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Detection of hidden antibiotic resistance through real-time genomics.
Get PDFReal-time genomics through nanopore sequencing holds the promise of fast antibiotic resistance prediction directly in the clinical setting. However, concerns about the accuracy of genomics-based resistance predictions persist, particularly when compared to traditional, clinically established diagnostic methods. Here, we leverage the case of a multi-drug resistant Klebsiella pneumoniae infection to demonstrate how real-time genomics can enhance the accuracy of antibiotic resistance profiling in complex infection scenarios. Our results show that unlike established diagnostics, nanopore sequencing data analysis can accurately detect low-abundance plasmid-mediated resistance, which often remains undetected by conventional methods. This capability has direct implications for clinical practice, where such "hidden" resistance profiles can critically influence treatment decisions. Consequently, the rapid, in situ application of real-time genomics holds significant promise for improving clinical decision-making and patient outcomes
Global and regional seroprevalence, incidence, mortality of, and risk factors for scrub typhus: A systematic review and meta-analysis.
Get PDFOBJECTIVES: Scrub typhus is underdiagnosed and underreported but emerging as a global public health problem. We aimed to provide the first comprehensive review on the seroprevalence, incidence, mortality of and risk factors for scrub typhus.
METHODS: We searched PubMed, Scopus, Web of Science, China National Knowledge Infrastructure and other databases. Trended incidence and median mortality were calculated and pooled seroprevalence and risk factors for scrub typhus were evaluated using the random-effects meta-analysis.
RESULTS: We included 663 articles from 29 countries/regions. The pooled seroprevalence was 10.73% (95%CI 9.47-12.13%) among healthy individuals and 22.58% (95%CI: 20.55%-24.76%) among febrile patients. Mainland China reported the highest number of cases and South Korea and Thailand had the highest incidence rates. Median mortalities were 5.00% (range: 0.00-56.00%) among hospital inpatients, 6.70% (range: 0.00-33.33%) among patients without specified admission status and 2.17% (range: 0.00-22.22%) among outpatients. The significant risk factors included agricultural work, specific vegetation exposure, other outdoor activities, risky personal health habits, and proximity to rodents, livestock, or poultry.
CONCLUSIONS: Our comprehensive review elucidates the significant yet variable burden of scrub typhus across different regions, underscoring its emergence as a critical public health concern globally
Ursodeoxycholic acid and severe COVID-19 outcomes in a cohort study using the OpenSAFELY platform.
Get PDFBACKGROUND: Biological evidence suggests ursodeoxycholic acid (UDCA)-a common treatment of cholestatic liver disease-may prevent severe COVID-19 outcomes. We aimed to compare the hazard of COVID-19 hospitalisation or death between UDCA users versus non-users in a population with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).
METHODS: With the approval of NHS England, we conducted a population-based cohort study using primary care records between 1 March 2020 and 31 December 2022, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-varying UDCA exposure and COVID-19 related hospitalisation or death, stratified by geographical region and considering models unadjusted and fully adjusted for pre-specified confounders.
RESULTS: We identify 11,305 eligible individuals, 640 were hospitalised or died with COVID-19 during follow-up, 400 (63%) events among UDCA users. After confounder adjustment, UDCA is associated with a 21% relative reduction in the hazard of COVID-19 hospitalisation or death (HR 0.79, 95% CI 0.67-0.93), consistent with an absolute risk reduction of 1.35% (95% CI 1.07%-1.69%).
CONCLUSIONS: We found evidence that UDCA is associated with a lower hazard of COVID-19 related hospitalisation and death, support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes
Temperature-related neonatal deaths attributable to climate change in 29 low- and middle-income countries.
Get PDFExposure to high and low ambient temperatures increases the risk of neonatal mortality, but the contribution of climate change to temperature-related neonatal deaths is unknown. We use Demographic and Health Survey (DHS) data (n = 40,073) from 29 low- and middle-income countries to estimate the temperature-related burden of neonatal deaths between 2001 and 2019 that is attributable to climate change. We find that across all countries, 4.3% of neonatal deaths were associated with non-optimal temperatures. Climate change was responsible for 32% (range: 19-79%) of heat-related neonatal deaths, while reducing the respective cold-related burden by 30% (range: 10-63%). Climate change has impacted temperature-related neonatal deaths in all study countries, with most pronounced climate-induced losses from increased heat and gains from decreased cold observed in countries in sub-Saharan Africa. Future increases in global mean temperatures are expected to exacerbate the heat-related burden, which calls for ambitious mitigation and adaptation measures to safeguard the health of newborns
Laboratory evaluation of the regeneration time, efficacy and wash-resistance of PermaNet Dual (a deltamethrin-chlorfenapyr net) against susceptible and pyrethroid-resistant strains of Anopheles gambiae sensu lato.
