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A timeline of reckoning: Tracking the historical rise of antimicrobial resistance across HIV, TB, and malaria.
Get PDFAntimicrobial resistance is one of the major health challenges of this century. Here, we provide an in-depth perspective on the evolution of antimicrobial resistance in three globally relevant infectious diseases, HIV, tuberculosis (TB), and malaria. Specifically, we scrutinize the timelines between deployment and the subsequent emergence of resistance for all drugs that have been mobilized in the fight against these three diseases. Our data reveals that malaria exhibits a slower rate of resistance development to monotherapies in comparison to HIV and TB. While the adoption of combination therapies significantly reduces the risk of de novo emergence of resistance, the challenge of pre-existing drug resistance persists, necessitating continuous surveillance and emphasizing the critical need for diverse and innovative approaches to manage and mitigate the ever-growing threat of antimicrobial resistance
Increasing Birth-Dose Hepatitis B Vaccination in Nigeria: Qualitative Analysis of Data From a Crowdsourcing Open Call.
No full textBACKGROUND: Despite World Health Organization and Nigerian recommendations for hepatitis B birth-dose (HepB-BD) vaccination, only one-third of Nigerian newborns receive timely HepB-BD vaccination, This study identified facilitators to increasing HepB-BD vaccination based on data from a crowdsourcing open call in Nigeria. METHODS: Our team conducted an open call across Nigeria for teams to submit ideas on how to increase HepB-BD vaccination. Independent judges evaluated the submissions based on predefined criteria. We analyzed textual data from the top 29 entries using iterative coding and thematic analysis within a socioecological model to identify priority facilitators. RESULTS: The open call received 362 total submissions, and 58.5% (215/362) of submissions were from women. Analysis of the top 29 submissions revealed 6 priority facilitators for increasing HepB-BD vaccination: (1) engage religious and healthcare leaders to educate pregnant women; (2) strengthen national policies for vaccination support and tracking; (3) counter misconceptions to promote attitude and behavior changes; (4) utilize rural infrastructure like town halls and radio programs to disseminate information; (5) translate educational materials into local languages like pidgin; and (6) organize financial or social incentives. CONCLUSIONS: Our crowdsourcing open call identified key facilitators and strategies for increasing HepB-BD vaccination among Nigerian newborns. The findings from this study can inform HepB-BD initiatives in Nigeria and other low- and middle-income countries
Are oldest old patients with diffuse large B-cell lymphoma different than their younger counterparts: Results from the REALYSA real-life cohort.
Get PDFINTRODUCTION: Over a half of diffuse large B-cell lymphoma (DLBCL) cases are diagnosed in adults aged 65 years and older. Older adults are a heterogeneous group, and few studies reported differences in care management and survival in the oldest old. We aimed to describe characteristics, care management, and survival of older adults aged 60 and over included in the REal-world dAta in LYmphoma and Survival in Adults (REALYSA) study. MATERIALS: and methods: Patients newly diagnosed with DLBCL, aged over 60 years, included in REALYSA cohort between 2018/11 and 2021/12 and receiving therapy (RCHOP/miniRCHOP/Other) were included. Sociodemographic, living area and clinical characteristics, as well as the type of care center and pathway during the first year after diagnosis were described by age (60-69 y/70-79 y/≥80 y). Survival was described using Kaplan-Meier curves, the Cox model for adjusted survival, and net survival (Pohar-Perme estimator). RESULTS: A total of 560 DLBCL patients with a median age at diagnosis of 72 years (IQR=67-77) were included. R-CHOP was the main curative treatment in patients aged 60-79, and R-miniCHOP in the oldest old. More than half of the patients were male, married or in a relationship, living in urban and low deprived area. With increasing age, the proportion of patients with performance status 0-1 or no Charlson comorbidity at diagnosis decreased. Two thirds of patients were diagnosed at advanced stage with comparable trends between age groups. However, the oldest patients were more likely to have high-risk disease and geriatric frailty at diagnosis. One-year net survival, in contrast to OS (91 %vs 95 % and 75 % for each age group), showed no significant reduction in survival for 80 + (93 %, 100 % and 87 % for each age group). CONCLUSION: As the fastest-growing age group in developed countries, the oldest old require a special attention and further work on this population is needed
Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals.
Get PDFWith the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments
Evolutionary dynamics in the genome of ocular Chlamydia trachomatis strains from Northern Tanzania following mass drug administration.
