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The Nuffield Department of Medicine (NDM) at the University of Oxford has a global reach and significant breadth in terms of capabilities and capacity.
TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord
Abstract Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson’s disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer’s disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.
Proposed framework for triage of putative germline variants detected via tumour genomic testing in UK oncology practice.
In the UK, most patients receive publicly funded medical care through the National Health Service (NHS), which funds tumour and/or germline testing for eligible patients with cancer to inform clinical management.Testing on tumour-derived DNA may identify putative heritable variants, with implications for the proband and their wider family, but is not a reliable substitute for germline genetic testing when hereditary cancer predisposition is suspected.The likelihood that a variant identified through tumour testing is of germline origin depends on multiple clinical and technical factors. Certain genotypes significantly influence a patient's cancer risk, and intervention in those carriers may facilitate cancer prevention or early detection, while other genotypes are associated with lower cancer risk, and associated intervention in such cases have limited clinical utility.We convened a national meeting of clinical cancer genetics and scientific leads to rationalise germline follow-up testing of variants identified through tumour-based testing. After contrasting potential approaches, implementation of an NHS-contextualised 'intermediate conservative' approach was agreed and refined by the authors, with the final pathway recirculated to the UK clinical and scientific community for consensus agreement and publication.We outline relevant patient, genetic and technical considerations informing likely origin of variants, a review of current relevant guidance and NHS laboratory practices and a workflow for laboratory and clinical teams to triage tumour-detected variants requiring onward germline follow-up. This approach aims to direct limited resources towards identifying germline variants associated with the greatest potential clinical impact, with a view to supporting more efficient and equitable delivery of genomic medicine in oncology.
[Rejection of the preventive discussion and at-risk sexual behavior: a qualitative study among gay men in Portugal].
The dominant preventive discourse imposed on sexual minorities is one that orders and prescribes condom use and an adjusted lifestyle. High-risk sexual behaviors seem to express, in part, the rejection of this dominant discourse. The objective of this study is to better understand the links between the risky sexual behaviors of gays and the socio-cultural context that leads to the rejection of preventive practices. An ethnological study was carried out in Portugal This study included seven gay men aged between 19 and 64 years old. The study also included accounts from interviews of three lesbian and bisexual women. The results show that the social pressure of a hetero-normative environment can result in the refusal or denial of prevention practices. Thus, risky sexual behaviors can reflect desire and aspirations for more rights and freedoms. New and alternative spaces for meeting gays, namely on the Internet, also seem to create more opportunities for sexual liberation and open the way for relaxed prevention practices and engaging in risky sexual behavior. However, preventive practices are not entirely absent; the reduction of risks is being expressed by the choice of sexual partners and the avoidance of certain sexual practices when a condom is not used. Through this study, the importance of peer groups in the acceptance and internalization of the preventive discourse is re-affirmed.
Ivermectin to Control Malaria - A Cluster-Randomized Trial.
BackgroundMalaria control and elimination is threatened by the spread of insecticide resistance and behavioral adaptation of vectors. Whether mass administration of ivermectin, a broad-spectrum antiparasitic drug that also kills mosquitoes feeding on treated persons, can reduce malaria transmission is unclear.MethodsWe conducted a cluster-randomized trial in Kwale, a county in coastal Kenya in which malaria is highly endemic and coverage and use of insecticide-treated nets are high. Clusters of household areas were randomly assigned in a 1:1 ratio to receive mass administration of ivermectin (400 μg per kilogram of body weight) or albendazole (400 mg, active control) once a month for 3 consecutive months at the beginning of the "short rains" season. Children 5 to 15 years of age were tested for malaria infection monthly for 6 months after the first round of treatment. The two primary outcomes were the cumulative incidence of malaria infection (assessed among children 5 to 15 years of age) and of adverse events (assessed among all eligible participants). Analyses were performed with generalized estimating equations in accordance with the intention-to-treat principle.ResultsA total of 84 clusters comprising 28,932 eligible participants underwent randomization. The baseline characteristics of the participants were similar in the trial groups. Six months after the first round of treatment, the incidence of malaria infection was 2.20 per child-year at risk in the ivermectin group and 2.66 per child-year at risk in the albendazole group; the adjusted incidence rate ratio (ivermectin vs. albendazole) was 0.74 (95% confidence interval [CI], 0.58 to 0.95, P = 0.02). The incidence of serious adverse events per 100 treatments did not differ significantly between the trial groups (incidence rate ratio, 0.63; 95% CI, 0.21 to 1.91).ConclusionsAmong children 5 to 15 years of age who were living in an area with high coverage and use of bed nets, ivermectin, administered once a month for 3 consecutive months, resulted in a 26% lower incidence of malaria infection than albendazole. No safety concerns were identified. (Funded by Unitaid; BOHEMIA ClinicalTrials.gov number, NCT04966702; Pan African Clinical Trial Registry number, PACTR202106695877303.).
Toxicity of ivermectin to bed bugs (Cimex hemipterus) and risk factors associated with infestation in Kwale County, coastal Kenya.
