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Relationship between vaginal and gut microbiome and pregnancy outcomes in eastern Ethiopia: a protocol for a longitudinal maternal-infant cohort study (the EthiOMICS study).
Get PDFIntroduction. Although evidence exists on the impact of microbiota on pregnancy outcomes in many high-resource settings, there is a lack of research in many low-resource settings like Ethiopia. This study aims to fill this gap by studying the gut and vaginal microbiota changes throughout pregnancy and assess how these changes relate to pregnancy outcomes among a cohort of pregnant women in eastern Ethiopia.Methods and analysis. Vaginal and stool samples will be collected using DNA/RNA Shield Collection kits three times starting at 12–22 weeks, 28–36 weeks and at birth (within 7 days). Postnatally, newborns’ skin swabs (at birth) and rectal swabs will be obtained until 2 years of age. Moreover, breast milk samples at birth and 6 months and environmental samples (water, indoor air and soil) will be collected at enrolment, birth, 6, 12 and 24 months post partum. DNA will be extracted using Roche kits. Metagenomic sequencing will be performed to identify metataxonomic profiling and assess variations in microbial profiles, and α and β diversity of the microbiota. Information on socioeconomic, behavioural, household and biological factors will be collected at enrolment. The collected data will be coded, entered into EpiData 3.1 and analysed using Stata 17.Ethics and dissemination The Institutional Health Research Ethics Review Committee (Ref No. IHRERC/033/2022) of Haramaya University, Ethiopia has approved this study ethically. Written informed consent regarding the study and sample storage for biobanking will be obtained from all participants. Results will be published in international peer-reviewed journals, and summaries will be provided to the study funders. Clinical study data will be submitted to Data Compass (https://datacompass.lshtm.ac.uk/), and molecular profiles of the microbiome and whole-genome sequences will be submitted to the European Nucleotide Archive (https://www. ebi.ac.uk/ena). Requests for data should be directed to [email protected]. The decision to share data will be made by the study steering committee under the College of Health and Medical Sciences, Haramaya University, Ethiopia.</p
Interventions for the management of post-COVID-19 condition (long COVID): protocol for a living systematic review and network meta-analysis
Get PDFBackground: Up to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia and impaired cognitive function, termed post-COVID-19 condition or long COVID. Several trials that study the benefits and harms of various interventions to manage long COVID have been published and hundreds more are planned or are ongoing. Trustworthy systematic reviews that clarify the benefits and harms of interventions are critical to promote evidence-based practice. Objective: To create and maintain a living systematic review and network meta-analysis addressing the benefits and harms of pharmacologic and non-pharmacologic interventions for the treatment and management of long COVID. Methods: Eligible trials will randomise adults with long COVID to pharmacologic or non-pharmacologic interventions, placebo, sham or usual care. We will identify eligible studies by searching MEDLINE, EMBASE, CINAHL, PsycINFO, AMED and CENTRAL from inception, without language restrictions. Reviewers will work independently and in duplicate to screen search records, collect data from eligible trials, including trial and patient characteristics and outcomes of interest and assess risk of bias. Our outcomes of interest will include patient-reported fatigue, pain, postexertional malaise, changes in education or employment status, cognitive function, mental health, dyspnoea, quality of life, physical function, recovery and serious adverse events. For each outcome, when possible, we will perform a frequentist random-effects network meta-analysis. When there are compelling reasons to suspect that certain interventions are only applicable or effective for a subtype of long COVID, we will perform separate network meta-analyses. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach will guide our assessment of the certainty of evidence. We will update our living review biannually, on the publication of a seminal trial, or when new evidence emerges that may change clinical practice. Conclusion: This living systematic review and network meta-analysis will provide comprehensive, trustworthy and up-to-date summaries of the evidence addressing the benefits and harms of interventions for the treatment and management of long COVID. We will make our findings available publicly and work with guideline-producing organisations to inform their recommendations. Ethics and dissemination: The study describes the protocol for a systematic review that uses data from published trial reports. Therefore, the study is exempt from ethics review. We intend to deposit all data in a public repository and publish each iteration of the living review online.</p