Get PDFTrachoma, caused by Chlamydia trachomatis (Ct), remains a leading cause of preventable infection-induced blindness worldwide. We conducted a 4-year longitudinal study in three trachoma-endemic villages in Northern Tanzania, tracking infection dynamics and factors influencing trachomatous scarring progression and persistence pre- and post-mass drug administration (MDA) interventions. We analysed 118 whole genomes of Ct originating from ocular swabs of children. Sample collection was conducted at 3-month intervals over 4 years, encompassing 15 timepoints. We studied Ct phylogeny and patterns of SNP accumulation within sequences in the Ct genotype A (CtA) and Ct genotype B (CtB) phylogenetic clades, with the association of clinical signs of trachoma and scarring progression. Of the samples analysed, 71 (60.2%) were identified as CtA and 47 (39.8%) as CtB. We observed a significant shift in genotype prevalence: CtB predominated in pre-MDA samples (36 out of 40, 90%), whilst CtA became the dominant genotype after the first MDA round (67 out of 78, 85.9%) (P<0.0001). Phylogenetic analysis revealed two distinct CtA clades: clade 1 (29 sequences) was primarily found pre-MDA and shared a common ancestor with Tanzanian CtA reference genomes, whilst clade 2 (42 sequences) emerged post-MDA and exhibited a characteristic ~6 kbp reduction in the plasticity zone (PZ). Similarly, CtB sequences formed two distinct clades, both sharing ancestry with a Tanzanian CtB reference genome. Notably, we identified variable genome reduction in the PZ (~4 and ~10 kbp) amongst 13 CtB sequences distributed across both clades. We documented a significant shift in Ct genotype distribution following the first round of MDA, characterized by the emergence of CtA strains with distinct genetic profiles compared to pre-MDA strains. The observed reductions in Ct genome size suggest ongoing evolutionary processes shaping these bacterial populations. Additional research is needed to understand the dynamic changes in Ct lineage composition before and after antibiotic interventions and to determine how variations in genome size influence Ct biology and its susceptibility to azithromycin treatment
Geospatial analysis of leptospirosis clusters and risk factors in two provinces of the Dominican Republic.
Get PDFBACKGROUND: Drivers of leptospirosis transmission can vary across regions, leading to spatial clustering of infections. This study aims to identify clusters of leptospirosis seroprevalence in the Dominican Republic (DR) and factors associated with high-risk areas. METHODOLOGY/PRINCIPAL FINDINGS: We analysed data from two provinces, Espaillat and San Pedro de Macoris (SPM), obtained on a national survey conducted in 2021 (n = 2,078). Samples were tested by microscopic agglutination testing (MAT) to detect leptospirosis antibodies. We used flexible spatial scan statistics to locate significant clusters for seropositive individuals (all serogroups combined) in each province and calculated risk ratios (RR) at the household and community level. Environmental and sociodemographic risk factors associated with clusters were assessed by logistic regression. One cluster was identified in each province. Participants living inside a cluster were more likely to live further from health facilities (OR 1.86, p < 0.001 and OR 4.41, p = 0.044 by motorized travel time in Espaillat and SPM, respectively). Cluster participants were also less likely to live in areas of higher population density (OR 0.76, p < 0.01 and OR 0.29, p < 0.001 in Espaillat and SPM, respectively) and in communities with higher gross domestic product (GDP) (OR 0.70, p < 0.001 and OR 0.42, p < 0.001 in Espaillat and SPM, respectively). Additional risk factors varied between Espaillat and SPM. CONCLUSION/SIGNIFICANCE: Our findings confirm the clustered spatial pattern of leptospirosis and highlight that transmission drivers vary by province. While both provinces show higher transmission in impoverished areas, modifiable factors differ, requiring tailored public health interventions
Guidelines and Best Practices for the Use of Targeted Maximum Likelihood and Machine Learning When Estimating Causal Effects of Exposures on Time-To-Event Outcomes.
