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Application of a targeted amplicon sequencing panel to screen for insecticide resistance mutations in Anopheles darlingi populations from Brazil.
Get PDFLarge-scale surveillance and informed vector control approaches are urgently needed to ensure that national malaria programs remain effective in reducing transmission and, ultimately, achieving malaria elimination targets. In South America, Anopheles darlingi is the primary malaria vector and is responsible for the majority of Plasmodium species transmission. However, little is known about the molecular markers associated with insecticide resistance in this species. In this study, we developed a low-cost, high throughput amplicon sequencing ("amp-seq") panel, consisting of 11 amplicons targeting genes linked to mosquito species identification (cox-1 and its2) and insecticide resistance (ace-1, GSTe2, vgsc and rdl). When used in tandem with dual-index barcoding of amplicons, this approach permits high numbers of loci and samples to be sequenced in single runs, thereby decreasing costs and increasing efficiency. By screening 200 An. darlingi mosquitoes collected in Brazil, our amp-seq approach identified 10 point mutations leading to amino acid changes in ace-1 (V243I, N294H, S673N, S674N/T) and GSTe2 genes (I114V, D128E, T166I, T179I, and T205A). Overall, our work has demonstrated the utility of amp-seq to provide insights into the genetic diversity of An. darlingi mosquitoes. The amp-seq approach can be applied as a wide-scale insecticide-resistance surveillance technique to better inform vector-control methods
Disentangling the relationship between glucose, insulin and brain health: A UK Biobank study.
Get PDFBACKGROUND: Glycaemic traits are associated with poorer brain health and dementia risk. Recent advances in genetic instruments for specific glycaemic markers enable an in-depth investigation of the likely nature of associations and underlying mechanisms between diabetes-related mechanisms and brain health and dementia. METHODS: We used two-sample Mendelian randomisation (MR) in the UK Biobank (UKB) (maximum N = 357 883 White British, mean age 56.9 years, 54% female) applying inverse-variance weighted MR as our main estimator alongside MR-Egger, weighted median estimator (WME) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as sensitivity tests. Instruments were 53 insulin resistance, 109 fasting glucose, 48 fasting insulin and 15 2-h post-load glucose genetic variants with variant-outcome effects estimated adjusting for 10 PCs. We checked core MR assumptions and sought to replicate results in an independent Alzheimer's dementia genome-wide association study (GWAS). RESULTS: In UKB, higher 2-h post-load glucose was associated with a 69% increased Alzheimer's dementia risk (odds ratio 1.69 [95% confidence interval 1.38-2.07]), though this did not replicate in an independent GWAS. Fasting insulin, fasting glucose and postprandial glucose did not influence total brain, hippocampal or white-matter hyperintensity volumes. DISCUSSION: The association between elevated 2-h post-load glucose and increased Alzheimer's risk supports a potential role for postprandial hyperglycaemia in dementia. The lack of associations between fasting or postprandial glucose and hippocampal, total-brain or white matter hyperintensity volumes suggests this risk may operate independently of gross structural atrophy. CONCLUSION: Genetically proxied postprandial hyperglycaemia contributes to increased Alzheimer's risk in mid-life, warranting replication in other populations and ancestries to confirm and clarify underlying mechanisms
Rule-Breaking and Rulemaking: Governance of the Antibiotic Value Chain in Rural and Peri-Urban India.
Get PDFBackground/Objectives: Antimicrobial resistance (AMR) is a growing global health challenge, driven in part by how antibiotics are accessed, distributed, and used within complex value chains. In peri-urban India, these supply chains involve a range of formal and informal actors and practices, making them a critical yet underexamined focus for antimicrobial stewardship efforts. While much research has focused on the manufacturing and regulatory end, less is known about how antibiotics reach consumers in rural and peri-urban settings. This study aimed to map the human antibiotic value chain in West Bengal, India, and to analyse how formal and informal governance structures influence antibiotic use and stewardship.
Methods: This qualitative study was conducted in two Gram Panchayats in South 24 Parganas district, West Bengal, India. Semi-structured interviews were carried out with 31 key informants, including informal providers, medical representatives, wholesalers, pharmacists, and regulators. Interviews explored the structure of the antibiotic value chain, actor relationships, and regulatory mechanisms. Data were analysed thematically using a value chain governance framework and NVivo 12 for coding.