Landscape of guidance documents used at TropNet and GeoSentinel centres for the clinical management of schistosomiasis outside endemic areas: a systematic appraisal
Get PDFBackgroundThe diagnostic and treatment approaches for schistosomiasis in individual patients, outside endemic areas, are not standardised. This study aimed to appraise the reference documents that the experts from the TropNet and GeoSentinel networks use in practice as guidance for the clinical management of their patients with (suspect) schistosomiasis. MethodsWe systematically appraised the following data from the referenced guidance documents: i) document type, ii) case definitions, iii) diagnostic techniques envisaged; iv) treatment recommendations; v) follow-up recommendations; vi) screening recommendations, and vii) symptom-based diagnostic suspicion. ResultsTwenty-two of the 30 responders (73.3%) indicated 19 reference documents, three of which were WHO material not intended for individual clinical management. Only 4/19 (21.1%) documents were national recommendations; no international guideline was indicated. Case definitions were explicitly presented in only one document (1/19; 5.3%). Diagnostic tools were detailed in 11/16 (68.8%) and follow-up guidance in 8/16 (50%) documents. Treatment guidance was provided in 14/16 (87.5%) documents. ConclusionsHeterogeneity in clinical guidance was evident, although with noticeable overlap at least for chronic schistosomiasis. This confirms the need to formalise case definitions, which should be used to design trials to rigorously assess diagnostic tools and treatment schemes, and eventually come to harmonisation of clinical management guidance.</p
Dietary habits and complex food relations in Northwest China:A population-based network analysis
Get PDFIntroduction: This study examines dietary network in Northwest China, focusing on food group consumption and regional trends using network analysis. Methods: Data from 106 424 participants in the Regional Ethnic Cohort Study were calculated using a semiquantitative food frequency questionnaire. We compared intake with the 2022 Chinese Dietary Guidelines and employed the EBICglasso method to construct dietary and staple food-related network, assessing its stability and accuracy. Results: Northwest China's staple food intake was 37.5% of total consumption, dominated by wheat. Compared with the Chinese dietary guidelines, participants' intake of staple foods, soybeans and nuts was within the acceptable range, with insufficient intake of whole grains and beans, animal source of foods, eggs, fruits and vegetables but excessive intake of salt. Intake varied by province, sex and age. In overall participants, the strongest correlations were found between the two food groups, namely fruits and vegetables (0.33), and animal source of foods and dairy products (0.24) in dietary network. Soybeans and nuts appeared to connect to more other foods and also higher correlation with other foods and were followed by animal source of food. The staple food-related food network indicated that the intake of rice, whole grains and beans, and potatoes was positively correlated with the intake of most other foods, while intake of wheat was negatively correlated with foods of animal source of food, milk and dairy products. Conclusions: Northwest China's diet exhibits irrational patterns, highlighting the importance of assessing overall dietary patterns in nutritional evaluation.</p
The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake
Get PDFBackground: Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in patterns that are not necessarily adaptive but instead likely result from constraints associated with protein secretion. Results: We generate a high-quality draft genome of the Cape coral snake (Aspidelaps lubricus) and combine analyses of venom gland single-cell RNA-seq data with spatial venom gland in situ toxin distributions. Our results reveal that while different toxin families are produced by distinct populations of cells, toxin expression is fine-tuned by regulatory modules that result in further specialization of toxin production within each cell population. We also find that the evolution of regulatory elements closely mirrors the evolution of their associated toxin genes, resulting in spatial association of closely related and functionally similar toxins in the venom gland. While this compartmentalization is non-adaptive, the modularity of the underlying regulatory network likely facilitated the repeated evolution of defensive venom in spitting cobras. Conclusions: Our results provide new insight into the variability of toxin regulation across snakes, reveal the molecular mechanisms underlying the heterogeneous toxin production in snake venom glands, and provide an example of how constraints can result in non-adaptive character states that appear to be adaptive, which may nevertheless facilitate evolutionary innovation and novelty.</p