Get PDFTargeted maximum likelihood estimation (TMLE) is an increasingly popular framework for the estimation of causal effects. It requires modeling both the exposure and outcome but is doubly robust in the sense that it is valid if at least one of these models is correctly specified. In addition, TMLE allows for flexible modeling of both the exposure and outcome with machine learning methods. This provides better control for measured confounders since the model specification automatically adapts to the data, instead of needing to be specified by the analyst a priori. Despite these methodological advantages, TMLE remains less popular than alternatives in part because of its less accessible theory and implementation. While some tutorials have been proposed, none address the case of a time-to-event outcome. This tutorial provides a detailed step-by-step explanation of the implementation of TMLE for estimating the effect of a point binary or multilevel exposure on a time-to-event outcome, modeled as counterfactual survival curves and causal hazard ratios. The tutorial also provides guidelines on how best to use TMLE in practice, including aspects related to study design, choice of covariates, controlling biases and use of machine learning. R-code is provided to illustrate each step using simulated data ( https://github.com/detal9/SurvTMLE). To facilitate implementation, a general R function implementing TMLE with options to use machine learning is also provided. The method is illustrated in a real-data analysis concerning the effectiveness of statins for the prevention of a first cardiovascular disease among older adults in Québec, Canada, between 2013 and 2018
Proteomic Profiling of the Large-Vessel Vasculitis Spectrum Identifying Shared Signatures of Innate Immune Activation and Stromal Remodeling.
Get PDFOBJECTIVE: Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. METHODS: Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n = 96) and large-vessel GCA (LV-GCA) (n = 35) in addition to healthy control participants (HCs) (n = 35). Cohort 2 comprised patients presenting acutely with possible cranial GCA (C-GCA) in whom the diagnosis was subsequently confirmed (C-GCA, n = 150) or excluded (Not C-GCA, n = 89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. RESULTS: In cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 DAPs in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In cohort 2, comparing C-GCA versus not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA, and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including interleukin 6 (IL-6), monocyte/macrophage-related proteins (CCL7, CSF1), tissue remodeling proteins (TIMP1, TNC), and novel associations (TNFSF14, IL-7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. CONCLUSION: These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis, and tissue remodeling. Network-based analyses highlighted immune-stromal cross-talk and identified novel therapeutic targets (eg, TNFSF14)
Tecovirimat in the management of poxviruses: a narrative review of available evidence
Get PDFIntroduction: Tecovirimat (TPOXX) is an effective antiviral medication recommended for treating smallpox and other Orthopoxvirus infections. With the rise in monkeypox (mpox) cases globally, there is an urgent need to explore therapeutic options to manage potential outbreaks.
Methodology: A literature search was conducted using keywords from Scopus and ClinicalTrials.gov. English studies from 2018 to 2024 were included.
Results: Ten studies assessing the effectiveness and safety of tecovirimat for poxvirus infections were evaluated, reporting diverse findings across different patient populations and study designs. Clinical trials have shown significant therapeutic potential. Various doses of tecovirimat were used in rabbit and mpox models. Early intervention slowed disease progression in vulnerable populations, such as people living with HIV (PLWHIV). Recovery times, virus eradication, and symptom relief varied among studies, but wider access and usage showed better clinical symptoms and tolerable side effects. Tecovirimat’s efficacy against circulating strains has been experimentally demonstrated.
Conclusion: Tecovirimat shows promise for treating poxvirus infections. Clinical trials are expected to provide more evidence-based findings to inform future therapeutic approaches and public health campaigns. Future research should explore tecovirimat’s potential in managing emerging poxvirus outbreaks, such as borealpox and mpox, to strengthen and promote public health
Leprosy research updates: Shaping the future of global health.
Get PDFLeprosy, or Hansen’s disease, remains a majorly neglected tropical disease. In 2023, 1,82,815 new cases were reported globally, primarily from India, Brazil, and Indonesia. The disease, caused by Mycobacterium leprae (M. leprae) and M. lepromatosis, is known for its skin lesions but often leads to severe complications, including neural damage resulting in permanent disabilities.
Despite significant advances, leprosy’s transmission mechanisms remain unclear, with zoonotic transmission via armadillos emerging as a concern, especially in Latin America. Diagnostic challenges persist, with skin smears offering limited sensitivity, underscoring the need for advanced, point-of-care diagnostics, such as anti-PGL-I antibody tests and multiplex PCR assays. Recent advancements in PCR technology and M. leprae genotyping have enhanced the accuracy of diagnostics, aiding in the detection of the disease and understanding its transmission patterns. Additionally, new therapies, including bedaquiline, and Telacebec, show promise in treating leprosy, although management of reactions and neuritis remains a challenge.
Leprosy prevention efforts are focused on post-exposure prophylaxis (PEP) and vaccines, with the BCG vaccine showing limited efficacy in leprosy prevention. Innovative approaches, including single-dose rifapentine and bedaquiline for PEP, are being explored. Mental health support and addressing stigma through human rights-based interventions are critical for improving the quality of life for those affected