalence ratios (PR) and 95% confidence intervals (CI) were reported using Poisson regression models. Results: Data from 1,607 participants, of mean age 48.2 (SD: 10.6) years, and 809 (50.3%) females, were analyzed. Of all participants, 176 (11.0%; 95% CI: 9.5%–12.6%) had T2DM, 105 (59.7%) were aware of previous diagnosis, and 674 (41.9%; 95% CI: 39.5%–44.4%) had anxiety symptoms. In multivariable model, T2DM was not associated with anxiety symptoms (PR = 1.16; 95% CI: 0.99–1.36); however, individuals aware of T2DM diagnosis had a 36% (95% CI: 14%–64%) greater prevalence of anxiety symptoms compared to those without T2DM. Additionally, those aware of T2DM diagnosis had a 56% (95% CI: 13%-116%) higher probability to have anxiety symptoms compared to those not aware of T2DM diagnosis. Conclusions: The association between T2DM and anxiety symptoms was present among those participants who self-reported T2DM diagnosis, as opposed to those with T2DM but not aware and to those without T2DM. Evaluation of anxiety symptoms may be relevant among those with previous T2DM diagnosis.
, Sadie Bell, Zaid Chalabi, Fouad M. Fouad, Reinhard Mechler, Andrada Tomoaia-Cotisel, , Josephine Borghi
Published: 13 May 2022
Wellcome Open Research, Volume 7; https://doi.org/10.12688/wellcomeopenres.17834.1

Abstract:
Health systems worldwide face major challenges in anticipating, planning for and responding to shocks from infectious disease epidemics, armed conflict, climatic and other crises. Although the literature on health system resilience has grown substantially in recent years, major uncertainties remain concerning approaches to resilience conceptualisation and measurement. This narrative review revisits literatures from a range of fields outside health to identify lessons relevant to health systems. Four key insights emerge. Firstly, shocks can only be understood by clarifying how, where and over what timescale they interact with a system of interest, and the dynamic effects they produce within it. Shock effects are contingent on historical path-dependencies, and on the presence of factors or system pathways (e.g. financing models, health workforce capabilities or supply chain designs) that may amplify or dampen impact in unexpected ways. Secondly, shocks often produce cascading effects across multiple scales, whereas the focus of much of the health resilience literature has been on macro-level, national systems. In reality, health systems bring together interconnected sub-systems across sectors and geographies, with different components, behaviours and sometimes even objectives – all influencing how a system responds to a shock. Thirdly, transformability is an integral feature of resilient social systems: cross-scale interactions help explain how systems can show both resilience and transformational capability at the same time. We illustrate these first three findings by extending the socioecological concept of adaptive cycles in social systems to health, using the example of maternal and child health service delivery. Finally, we argue that dynamic modelling approaches, under-utilised in research on health system resilience to date, have significant promise for identification of shock-moderating or shock-amplifying pathways, for understanding effects at multiple levels and ultimately for building resilience.
New version
, Sopuruchukwu Obiesie, , , David Gathara,
Published: 12 May 2022
Wellcome Open Research, Volume 6; https://doi.org/10.12688/wellcomeopenres.17430.2

Abstract:
Background: Adequate staffing is key to the delivery of nursing care and thus to improved inpatient and health service outcomes. Several systematic reviews have addressed the relationship between nurse staffing and these outcomes. Most primary studies within each systematic review are likely to be from high-income countries which have different practice contexts to low and middle-income countries (LMICs), although this has not been formally examined. We propose conducting an umbrella review to characterise the existing evidence linking nurse staffing to key outcomes and explicitly aim to identify evidence gaps in nurse staffing research in LMICs. Methods and analysis: This protocol was developed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P). Literature searching will be conducted across Ovid Medline, Embase and EBSCO Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. Two independent reviewers will conduct searching and data abstraction and discordance will be handled by discussion between both parties. The risk of bias of the individual studies will be performed using the AMSTAR-2. Ethics and dissemination: Ethical permission is not required for this review as we will make use of already published data. We aim to publish the findings of our review in peer-reviewed journals. PROSPERO registration number: CRD42021286908
New version
, Graeme Meintjes, , Andre Pascal Kengne
Published: 12 May 2022
Wellcome Open Research, Volume 5; https://doi.org/10.12688/wellcomeopenres.15824.2

Abstract:
Background: Early diagnosis is essential to reduce the morbidity and mortality of HIV-associated tuberculosis. We developed a multi-parameter clinical decision tree to facilitate rapid diagnosis of tuberculosis using point-of-care diagnostic tests in HIV-positive patients presenting to an emergency centre. Methods: A cross-sectional study was performed in a district hospital emergency centre in a high-HIV-prevalence community in South Africa. Consecutive HIV-positive adults with ≥1 WHO tuberculosis symptoms were enrolled over a 16-month period. Point-of-care ultrasound (PoCUS) and urine lateral flow lipoarabinomannan (LF-LAM) assay were done according to standardized protocols. Participants also received a chest X-ray. Reference standard was the detection of Mycobacterium tuberculosis using Xpert MTB/RIF or culture. Logistic regressions models were used to investigate the independent association between prevalent microbiologically confirmed tuberculosis and clinical and biological variables of interest. A decision tree model to predict tuberculosis was developed using the classification and regression tree algorithm. Results: There were 414 participants enrolled: 171 male, median age 36 years, median CD4 cell count 86 cells/mm3. Tuberculosis prevalence was 42% (n=172). Significant variables used to build the classification tree included ≥2 WHO symptoms, antiretroviral therapy use, LF-LAM, PoCUS independent features (pericardial effusion, ascites, intra-abdominal lymphadenopathy) and chest X-ray. LF-LAM was positioned after WHO symptoms (75% true positive rate, representing 17% of study population). Chest X-ray should be performed next if LF-LAM is negative. The presence of ≤1 PoCUS independent feature in those with ‘possible or unlikely tuberculosis’ on chest x-ray represented 47% of non-tuberculosis participants (true negative rate 83%). In a prediction tree which only included true point-of-care tests, a negative LF-LAM and the presence of ≤2 independent PoCUS features had a 71% true negative rate (representing 53% of sample). Conclusions: LF-LAM should be performed in all adults with suspected HIV-associated tuberculosis (regardless of CD4 cell count) presenting to the emergency centre.
New version
Dominik Trzupek, Mercede Lee, Fiona Hamey, Linda S. Wicker, ,
Published: 12 May 2022
Wellcome Open Research, Volume 6; https://doi.org/10.12688/wellcomeopenres.16883.2