Factors associated with laboratory-confirmed SARS-Cov-2 infection among patients with severe respiratory illness (SRI):Findings from the COVID-19 vaccine effectiveness evaluation in Kenya and Mali, 2022-2023
Get PDFBackground: Understanding the epidemiology of SARS-CoV-2 infection in settings with limited data, especially given the dynamic nature of the virus and the reported epidemiological heterogeneity across countries, is important. We used data from the COVID-19 Vaccine effectiveness evaluation to determine factors associated with SARS-COV-2 infection among patients (≥ 12 years) with severe respiratory illness (SRI) in Kenya and Mali. Methods: SRI was defined as acute onset (≤ 14 days) of at least two of the following: cough, fever, chills, rigors, myalgia, headache, sore throat, fatigue, congestion or runny nose, loss of taste or smell, or pneumonia diagnosis. We collected demographic and clinical characteristics of the patients, and nasopharyngeal and oropharyngeal specimens for SARS-CoV-2 testing using RT-PCR. We used a mixed effect logistic regression to determine factors associated with SARS-CoV-2 infection adjusting for age and sex while controlling for clustering by site and month of illness onset. Results: Between July 2022 and October 2023, a total of 9941 patients with SRI were enrolled, of whom, 588 (5.9 %) tested positive for SARS-CoV-2. Compared to patients aged 12-24 years, those who were aged >64 years were more likely to have SARS-CoV-2 infection (adjusted Odds Ratio [aOR] = 1.60; 95 % Confidence Interval [95 % CI] 1.07-2.40). Additionally, SRI patients presenting with cough (aOR = 1.37; 95 % Confidence Interval [95 % CI] 1.05-1.80), sore throat (aOR = 1.56; 95 % CI 1.23-1.99), runny nose (aOR = 1.51; 95 % CI 1.18-1.94), and ear pain discharge (aOR = 2.58; 95 % CI 1.43-4.66) were more likely to have SARS-CoV-2 infection compared to those who did not. SRI patients who had HIV were also more likely to have SAR-CoV-2 infection compared to those who did not (aOR =1.32; 95 % CI 1.04-1.67). Conclusion: Older adults and HIV patients were at increased-risk of SARS-CoV-2 infection consistent with WHO guidelines highlighting the need for targeted prevention and management strategies focused on them.</p
Bisoprolol for patients with chronic obstructive pulmonary disease at high risk of exacerbation:the BICS RCT
Get PDFBackground: Observational studies of people with chronic obstructive pulmonary disease using beta-blockers for cardiovascular disease indicate that beta-blocker use is associated with reduced risk of chronic obstructive pulmonary disease exacerbation. However, at the time this study was initiated, there had been no randomised controlled trials confirming or refuting this. Objective(s): To determine the clinical and cost-effectiveness of adding bisoprolol (maximal dose 5 mg once daily) to usual chronic obstructive pulmonary disease therapies in patients with chronic obstructive pulmonary disease at high risk of exacerbation. Design: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. Setting: Seventy-six United Kingdom primary and secondary care sites. Participants: People aged ≥ 40 years with a diagnosis of at least moderately severe chronic obstructive pulmonary disease with a history of at least two exacerbations in the previous year. Interventions: Participants were randomised (1: 1) to receive either bisoprolol or placebo for 1 year. During a 4-to 7-week titration period, the maximum tolerated dose was established (1.25 mg, 2.5 mg, 3.75 mg, 5 mg once daily). Primary outcome: A number of participant-reported exacerbations during the 1-year treatment period. Results: In total, 519 participants were recruited and randomised. Four post-randomisation exclusions left 259 in the bisoprolol group and 256 in the placebo group. Treatment groups were balanced at baseline: mean (standard deviation) age 68 (7.9) years; 53% men; mean (standard deviation) pack year smoking history 45 (25.2); mean (standard deviation) 3.5 (1.9) exacerbations in previous year. Primary outcome data were available for 99.8% of participants (bisoprolol 259, placebo 255). The mean (standard deviation) number of exacerbations was 2.03 (1.91) in the bisoprolol group and 2.01 (1.75) in the placebo group (adjusted incidence rate ratio 0.97, 95% confidence interval 0.84 to 1.13), p = 0.72. The number of participants with serious adverse events was similar between the two groups (bisoprolol 37, placebo 36). The total number of adverse reactions was also similar between the two groups. As expected, bisoprolol was associated with a higher proportion of vascular adverse reactions (e.g. hypotension, cold peripheries) than placebo, but was not associated with an excess of other adverse reactions, including those classified as respiratory. Adding bisoprolol resulted in a statistically insignificant trend towards higher costs (£636, 95% confidence interval £118 to £1391) and fewer quality-adjusted life-years (0.035, 95% confidence interval 0.059 to 0.010) compared to placebo. Limitations: The study findings should be interpreted with caution as the target sample size of 1574 was not achieved because the funder considered the study to be unviable in the COVID-19 pandemic clinical research environment. Although 28% of participants did not initiate bisoprolol/placebo (1.6%) or ceased during the treatment period (26.2%), this is consistent with similar trials in the United Kingdom. Conclusions: In this underpowered study, the addition of bisoprolol to usual chronic obstructive pulmonary disease treatment did not reduce the likelihood of exacerbations, and bisoprolol cannot be recommended as a treatment for chronic obstructive pulmonary disease. Future work: To incorporate definitive statements into appropriate clinical guidelines about the safety of bisoprolol for cardiovascular indications in people with chronic obstructive pulmonary disease.</p
