69832 research outputs found
Sort by
Unveiling mismatch of RTS S AS01 and R21 Matrix M malaria vaccines haplotype among Ethiopian Plasmodium falciparum clinical isolates.
Get PDFMalaria vaccines, RTS, S/AS01 and R21/Matrix which are based on the Plasmodium falciparum circumsporozoite protein (Pfcsp) have been approved by WHO for broad use in children in Africa. However, the extensive genetic diversity of Pfcsp limited its effectiveness, as vaccine efficacy reduced against non-vaccine strains. Using Oxford Nanopore Technology, we conducted amplicon sequencing of the full-length Pfcsp gene from 96 clinical isolates collected from three health centers in Ethiopia and compared the results against a reference genome. The result showed absence of population differentiation among the Ethiopian isolates. The N-terminal region was relatively conserved, with a KLKQP motif was present across all isolates. However, mutation at position A98G and an insertion of amino acids (DGNNNNGDNGREGKDEDKR) were identified in this region. The number of NANP and NVDP repeats of the central region per haplotype ranged from 39 to 42. Additionally, the Th2R and Th3R epitopes in the C-terminal region exhibited extensive polymorphism with at least one amino acid substitution compared to the reference strains. Notably, none of the Ethiopian Pfcsp haplotypes matched the vaccine haplotype. Furthermore, haplotype network and phylogenetic tree analyses shown considerable similarity among local and global isolates. The findings of this study revealed a high Pfcsp genetic diversity highlighting the need for further studies to inform allele selection for universal or region-specific vaccine development as this may influence vaccine efficacy
Cost-effectiveness of one-off upper abdominal CT screening as an add-on to lung cancer screening in England.
Get PDFBACKGROUND: Low-dose computed tomography (CT) screening for lung cancer is available for high-risk individuals in England. Screening simultaneously for upper abdominal conditions, including cancer, is feasible. Here, we estimate the cost-effectiveness of one-off upper abdominal CT screening, added onto lung cancer screening, based on the Yorkshire Kidney Screening Trial (YKST) feasibility study. METHODS: A multi-disease health economic model was developed. Ten cancers and abdominal aortic aneurysm (AAA) were modelled over a lifetime horizon. YKST data informed disease prevalence, resource use and screening costs. Costs, quality-adjusted life-years (QALYs) and cost-effectiveness were estimated probabilistically. RESULTS: Screening per person costs £70.89, produces 0.0059 QALYs, and has 96% probability of being cost-effective, with an incremental cost-effectiveness ratio of £12,085. AAA contributes most to cost-effectiveness, followed by kidney cancer, but some cancer findings reduce cost-effectiveness. Screening is more cost-effective at younger ages. Screen-detectable disease prevalence, severity and mortality risk contribute most to uncertainty. CONCLUSIONS: One-off upper abdominal CT screening is potentially cost-effective, but costs, harms and benefits vary between conditions. Cost-effectiveness is driven by early diagnosis of AAA, then kidney cancer, illustrating the importance of considering all relevant diseases in screening models. A larger trial would provide more robust data to refine the cost-effectiveness argument. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT05005195
Willingness-to-Pay and Costs for Novel Manual Emptying Services for Shared Onsite Sanitation Facilities in an Informal Settlement of Nairobi, Kenya
Get PDFSafely managed sanitation is essential for the environment and public health, yet emptying services for onsite sanitation are often unsafe and unaffordable. This study aims to assess the stated willingness-to-pay (WTP) for two safer manual emptying services. The first is referred to as the “Standard Plan”, a hypothetical safer manual emptying service, and the second is the “Small-amount Plan”, a hypothetical service with a volumetric limit. The service costs were also estimated to assess the financial feasibility. We surveyed 400 households in an informal settlement in Nairobi, Kenya, using a contingent valuation method: respondents answered two dichotomous questions about price bids and then a question about the maximum amount they could pay. The mean WTP for the Small-amount Plan was 0.2/drum lower than the WTP for the Standard Plan. While the WTP was lower, the estimated cost of the Small-amount Plan where emptiers can visit multiple toilets was $0.9/drum lower than the Standard Plan where emptiers visit one toilet. Our results suggest that grouping multiple toilets could be a market viable cost-reduction strategy for manual emptying and warrant further research to develop and test this approach, which may increase access to safely managed sanitation in low-income informal urban areas
Accounting for Time-Varying Confounding in a Self-Controlled Case Series of Fluoroquinolone Treatment for Uncomplicated Urinary Tract Infections and Risk of Collagen-Related Events.