Abstract:
Background: The characterisation of the peripheral immune system in the autoimmune disease systemic lupus erythematosus (SLE) at the single-cell level has been limited by the reduced sensitivity of current whole-transcriptomic technologies. Here we employ a targeted single-cell multi-omics approach, combining protein and mRNA quantification, to generate a high-resolution map of the T lymphocyte and natural killer (NK) cell populations in blood from SLE patients. Methods: We designed a custom panel to quantify the transcription of 534 genes in parallel with the expression of 51 surface protein targets using the BD Rhapsody AbSeq single-cell system. We applied this technology to profile 20,656 T and NK cells isolated from peripheral blood from an SLE patient with a type I interferon (IFN)-induced gene expression signature (IFNhi), and an age- and sex- matched IFNlow SLE patient and healthy donor. Results: We confirmed the presence of a rare cytotoxic CD4+ T cell (CTL) subset, which was exclusively present in the IFNhi patient. Furthermore, we identified additional alterations consistent with increased immune activation in this patient, most notably a shift towards terminally differentiated CD57+ CD8+ T cell and CD16+ NKdim phenotypes, and the presence of a subset of recently-activated naïve CD4+ T cells. Conclusions: Our results identify IFN-driven changes in the composition and phenotype of T and NK cells that are consistent with a systemic immune activation within the IFNhi patient, and underscore the added resolving power of this multi-omics approach to identify rare immune subsets. Consequently, we were able to find evidence for novel cellular peripheral biomarkers of SLE disease activity, including a subpopulation of CD57+ CD4+ CTLs.
New version
The MindKind Consortium
Published: 12 May 2022
Wellcome Open Research, Volume 6; https://doi.org/10.12688/wellcomeopenres.17167.2

Abstract:
Background: While an estimated 14-20% of young adults experience mental health conditions worldwide, the best strategies for prevention and management are not fully understood. The ubiquity of smartphone use among young people makes them excellent candidates for collecting data about lived experiences and their relationships to mental health. However, not much is known about the factors affecting young peoples’ willingness to share information about their mental health. Objective: We aim to understand the data governance and engagement strategies influencing young peoples’ (aged 16-24) participation in app-based studies of mental health. We hypothesize that willingness to participate in research is influenced by involvement in how their data is collected, shared, and used. Methods: Here, we describe the MindKind Study, which employs mixed methods to understand the feasibility of global, smartphone-based studies of youth mental health. A pilot 12-week app-based substudy will query participants’ willingness to engage with remote mental health studies. Participants will be randomized into one of four different data governance models designed to understand their preferences, as well as the acceptability of models that allow them more or less control over how their data are accessed and used. Enrolees will receive one of two different engagement strategies. A companion qualitative study will employ a deliberative democracy approach to examine the preferences, concerns and expectations of young people, with respect to remote mental health research. We also detail our engagement with young people as co-researchers in this study. This pilot study is being conducted in India, South Africa and the United Kingdom. Conclusions: This study is expected to generate new insights into the feasibility of, and best practices for, remote smartphone-based studies of mental health in youth and represents an important step toward understanding which approaches could help people better manage their mental health.
, Cristina Zuccato, , , , Alessia Finotti, Roberto Gambari
Published: 12 May 2022
Wellcome Open Research, Volume 7; https://doi.org/10.12688/wellcomeopenres.17845.1

Abstract:
Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', ‘drug rescue’, ‘drug re-tasking’ and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the “off-label” use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.
New version
Robin Brown, Philip Goulder,
Published: 11 May 2022
Wellcome Open Research, Volume 7; https://doi.org/10.12688/wellcomeopenres.17601.3

Abstract:
Sexual dimorphism in infectious diseases refers to the different infection susceptibilities and outcomes between males and females, and has been described for many pathogens, including hepatitis B virus (HBV). HBV is a substantial global health problem, with close to 300 million people chronically infected, and accounting for a million deaths each year, with an urgent need for enhanced interventions to support progress towards elimination goals. Sexual dimorphism has a strong influence in HBV infection, with males more likely to be exposed, to develop chronic infection, and to suffer from complications including cirrhosis and hepatocellular carcinoma (HCC) compared to females. Different outcomes are driven by differential immune responses, sexual dimorphism of the liver, and androgen response elements in the HBV genome. The impact of sex may also vary with age, with changes at puberty and influences of menarche, pregnancy and menopause in females. In addition, gender has complex influences on education, beliefs, behaviour and access to / engagement with healthcare services, which may contribute to differences in diagnosis and treatment. Interplay between these complex factors, alongside other attributes of host, virus and the environment, accounts for different outcomes of infection. However, gaps remain in our understanding of sexual dimorphism in HBV, and little effort has previously been made to harness this knowledge for translational gains. In this review, we assimilate human and animal data to consider the mechanism, outcomes and impact of sexual dimorphism, and consider how these insights can be used to inform advances in surveillance, treatment and prevention for HBV infection.
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