Derivatization of pBACpAK entrapment vectors for enhanced mobile genetic element transposition detection in multidrug-resistant Escherichia coli
Get PDFAim. Antimicrobial resistance poses a critical global health threat, driven by the dissemination of resistance genes via mobile genetic elements (MGEs). This study aims to enhance the detection of MGE insertions in multidrug-resistant Escherichia coli by derivatizing the pBACpAK entrapment vector. Methods and results. Three derivatives were constructed with additional nucleotides upstream of the cI repressor gene, based on conserved regions identified from GenBank sequences containing known IS26 and IS1 insertions. Using colony PCR, intracellular transposition screening was performed on 194 tetracycline-resistant colonies from four E. coli ESI123 strains carrying different pBACpAK constructs. The derivatives showed increased MGE capture rates (10.7–73.1%) compared to the WT vector (3.75%), identifying multiple MGEs, including the novel composite transposon Tn7824. Tn7824 harbours the blaOXA-181 carbapenem resistance gene and the qnrS1 quinolone resistance gene, highlighting the clinical relevance of these findings. Long-read sequencing of transposants confirmed the accuracy of MGE identification and structural characterization, which also revealed chromosomal integration events of the pBACpAK derivatives mediated by flanking insertion sequences. Conclusions. The modifications introduced in the pBACpAK derivatives could increase the detection of transposition events by alleviating spatial constraints, allowing for more robust MGE detection.</p
Developing and evaluating a community-driven intervention to promote uptake of HIV and contraception services among students enrolled in colleges and universities in Zimbabwe
Get PDFIntroductionThere is a growing appreciation that community-led interventions are key to sustaining the HIV response and achieving HIV prevention and treatment targets. Together with young people in colleges/universities and Ministry of Health (MOH), we developed and evaluated a student-led intervention for promoting the uptake of HIV self-testing (HIVST), post-exposure prophylaxis (PEP) and emergency contraception (EC) among college/university students.MethodsOver 3 months, in biweekly study team meetings, two workshops with students, two meetings with MOH, and a joint workshop with students, MOH and relevant stakeholders, we co-developed an intervention for peer-led promotion/distribution of HIVST, PEP, EC and condoms. The agreed intervention was piloted in three Zimbabwean colleges/universities from December 2023 to February 2024. Student peers distributed HIVST and condoms directly, and vouchers for PEP and EC that were redeemed at college/nearby clinics. During co-development, students strongly preferred peer distribution of all commodities but this was restricted by regulatory requirements for PEP and EC. Peer distributors (n = 14) kept daily audio diaries of their experiences. In-depth interviews were held with students (n = 18), peer distributors (n = 11) and key informants (n = 12) to explore views/preferences, with participant observations and four focus group discussions to provide additional insights. We determined the intervention development and implementation costs.ResultsPeer-led distribution of HIVST, PEP and EC to college/university students was acceptable, feasible, appropriate and generally implemented as intended. PEP and EC acceptability was driven by high HIV and pregnancy risk among students, who had no easy access to services. Of 100 PEP and 257 EC vouchers distributed, 30% and 40% were redeemed, respectively. The main barrier to PEP and EC uptake was moral judgement against premarital sex, which affected female students more. Judgemental health worker attitudes also limited uptake of PEP and EC. EC voucher redemption among female students was lower versus males, aOR = 0.4 (95% CI = 0.2−0.8), p = 0.019. Redemption was also higher at the college where the nearby clinic could be accessed discreetly. Total cost of the intervention per student was 7.26−$35.52).ConclusionsStudent-led distribution of HIVST, PEP and EC was feasible, acceptable and affordable. Making the intervention more community-driven according to the 2024 WHO PEP guidelines will likely achieve great impact