Results: The antibiotic value chain in rural West Bengal is highly fragmented and governed by overlapping formal and informal rules. Multiple actors-many holding dual or unofficial roles-operate across four to five tiers of distribution. Informal providers play a central role in both prescription and dispensing, often without legal licences but with strong community trust. Informal norms, credit systems, and market incentives shape prescribing behaviour, while formal regulatory enforcement is inconsistent or absent.
Conclusions: Efforts to promote antibiotic stewardship must move beyond binary formal-informal distinctions and target governance structures across the entire value chain. Greater attention should be paid to actors higher up the chain, including wholesalers and pharmaceutical marketing networks, to improve stewardship and access simultaneously. This study highlights how fragmented governance structures, overlapping actor roles, and uneven regulation within antibiotic value chains create critical gaps that must be addressed to design effective antimicrobial stewardship strategies
The epidemiology of pathogens with pandemic potential: A review of key parameters and clustering analysis.
Get PDFINTRODUCTION: In the light of the COVID-19 pandemic many countries are trying to widen their pandemic planning from its traditional focus on influenza. However, it is impossible to draw up detailed plans for every pathogen with epidemic potential. We set out to try to simplify this process by reviewing the epidemiology of a range of pathogens with pandemic potential and seeing whether they fall into groups with shared epidemiological traits.
METHODS: We reviewed the epidemiological characteristics of 19 different pathogens with pandemic potential (those on the WHO priority list of pathogens, different strains of influenza and Mpox). We extracted data on key parameters (reproduction number serial interval, proportion of presymptomatic transmission, case fatality risk and transmission route) and applied an unsupervised learning algorithm. This combined Monte Carlo sampling with ensemble clustering to classify pathogens into distinct epidemiological archetypes based on their shared characteristics.
RESULTS: From 154 articles we extracted 302 epidemiological parameter estimates. The clustering algorithms categorise these pathogens into six archetypes (1) highly transmissible Coronaviruses, (2) moderately transmissible Coronaviruses, (3) high-severity contact and zoonotic pathogens, (4) Influenza viruses (5) MERS-CoV-like and (6) MPV-like.
CONCLUSION: Unsupervised learning on epidemiological data can be used to define distinct pathogen archetypes. This method offers a valuable framework to allocate emerging and novel pathogens into defined groups to evaluate common approaches for their control
Naturally Acquired Immune Responses to Antigens of the Sexual and Asexual Stages of Plasmodium Falciparum in the Southern and Central Regions of Senegal
Get PDFIn Senegal, despite numerous malaria control interventions, transmission is still seasonal. Malaria transmission depends on the presence of infectious parasites in the sexual stage in human peripheral blood. Immune responses acquired naturally at these or other stages can affect malaria transmission, resulting in protection against malaria, reduced transmission, and also form the basis for the development of transmission-blocking vaccines. To evaluate the antibody response profile against the asexual antigens PfAMA1, PfMSP119, Pf GLURP R2 and the sexual antigens Pfs230C1, Pfs48.45.6C in inhabitants naturally exposed to malaria in areas with different levels of transmission in Senegal. A cross-sectional study was carried out at the end of the transmission season in central (Keur Socé) and southern (Saraya) Senegal in 2018. We included 1106 asymptomatic volunteers aged 5 and over. Capillary blood was collected from each participant for an RDT, 2 slides for microscopy and a dried blood spot samples for immunology. A Luminex serological multiplex bead assay was then used to assess Plasmodium falciparum seroprevalence Our study population was characterized by a very young population with a median age of 12 15 years. The parasite prevalence of Plasmodium falciparum was 21.75% and 2.75% by RDT and 22.1% and 2.2% by microscopy for the southern and central regions respectively. Two other plasmodial species were found in Saraya, with prevalences of 1.61% for P. malariae and 0.18% for P. ovale. The mean seroprevalences of antibodies against three asexual blood-stage antigens (PfAMA1, PfGLURP and PfMSP119) and two sexualstage antigens (Pfs48.45.6C and Pfs230C1) were significantly higher in Saraya. In Keur Socé, the mean seroprevalence of antibodies against the PfAMA1 antigen was highest (1.83%), while in Saraya, PfMSP119 was highest (49.91%). The antigenicity of these proteins depended on endemicity levels, as antibody prevalence was statistically different in the two sites and increased with transmission intensity. With the exception of anti-Pfs48.45.6C antibody levels, all other antibody responses increased with age. Overall, these data indicate that the seroprevalence and antivody levels of individuals with antibodies recognizing all five antigens increase with exposure to infection, and that these antibodies may contribute to immunity against parasites. Children receiving SMC should also be monitored, as we have noted a loss of immunity in this group
The Use of First-Void Urine to Screen Women Aged 60-79 for HPV in the UK: The Catch-Up Screen Study.