Get PDFPyrethroid-chlorfenapyr nets have been recommended for malaria control by the World Health Organisation (WHO) after an alpha-cypermethrin-chlorfenapyr net showed improved impact in epidemiological trials. PermaNet® Dual is a new deltamethrin-chlorfenapyr net developed by Vestergaard Sàrl to expand options to control programmes. A series of laboratory studies were performed according to WHO guidelines to assess the regeneration time, efficacy and wash-resistance of PermaNet® Dual. Regeneration time was determined by subjecting net pieces to cone bioassays and tunnel tests before and 0, 1, 2, 3, 5 and 7 days after washing. The wash-resistance of PermaNet® Dual was evaluated compared to WHO-prequalified pyrethroid-only (PermaNet® 2.0) and pyrethroid-chlorfenapyr (Interceptor® G2) nets by testing net pieces washed 0, 1, 3, 5, 10, 15 and 20 times in cone bioassays and tunnel tests. Tests were performed with susceptible and pyrethroid-resistant strains of Anopheles gambiae to assess the pyrethroid and chlorfenapyr components separately. Net pieces were also analysed to determine insecticide content. In regeneration time studies, the biological activity of the deltamethrin and chlorfenapyr components of PermaNet® Dual regenerated within one day after washing and a 1-day washing interval was adopted for wash-resistance studies. PermaNet® Dual induced high mortality (98%) and blood-feeding inhibition (98%) of the susceptible strain after 20 washes fulfilling WHO efficacy criteria in tunnel tests (≥80% mortality, ≥90% blood-feeding inhibition). Similar results were obtained with PermaNet® 2.0 (99% mortality, 99% blood-feeding inhibition) and Interceptor® G2 (99% mortality, 98% blood-feeding inhibition) washed 20 times. In wash-resistance tunnel tests against the pyrethroid-resistant strain, PermaNet® Dual washed 20 times induced high mortality (91%) and blood-feeding inhibition (73%), which was similar to Interceptor® G2 (87% mortality, 79% blood-feeding inhibition) and superior to PermaNet® 2.0 (47% mortality, 68% blood-feeding inhibition). PermaNet® Dual fulfilled WHO efficacy criteria in laboratory bioassays and showed potential to improve control of pyrethroid-resistant malaria vectors
Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial.
Get PDFBACKGROUND: The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized.
METHODS: This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply-demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type.
RESULTS: There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620-0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61-1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41-1.10)].
CONCLUSIONS: In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2.
TRAIL REGISTRATION: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT01131676
Health Economic Evaluation of Lung Cancer Screening Using a Diagnostic Blood Test: The Early Detection of Cancer of the Lung Scotland (ECLS).
Get PDFBACKGROUND: Diagnostic blood tests have the potential to identify lung cancer in people at high risk. We assessed the cost-effectiveness of a lung cancer screening intervention, using the EarlyCDT®-Lung Test (ECLS) with subsequent X-ray and low-dose chest CT scans (LDCT) for patients with a positive test result, compared to both usual care and LDCT screening for the target population.
METHODS: We conducted a model-based lifetime analysis from a UK NHS and personal social services perspective. We estimated incremental net monetary benefit (NMB) for the ECLS intervention compared to no screening and to LDCT screening.
RESULTS: The incremental NMB of ECLS intervention compared to no screening was GBP 33,179 (95% CI: -GBP 81,396, GBP 147,180) and GBP 140,609 (95% CI: -GBP 36,255, GBP 316,612), respectively, for a cost-effectiveness threshold of GBP 20,000 and GBP 30,000 per quality-adjusted life year. The same figures compared with LDCT screening were GBP 162,095 (95% CI: GBP 52,698, GBP 271,735) and GBP 52,185 (95% CI: -GBP 115,152, GBP 219,711).
CONCLUSIONS: The ECLS intervention is the most cost-effective screening alternative, with the highest probability of being cost-effective, when compared to no screening or LDCT screening. This result may change with modifications of the parameters, suggesting that the three alternatives considered in the main analysis are potentially cost-effective
Modeling the Contribution of Multiple Micronutrient Fortification of Salt to Daily Nutrient Intake Among the Ethiopian Population.
Get PDFBackground: Salt is an affordable commodity and has wide coverage regardless of economic and social status and, hence, could be suitable vehicle for multiple micronutrient fortification.
Objectives: This study aimed to simulate the contribution folic acid and zinc fortification of iodized salt to nutrient intake among the Ethiopian population.
Methods: The 2013 Ethiopian National Food Consumption Survey and various food composition tables were used to estimate baseline individual-level micronutrient intake. Usual intake was estimated using the Simulating Intake of Micronutrients for Policy Learning and Engagement macro tool. Discretionary salt consumption was calculated from total salt intake estimated using urinary sodium excretion. Fortificant addition rates were set to obtain maximum nutrient intake while simultaneously constraining that population with intake above the tolerable upper intake level to <5%. Addis Ababa and Somali (N = 2271), the regions with relatively the lowest and highest micronutrient deficiency prevalence in Ethiopia, were selected.