BackgroundBed bugs (Cimex spp.) are obligate ectoparasites that have long been associated with human dwellings, causing discomfort and psychosocial distress. Conventional control strategies relying on insecticides are increasingly challenged by resistance, necessitating alternative interventions. Ivermectin, an endectocide known to impact various neglected tropical diseases and hematophagous arthropods, is currently being assessed for malaria vector control. This study aimed to evaluate the toxicity of ivermectin on Cimex hemipterus, the predominant bed bug species in Africa, within the framework of the Broad One Health Endectocide-based Malaria Intervention in Africa (BOHEMIA) project in Kwale, Kenya.MethodsA cross-sectional survey was conducted in 352 households to obtain information on self-reported bed bug infestations, socioeconomic status, and household characteristics. Bed bugs were collected from 40 infested households. After collection, bed bugs were acclimatized and exposed to blood meals spiked with ivermectin at five concentrations (85 ng/ml, 64 ng/ml, 43 ng/ml, 21 ng/ml, and 11 ng/ml), corresponding to expected serum levels 4 h to 6-7 days following a 400 µg/kg oral dose. Mortality and fecundity were monitored over a 14-day period. Statistical analyses, including Cox proportional hazard models and probit regression, were applied to assess dose-response relationships.ResultsBed bug infestation was common, with 75% of participating households reporting their presence, with infestations being strongly associated with the number of people residing in a household. Ivermectin exposure resulted in significant dose-dependent mortality in Cimex hemipterus, with the higher concentrations (43, 64, and 85 ng/ml) inducing over 90% mortality within 3 days postfeeding. Bed bugs that ingested blood meals containing sublethal doses of ivermectin did not lay eggs. Kaplan-Meier survival analyses demonstrated a clear inverse relationship between ivermectin concentration and bed bug survival.ConclusionsThese findings provide evidence that ivermectin, administered as part of a mass drug administration campaign, could contribute to bed bug control alongside its intended impact on other diseases or vectors. The results underscore the potential for integrated public health approaches leveraging endectocide interventions. Further field evaluations in diverse locations are needed to determine the optimal number of administrations and treatment intervals required for complete infestation elimination.
Phenotypic and genotypic insecticide resistance profiles of main malaria vectors in Kwale county, coastal Kenya.
BackgroundLong-lasting insecticidal nets are the primary malaria vector control measure in coastal Kenya. In 2018, phenotypic resistance to pyrethroids and low frequency of L1014S kdr mutation were reported in the Anopheles gambiae complex. Since then, additional pyrethroid-treated nets were distributed in 2021. The objectives of this study were to determine the insecticide resistance profiles of An. gambiae and Anopheles funestus from Kwale County and evaluate potential resistance mechanisms.MethodsFrom July 2023 to May 2024, adult and larval collections of An. funestus and An. gambiae mosquitoes were done with the aim of conducting insecticide susceptibility bioassays using WHO protocol for permethrin, deltamethrin, bendiocarb, DDT and pirimiphos-methyl. Species found resistant to pyrethroids were subjected to synergism testing by pre-exposure to piperonyl-butoxide (PBO). This was followed by genotyping of resistance-associated mutations in An. funestus (CYP6P9a, CYP6P9b, GSTe2-L119F and 6.5kb S.V) and An. gambiae (kdr L1014S and L1014F). Sibling species identification was done using PCR. The association between genetic markers and phenotypic resistance was explored using logistic regression.ResultsA total of 1826 An. gambiae and 715 An. funestus were used in insecticide susceptibility bioassays. Both An. gambiae and An. funestus were resistant to permethrin (mortality, 58.7% and 57.1, respectively) and deltamethrin (mortality 51% and 76%, respectively), but susceptible to DDT, bendiocarb and Pirimiphos-methyl. Pre-exposure to PBO increased susceptibility to deltamethrin in both species. Both kdr west and east were detected in Anopheles arabiensis (L1014S freq = 0.083, L1014F freq = 0.063) and Anopheles quadriannulatus (L1014S freq = 0.074, L1014F freq = 0.043) at low frequencies. Anopheles funestus sensu stricto and Anopheles rivolurum had the presence of CYP6Pa, CYP6Pb, 6.5kb S.V and GSTe2-L119F, with low allele frequencies. There were no significant associations between the genotypes and phenotypic profile.ConclusionsMalaria vectors in Kwale are resistant to pyrethroids. PBO fully restored susceptibility, indicating this resistance could be caused by metabolic mechanism. The presence of kdr and metabolic resistance alleles suggests a recent selection on Anopheles mosquitoes. Pyrethroid-only nets may not fully ensure community protection against malaria in coastal Kenya due to resistance. Operational failure remains uncertain, requiring further studies. Net distribution programs should consider pyrethroid-PBO nets to enhance malaria control effectiveness.
Age structure and parity status determination of Afrotropical malaria vectors using MALDI-TOF MS.
The age structure of a mosquito population helps estimate the proportion of vectors capable of transmitting malaria. Many malaria transmission models rely on mosquito longevity as key parameter. However, these are rarely measured in the field due to lack of a reliable and scalable age-grading method. An accurate method could improve predictions of malaria risk and the impact assessment of interventions. This study aimed to investigate the use of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) for malaria vector age-grading using insectary-reared and wild-caught mosquitoes. Anopheles gambiae s.s. mosquitoes were reared in the insectary to different known physiological and chronological ages to evaluate if MALDI-TOF MS could be used to distinguish between different age groups. Wild mosquitoes were collected from Mozambique and Kenya and dissected to determine their parity status. Reference spectra were obtained from mosquito's cephalothorax and used to create predictive databases which were validated using independent samples. MALDI-TOF MS identified the physiological and chronological age of insectary-reared mosquitoes with 94.52% and 77% accuracy respectively. Field-collected mosquitoes were primarily An. funestus s.s. and An. gambiae s.s. Parity prediction accuracy was between 81% and 87%. MALDI-TOF MS was able to distinguish and differentiate mosquitoes based on their age structure (chronological and physiological) and parity status.