Get PDFOBJECTIVE: Almost half the deaths from cervical cancer in the UK are among women aged over 65 who were already above the upper age of screening when primary HPV screening was introduced in the UK in 2019. Our aim is to test the feasibility of a national catch-up HPV testing programme. DESIGN: This first phase of the Catch-Up Screen study involved randomizing over 3000 invited participants to receive a urine HPV test and a follow-up telephone call or text message. SETTING: GP practices in Hull and Manchester, UK. POPULATION: Women aged 60-79 who have not undergone primary HPV screening. METHODS: Eligible women were selected from GP practice records, and 3074 were invited to provide an at-home first-void urine sample for HPV testing. MAIN OUTCOME MEASURES: Uptake of at-home urine screening according to screening history, area-level index of deprivation, and randomised follow-up method. RESULTS: Overall, 59% (1816) of invited women returned a urine sample for HPV testing. Response varied by screening history and index of area-level deprivation, but 39% of those who declined their last invited NHS screen responded favorably and took part in Catch-Up Screen. Telephone reminders yielded a 5% absolute increase in response compared to the text message arm (p = 0.007). CONCLUSIONS: An at-home first-void urine sample is a viable method for a national catch-up HPV test and has the potential to address decreasing national coverage among older women being invited for their last screen
Caregiver experiences and healthcare provider perspectives on managing sick young infants in primary care: a qualitative study in Awi Zone, Northwest Ethiopia.
Get PDFBACKGROUND: Ethiopia implemented the community-based management of possible serious bacterial infection to improve access to lifesaving care for sick young infants aged 0-2 months. However, service utilization has been low, and the quality of care was sub-optimal, emphasizing the need to identify challenges within the primary healthcare system. This study explored mothers' and healthcare providers' experiences and perspectives on the management of sick young infants, including those with possible serious bacterial infections to inform policy and practice. METHODS: We conducted a qualitative study including 25 in-depth and six key informant interviews with purposively selected participants, including mothers seeking facility care for their infants, health extension workers, health center staff, and supervisors of health extension workers. We audio-recorded and transcribed the interviews, and conducted inductive thematic analysis. RESULTS: We present four major themes: caregivers' perceptions of young infant illnesses, caregivers' choice of place to seek care, caregivers' experiences with caring for sick young infants at the health facility, and factors affecting the provision of quality care. Mothers acknowledged the need to seek care if their young infants became ill, although often delayed when not recognizing signs of illness, believing that it would resolve. Once identified, they had the autonomy to seek care but lacked awareness of health post services, bypassing these and seeking care at health centers, which were further away. Health extension workers viewed poor infrastructure and the perceived low quality of service as being linked to low service utilization at health posts. Mothers described long waiting times at health centers, inadequate assessment, and missing communication about their children's conditions and treatment. Health extension workers felt they had gaps in knowledge and skills. Inconsistent availability of drugs, weak referral and feedback mechanisms, low-quality supervision, limited mentorship, and inadequate district-level ownership of newborn care constrained the delivery of high-quality services. CONCLUSIONS: This study identifies the challenges from the community to health system on sick young infants' service utilization and quality of care at primary healthcare settings. It highlights the importance of a comprehensive approach that integrates demand-creation activities with health system strengthening efforts to ensure the consistent availability of high-quality care
A metabolic atlas of the Klebsiella pneumoniae species complex reveals lineage-specific metabolism and capacity for intra-species co-operation.
