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Determination of the preliminary discriminating concentration of broflanilide against malaria vector mosquito Anopheles gambiae by multi-centre susceptibility testing
Get PDFBackground: Indoor residual spraying (IRS) of insecticides is widely used as an effective method to control malaria vector mosquitoes in sub-Saharan Africa. In 2023, a new IRS product, VECTRON™ T500 (Mitsui Chemicals Crop & Life Solutions, Inc.), was launched. This product contains broflanilide, a novel active ingredient for IRS, and has been confirmed to exhibit long-lasting insecticidal efficacy against malaria vector mosquitoes. However, the discriminating concentration to assess the susceptibility of wild Anopheles populations to broflanilide has not yet been determined.
Methods: In this study, WHO bottle bioassays were conducted in nine research facilities to collect dose response data on broflanilide against adult female mosquitoes of the insecticide susceptible Anopheles gambiae s.s.Kisumu strain. These data were statistically analysed and validated following WHO guidelines.
Results: It was determined that the preliminary discriminating concentration of broflanilide for An. gambiae mosquitoes should be 18 μg/bottle.
Conclusions: In this study, the preliminary discriminating concentration of broflanilide for An. gambiae mosquitoes was determined. The results of this study will provide a useful benchmark for susceptibility monitoring of wild mosquito populations in regions of sub-Saharan Africa into which VECTRON™ T500 is being introduced for malaria vector control
Clinical and cost-effectiveness of eculizumab withdrawal in atypical haemolytic uraemic syndrome: the SETS aHUS multi-centre, open-label, prospective and single-arm study.
Get PDFBACKGROUND: Atypical haemolytic uraemic syndrome is a rare disease (incidence: 0.4 cases per million per year) which, without treatment, is associated with high morbidity and mortality. Eculizumab, a monoclonal complement inhibitor, is an effective treatment but the optimal way to use this high-cost medication (£360,000 per year for an adult) has not been established.
OBJECTIVE: Establish the safety of eculizumab withdrawal and the effectiveness of a monitoring protocol to detect disease relapse and reintroduction of treatment if relapse occurs.
SETTING: Fifteen hospitals in the United Kingdom.
DESIGN: SETS aHUS is a multicentre, open label, prospective, single arm study of the safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome using Bayes single arm analysis with a health economic analysis and qualitative study.
PARTICIPANTS: Patients over 2 years of age with atypical haemolytic uraemic syndrome who were receiving eculizumab therapy for at least 6 months. Two study arms are described with 28 participants recruited to the withdrawal arm and 11 additional participants recruited to the standard of care arm of the study.
INTERVENTION: Withdrawal of eculizumab treatment and replacement with monitoring to assess disease activity with reintroduction of treatment if relapse occurs.
MAIN OUTCOME MEASURES: The primary outcome measure was to determine the safety of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome during the 2-year study period. Patients met a primary outcome of 'safety event occurred' if there was a permanent reduction in estimated glomerular filtration rate or requirement for renal replacement therapy or significant extra-renal manifestation of disease. The health economic analysis compared the cost and health outcomes on and off eculizumab treatment. The qualitative study explored the experiences of patients on living with atypical haemolytic uraemic syndrome and eculizumab treatment, views on withdrawing from treatment and the proposed monitoring plan.
RESULTS: One of 28 patients (3.6%) who withdrew from treatment met a primary outcome. Based on the pre-study analysis plan, withdrawal from treatment is not associated with a greater risk to patients compared to remaining on treatment. Of 17 patients with an abnormality in complement regulation, 4 relapsed. Of 11 patients with no abnormality in complement regulation, 0 relapsed. It was possible, by monitoring and rapid patient access, to reintroduce eculizumab treatment when relapse was identified. Most patients welcomed the opportunity to withdraw from treatment but identified concerns about monitoring and the risk of relapse, informed by initial experience at presentation. Withdrawing a patient from treatment saves £4.2M in healthcare costs (80 years time horizon).
LIMITATIONS: Reflecting the low prevalence, participant numbers are low, particularly in the standard of care group.
CONCLUSIONS: Withdrawal of eculizumab treatment with monitoring of disease activity exhibited a favourable safety profile compared to continuation of eculizumab, was acceptable to patients and carers and is associated with significant cost savings.
FUTURE WORK: More real-world data should be generated by continued assessment of patients after treatment withdrawal including risk of relapse, renal outcomes, real-world economic analysis and a better understanding of communicating change to patients and carers.
FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 15/130/94
OpenSAFELY: Effectiveness of COVID-19 Vaccination in Children and Adolescents.
Get PDFBACKGROUND: We assessed the safety and effectiveness of the first- and second-dose BNT162b2 COVID-19 vaccination, offered as part of the national COVID-19 vaccine roll-out from September 2021, in children and adolescents in England.
METHODS: Our observational study using OpenSAFELY-TPP, included adolescents aged 12-15 years and children aged 5-11 years. It compared individuals receiving (1) the first vaccination to unvaccinated controls and (2) the second vaccination to single-vaccinated controls. We matched vaccinated individuals with controls on age, sex, and other important characteristics. Outcomes were positive SARS-CoV-2 test (adolescents only), COVID-19 accident and emergency (A&E) attendance, COVID-19 hospitalization, COVID-19 critical care admission, and COVID-19 death; with safety outcomes, A&E attendance, unplanned hospitalization, pericarditis, and myocarditis.