Get PDFWe report findings from three SCCS conducted to quantify the association between fluoroquinolone (FQ) use for the treatment of uncomplicated urinary tract infection (uUTI) and tendon rupture, retinal detachment, and uveitis. Female patients aged ≥ 12 years old in the Optum Clinformatics Data Mart database with an outcome of interest and exposure to either oral FQ or trimethoprim/sulfamethoxazole (SXT) in the 5 days following a newly reported uUTI during the study period (01/01/2011-02/10/2019) were included. We considered a 90-day risk window for each outcome following drug exposure. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using conditional Poisson regression, adjusting for age and calendar time, incorporating SXT as an active comparator. We found little evidence of an association between FQ use compared to SXT and any of the outcomes of interest (tendon rupture: IRR = 1.01, 95% CI = 0.91-1.21; retinal detachment: IRR = 0.99, 95% CI = 0.86-1.14; and uveitis: IRR = 1.09, 95% CI = 0.97-1.22). Incorporating the active comparator using two different methods did not change conclusions. The lack of evidence for an association between short-term use of FQ and the comparator antibiotic (SXT) for the treatment of uUTI and collagen-related events also implies that there was no marked association between uUTI and these outcomes. However, power was limited, and a small increased risk cannot be ruled out. Using active comparators in SCCS can improve the robustness of studies of antibiotics and adverse events
Clinical characteristics and outcomes of paediatric acute lymphoblastic leukaemia in a tertiary hospital in Tanzania: a single-centre observational study.
Get PDFBACKGROUND: A wide inequality exists between high- and low-income countries in the outcome of paediatric acute lymphoblastic leukaemia (ALL). At a tertiary-level hospital in Tanzania, multidimensional approaches have been taken to improve cancer care for children. This study aimed to update the outcomes of paediatric ALL at Muhimbili National Hospital (MNH), Tanzania from 2016 to 2020. METHODS: We performed a retrospective chart review of children who were treated with modified UKALL2003 protocol at MNH from January 1, 2016 to December 31, 2020. We used the Cox proportional hazards model to estimate the effect of each prognostic factor on event-free survival (EFS). RESULTS: We identified 202 patients who had confirmatory diagnoses of ALL and initiated treatment at MNH. Fifty-two patients (26%, 52/202) died (n = 47) or abandoned treatment (n = 5) before the end of remission induction. The main causes of death during this period were infections and bleeding complications. The median EFS was 9 months and 2-year EFS was 36%. Oedema, non-early rapid responder, and non-remission were associated with short EFS in the multivariable analysis. CONCLUSIONS: The number of new paediatric ALL admissions at MNH has doubled in the past decade. The prevention of early deaths is critical to improve the long-term survival of paediatric ALL in Tanzania
Temporal dynamics of gene expression during the development of Campylobacter jejuni biofilms.
Get PDFCampylobacter jejuni, an important pathogen of bacterial gastrointestinal infections, forms biofilms that enable its survival in different environments. C. jejuni biofilm development is still poorly understood, and thus, in this study, we characterized gene expression changes at different biofilm stages using RNA sequencing. Early biofilms (after 16 and 24 h) showed increased expressions of genes involved in cysteine and methionine metabolism, whereas mature biofilms (after 48 and 72 h) showed decreased expression of genes encoding capsular polysaccharides and lipooligosaccharides. Both early and mature biofilms showed increased expressions of genes involved in flagella formation, leucine metabolism and the oxidative stress response and decreased expressions of genes involved in energy metabolism, iron acquisition and transmembrane transport. This study provides insights into the molecular mechanisms underlying C. jejuni biofilm maturation, environmental resistance and the dynamic nature of gene expression during biofilm development
"The child of your fellow is your child": Building on existing protective norms to engage men as caregivers; qualitative findings from an exploratory evaluation of an edutainment intervention to prevent age-disparate transactional sex.
Get PDFEvidence on the importance of engaging men in preventing violence against women and girls has increased over the past decade, yet efforts often focus on men as partners rather than caregivers. This paper examines qualitative data from an evaluation of the Learning Initiative on Norms, Exploitation and Abuse radio drama intervention aimed at preventing age-disparate transactional sex in Tanzania's Shinyanga region. We delivered the drama to households on flash drives and led structured household discussion sessions. We conducted in-depth interviews with 18 adult men caregivers before (September 2021) and after the intervention (December 2021) and used thematic analysis and the framework method to examine indications of change in attitudes, beliefs, norms and behaviours. Findings provided practical lessons for future interventions aiming to engage men, specifically as caregivers, and demonstrated promising indications of change. We found that the home-based delivery of the intervention coupled with household discussions led to high engagement from men. This engagement fostered expansion of participant's conceptualisation of fatherhood to include discussing (age-disparate transactional) sex with adolescent girls, as well as with other men in the community, with the goal of protecting girls. We also found that the drama led to an expansion of the existing norm that it is everyone's responsibility within a community to protect girls, to include protecting girls from age-disparate transactional sex; highlighting the success of norms programming that reinforces existing positive norms rather than introducing new norms. This study highlights the potential for edutainment using a variety of acceptable and relatable characters and storylines to model positive behaviours performed by men, and home-based, discussion-oriented approaches to foster meaningful change. Finally, this study's findings offer valuable insights for developing effective strategies to engage men in violence prevention, while ensuring they remain accountable to the needs and priorities of women and girls