Result: Baseline median intake of Zn was below the estimated average requirement for all demographic groups. Inadequate Zn intake ranged from 73% to 99%, the highest prevalence being observed among women in lower class of wealth quintiles from Somali region. Dietary folate inadequacy was as low as 2% among men in Addis Ababa but almost all (99%) women from Somali region had inadequate folate intake. Calculated discretionary salt intake was 7.5 g/d for adult men and women and 3.4 g/d for children. With addition 0.8 mg Zn and 30 μg of folic acid per gram of salt, multiple salt fortification is estimated to reduce Zn inadequacy by 38 percentage points in urban areas and19 percentage points in rural areas. Modeled reduction in folate inadequacy were 18% in urban areas and 22% in rural areas.
Conclusions: Multiple salt fortification could be an effective approach to address micronutrient adequacy in Ethiopia given efficacious, technological, and economical feasibility
The impact of an innovative community-based peer-led intervention on uptake and coverage of sexual and reproductive health services among adolescents and young people 15-24 years old: results from the Yathu Yathu cluster randomised trial.
Get PDFBACKGROUND: The Yathu Yathu ("For Us, By Us") cluster-randomized trial (CRT) evaluated a peer-led community-based sexual and reproductive health(SRH) intervention implemented to address persistent barriers to SRH service use among adolescents and young people (AYP). We report the impact of the intervention on coverage of key SRH services among AYP.
METHODS: The trial was conducted from Jul 2019-Oct 2021 in two urban communities in Lusaka, Zambia, divided into 20 zones (~ 2350 AYP/zone). Zones were randomly allocated to intervention (N = 10) or control (N = 10) arm. In all zones, a census was conducted and all AYP aged 15-24-years offered participation. The intervention consisted of peer-led community-based hubs providing SRH services; a prevention points card (PPC) system to incentivize and track SRH service use and community engagement. This paper reports on the outcome of coverage (accessing at least one key SRH service), comparing intervention and control arms using PPC data and standard methods of analysis for CRTs.
RESULTS: Among enumerated AYP, 93.6% (14,872/15,894) consented to participate from intervention zones and 95.1% (14,500/15,255) from control zones. Among those who accepted a PPC, 63.8% (9,493/14,872) accessed at least one key SRH service during the study period in the intervention arm, compared to 5.4% (776/14,500) in the control arm (adjPR 12.3 95%CI 9.3-16.2, p < 0.001).
CONCLUSIONS: The Yathu Yathu intervention increased coverage of key SRH services among AYP and reached two-thirds of AYP. These findings demonstrate the potential of providing peer-led community-based SRH services.
TRIAL REGISTRATION: ISRCTN75609016 (11/10/2021), clinicaltrials.gov number NCT04060420 (19/08/2019); retrospectively registered
Healthcare consumers' perceptions of incentive-linked prescribing: A scoping review.
Get PDFIncentive-linked prescribing (ILP) is considered a controversial practice universally. If incentivised, physicians may prioritise meeting pharmaceutical sales targets through prescriptions, rather than considering patients' health and wellbeing. Despite the potential harms of ILP to patients and important stakeholders in the healthcare system, healthcare consumers (HCCs) which include patients and the general public often have far less awareness about the practice of pharmaceutical incentivisation of physicians. We conducted a scoping review to explore what existing research says about HCCs' perceptions of the financial relationship between physicians and pharmaceutical companies. To conduct this scoping review, we followed Arksey and O'Malley's five-stage framework: identifying research questions, identifying relevant studies, selecting eligible studies, data charting, and collating, summarising, and reporting results. We also used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses' extension for scoping reviews (PRISMA-ScR), as a guide to organise the information in this review. Quantitative and qualitative studies with patients and the general public, published in the English language were identified through searches of Scopus, Medline (OVID), EMBASE (OVID), and Google Scholar. Three themes emerged through the analysis of the 13 eligible studies: understanding of incentivisation, perceptions of hazards linked to ILP, and HCCs' suggestions to address it. We found documentation that HCCs exhibited a range of knowledge from good to insufficient about the pharmaceutical incentivisation of physicians. HCCs perceived several hazards linked to ILP such as a lack of trust in physicians and the healthcare system, the prescribing of unnecessary medications, and the negative effect on physicians' reputations in society. In addition to strong regulatory controls, it is critical that physicians self-regulate their behaviour, and publicly disclose if they have any financial ties with pharmaceutical companies. Doing so can contribute to trust between patients and physicians, an important part of patient-focused care and a contributor to user confidence in the wider health system