Get PDFThe Klebsiella pneumoniae species complex inhabits a wide variety of hosts and environments, and is a major cause of antimicrobial resistant infections. Genomics has revealed the population comprises multiple species/sub-species and hundreds of distinct co-circulating sub-lineage (SLs) that are associated with distinct gene complements. A substantial fraction of the pan-genome is predicted to be involved in metabolic functions and hence these data are consistent with metabolic differentiation at the SL level. However, this has so far remained unsubstantiated because in the past it was not possible to explore metabolic variation at scale. Here, we used a combination of comparative genomics and high-throughput genome-scale metabolic modeling to systematically explore metabolic diversity across the K. pneumoniae species complex (n = 7,835 genomes). We simulated growth outcomes for each isolate using carbon, nitrogen, phosphorus, and sulfur sources under aerobic and anaerobic conditions (n = 1,278 conditions per isolate). We showed that the distributions of metabolic genes and growth capabilities are structured in the population, and confirmed that SLs exhibit unique metabolic profiles. In vitro co-culture experiments demonstrated reciprocal commensalistic cross-feeding between SLs, effectively extending the range of conditions supporting individual growth. We propose that these substrate specializations may promote the existence and persistence of co-circulating SLs by reducing nutrient competition and facilitating commensal interactions. Our findings have implications for understanding the eco-evolutionary dynamics of K. pneumoniae and for the design of novel strategies to prevent opportunistic infections caused by this World Health Organization priority antimicrobial resistant pathogen
Autoantibodies in long COVID in a black/mixed population compared with recovered and pre-pandemic controls.
Get PDFINTRODUCTION: Long COVID (LC), a clinical condition marked by persistent and new symptoms after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affects up to 10-20% of infected individuals. Although autoimmunity has been proposed as a key mechanism, the specific role of circulating autoantibodies in LC remains unclear. We characterized the autoantibody profiles in individuals with LC and assessed their association with persistent post-COVID symptoms, in comparison to recovered patients and pre-pandemic healthy controls (PPHC).
METHODS: We analyzed 17 autoantibodies in a cohort of 220 pre-pandemic controls and 291 COVID-19 patients, targeting self-antigens. Of those, 237 patients presented symptoms for a month or more after the onset of SARS-CoV-2 infection (long COVID patients), and 54 individuals recovered from the initial infection without chronic symptoms. Autoantibody frequencies and associations with clinical variables were assessed using logistic regression and subgroup analyses.
RESULTS: Autoantibody prevalence was higher in recovered individuals (37%) than in LC patients (24%) or PPHC (19%). While certain autoantibodies such as a-cardiolipin (a-CL) IgM, a-AML IgG, a-SSA IgG and a-SSB IgG were elevated in some COVID-19 patients, they were not significantly different in LC. The most frequently detected autoantibody was a-CL IgM, found across all groups and especially in individuals that fully recovered from COVID-19. However, a-CL did not differentiate individuals with long COVID or correlate with symptom persistence but was associated with the occurrence of dysphagia and anorexia as symptoms. No correlation was observed between autoantibody presence and disease severity.
DISCUSSION: These findings do not support a primary pathogenic role for the evaluated autoantibodies in LC and emphasize the need for longitudinal studies to explore their temporal dynamics and interaction with other immunological or clinical factors involved in post-COVID-19 conditions
A double-blind, randomized placebo-controlled trial examining the effect of MitoQ on myocardial energetics in patients with dilated cardiomyopathy.
No full textOxidative stress may be an important driver of dilated cardiomyopathy (DCM) causing mitochondrial dysfunction and reduced ATP production, which mitochondria-targeted antioxidants, such as MitoQ may improve.1 We investigated whether MitoQ had an effect on myocardial energetics in patients with DCM using 31phosphorus magnetic resonance spectroscopy (31P-MRS) in a phase-2 randomized, double-blind, placebo-controlled trial.
Participants provided written informed consent. The trial was approved by the National Research Ethics Committee (21/LO/0035) and registered on ClinicalTrials.gov (NCT05410873). Inclusion criteria were 1) patients with DCM, 2) LVEF ≤45% on two studies ≥3 months apart, 3) on guideline therapy for ≥3 months, 4) in sinus rhythm, 5) elevated NT-pro-BNP (>250 ng/L if >65 years, > 100 ng/L if ≤65 years). Exclusion criteria were 1) atrial fibrillation, 2) contraindication to CMR or gadolinium, 3) environmental trigger for DCM, 4) late gadolinium enhancement (LGE) > 25% 5) current cancer, 6) CoQ10 use and 7) cardiac device