Cereblon expression in human peripheral blood mononuclear cells in response to in vitro stimulation with M. leprae
Get PDFBackground The host immune responses associated with the clinical phenotypes of Mycobacterium leprae infection are not fully understood. The inflammatory complications of leprosy, leprosy reactions, particularly erythema nodosum leprosum (ENL), present therapeutic challenges. Thalidomide is an effective drug for ENL but is not widely available due to teratogenicity. Thalidomide binds cereblon (CRBN), a substrate receptor for the E3 ligase complex, promoting ubiquitination. Thus, we investigated the CRBN expression in human peripheral blood mononuclear cells (PBMCs) in response to in vitro stimulation with M. leprae with/without CRBN blockade peptide. Methods Blood samples were obtained from apparently BCG-vaccinated and BCG-unvaccinated healthy volunteers. PBMC was isolated and stimulated with irradiated M. leprae with or without CRBN blockade peptide. CRBN, NF-kB, and PARK2 proteins were determined by ELISA, and their gene expression by qPCR. Results Stimulation with M. leprae significantly increased CRBN gene expression and protein production. Incubation of PBMCs with M. leprae with CRBN blockade significantly increased NF-kB expression. In a subgroup analysis, CRBN and NF-kB gene expression following stimulation with M. leprae (p ≤ 0.05) was significantly higher in PBMCs from Mycobacterium bovis bacillus Calmette–Guérin (BCG)-vaccinated individuals compared to those from unvaccinated participants. PARK2 gene expression and parkin protein were significantly decreased in PBMCs stimulated with M. leprae compared to unstimulated PBMCs (p ≤ 0.05). In a subgroup analysis, PARK2 gene expression and parkin protein were decreased in the PBMCs from BCG-unvaccinated individuals following incubation with M. leprae compared to those from BCG-vaccinated individuals. Stimulation of the PBMCs with M. leprae with CRBN blockade increased PARK2 gene expression and parkin protein production (p ≤ 0.05). Conclusion The findings are evidence that CRBN may have a role in modulating PARK2 and NF-kB gene expression in response to M. leprae infection. This needs further investigation in individuals with leprosy. The differential gene expression of CRBN and PARK2 in BCG-vaccinated and BCG-unvaccinated individuals could be further explored to understand the mechanism of BCG protection against leprosy
Long-term follow-up of the TRED-HF trial: Implications for therapy in patients with dilated cardiomyopathy and heart failure remission.
Get PDFAIMS: In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after therapy withdrawal. This follow-up investigates the longer-term effects of therapy withdrawal.
METHODS AND RESULTS: TRED-HF was a randomized trial investigating heart failure therapy withdrawal in patients with recovered DCM over 6 months. Those randomized to continue therapy subsequently withdrew treatment between 6 and 12 months. Participants were recommended to restart therapy post-trial and were followed until May 2023. Clinical outcomes are reported in a non-randomized fashion from enrolment and from the end of the trial. The primary outcome was relapse defined as ≥10% reduction in left ventricular ejection fraction to 400 ng/L, or clinical features of heart failure. From enrolment to the last follow-up (median 6 years, interquartile range 6-7), 33 of 51 patients (65%) relapsed. The 5-year relapse rate from enrolment was 61% (95% confidence interval [CI] 45-73) and from the end of the trial was 39% (95% CI 19-54). Of 20 patients who relapsed during the trial, nine had a recurrent relapse during follow-up. Thirteen relapsed for the first time after the trial; seven had restarted low intensity therapy, four had not restarted therapy and two did not have therapy withdrawn. The mean intensity of therapy was lower after the trial compared to enrolment (mean difference -6 [-8 to -4]; p < 0.001). One third of relapses during follow-up had identifiable triggers (arrhythmia [n = 4], pregnancy [n = 1], hypertension [n = 1], infection [n = 1]). Corrected atrial fibrillation was associated with reduced risk of relapse (hazard ratio 0.33, 95% CI 0.12-0.96; p = 0.042).
CONCLUSIONS: The risk of relapse in the 5 years following the TRED-HF trial remained high. Restarting lower doses of heart failure medications at the end of the trial, external triggers and disease progression are likely to have contributed to relapse
New WHO guidelines for treating rhodesiense human African trypanosomiasis: expanded indications for fexinidazole and pentamidine.
Get PDFHuman African trypanosomiasis is a neglected tropical disease that is usually fatal without treatment. WHO has revised its rhodesiense human African trypanosomiasis treatment guidelines on the basis of an independent systematic literature review and following the GRADE methodology. This Review reports on the decision-making process and summarises the new recommendations and their potential implications for health-care professionals and policy makers. Due to data scarcity, all recommendations are conditional and based on very low certainty of evidence. Fexinidazole replaces suramin and melarsoprol as the first-line therapy in individuals aged 6 years and older with a bodyweight of 20 kg or more. As fexinidazole is effective in both stages of rhodesiense human African trypanosomiasis, a lumbar puncture for staging is no longer required. In settings in which first-choice drugs are not readily available, immediate interim treatment with pentamidine is suggested. The introduction of oral fexinidazole represents an advancement in the management of rhodesiense human African trypanosomiasis considering the life-threatening adverse reactions individuals can have to melarsoprol. However, children below the age or weight limits remain ineligible for treatment with fexinidazole