RESULTS: Among 820,926 previously unvaccinated adolescents, 20-week incidence rate ratios (IRRs) comparing vaccination with no vaccination were 0.74 for positive SARS-CoV-2 test, 0.60 for COVID-19 A&E attendance, and 0.58 for COVID-19 hospitalization. Among 441,858 adolescents who had received the first vaccination, IRRs comparing second dose with single-vaccination were 0.67 for positive SARS-CoV-2 test, 1.00 for COVID-19 A&E attendance, and 0.60 for COVID-19 hospitalization. In both children groups, COVID-19-related outcomes were too rare to allow IRRs to be estimated precisely. Across all analyses, there were no COVID-19-related deaths, and fewer than seven COVID-19-related critical care admissions. Myocarditis and pericarditis were documented only in the vaccinated groups, with rates of 27 and 10 cases/million after the first and second doses, respectively.
CONCLUSIONS: BNT162b2 vaccination in adolescents reduced COVID-19 A&E attendance and hospitalization, although these outcomes were rare. Protection against positive SARS-CoV-2 tests was transient
COVID-19: lessons from Brazil.
Get PDFBrazil did not have a good time of it during the COVID-19
pandemic and it had one of the highest death rates in the
world, accounting for >700 000 deaths, with large social
inequalities in mortality rates. There were also some remarkable events, including the ravaging of an area of the Amazon by COVID-19 infections that ripped through the population with little resistance. On the other hand, Brazil excelled in COVID-19 research, including the aforementioned Amazon studies, a number of studies of vaccine effectiveness and safety, and many others. There is therefore much that we can learn from the Brazilian experience and in comparisons with other countries.
In this issue of the Journal are published four further important contributions to the COVID-19 Brazilian literature. The papers are too broad-ranging to attempt a comprehensive summary here. Rather, we will comment on a few key themes that emerge
Building and Boosting Capitals for Health Care Access: A Qualitative Study of Homeless Health Peer Advocacy in London, UK.
Get PDFPeer support is widely promoted as enabling health care access with people experiencing homelessness, including through enabling independence, empowering individuals and managing stigma. However, there is little understanding of these processes, including how they relate to the wide range of potential activities involved in peer support. We studied peer support within a peer advocacy service at a charity run by and for people experiencing homelessness in London, UK. We report analysis from a sub-set of qualitative interviews and focus groups gathered for a qualitative study of peer advocacy. We include interviews that offered insight to particular cases of peer advocacy. These interviews came from 23 clients of the service, 6 peer advocates, 1 staff member and 2 stakeholders. We drew on Bourdieu's theory of capitals to develop a typology of different ways peer support works. The findings focus on reporting three types of experiences: where peer support builds cultural health capital amongst service clients, boosts cultural health capital, social and economic capital, and third, where boosting social and economic capital are priorities. The discussion considers how the analysis helps conceptualise processes of peer support with respect to empowerment, independence and stigma management
Nasal microbiota and clinical features in acute flu-like illness: COVID-19 status and long COVID follow-up.
Get PDFOBJECTIVES: Long COVID (LC) is a challenging medical condition. Reliable diagnostic and targetable biomarkers of LC for a proper and early diagnosis and clinical care are an unmet medical need. We aimed to evaluate targetable biomarkers for LC management.
DESIGN: Comparison of nasal microbiota and clinical features in 291 individuals with acute influenzae-like illness (ILI), comparing COVID-19-positive (n=193) and negative (n=98) groups, with further stratification by long COVID (LC) outcomes (persistent symptoms >3 months).
RESULTS: Clinical characteristics were balanced across groups, with upper respiratory symptoms predominating. Individuals who developed LC exhibited more cardiorespiratory symptoms during acute infection (70% vs 48%, P=0.002). Nasal microbiota analysis revealed lower alpha diversity in COVID-19-positive individuals vs other ILI (Wilcoxon: Chao2 index P=0.03305; Shannon diversity index P=0.02578; Simpson diversity index P=0.1082) but no differences in beta diversity or taxonomic composition between groups, including LC vs recovered individuals. EBV/CMV infection/reactivation was not associated with LC. Sensitivity analyses confirmed robustness to methodological and temporal biases.
CONCLUSIONS: Findings suggest acute nasal microbiota disruption in individuals with COVID-19, but no LC-specific microbial profile
Determining the dose-response relationship for pneumococcal conjugate vaccines: a nested analysis of the fractional dose PCV trial.
Get PDFBACKGROUND: The relationship between polysaccharide dose and immune response to pneumococcal conjugate vaccines (PCV) has never been established. An individually randomized controlled clinical trial was conducted in Kenyan infants to assess whether immune responses after fractional doses of PCV10 (Synflorix, GlaxoSmithKline plc.) or PCV13 (Prevnar13, Pfizer Inc.) were non-inferior to full-dose schedules (ClinicalTrials.org: NCT03489018; Pan African Clinical Trial Registry: PACTR202104717648755). We analysed these data to describe the serotype-specific dose-response relationships and evaluate factors associated with the immune response. METHODS: We analysed data from participants who received PCV doses at 6 and 14 weeks of age, with immunogenicity assessed at 18 weeks of age. Participants received 20 %, 40 % or full doses of PCV10 or PCV13. We used mixed-effects linear regression models to estimate the dose-response relationships between polysaccharide dose and log-transformed IgG concentrations and to determine factors associated with immune response. We estimated the minimum dose required to obtain a high (≥95 %) probability of an immunological response above the level considered to be associated with protection using logistic regression. RESULTS: 1342 infants were included. The polysaccharide dose, product, child's ethnicity, sex, maternal age, and interval between second PCV dose and immunogenicity sample were independently associated with IgG concentrations elicited by the primary schedule. For PCV13, the relationship between dose and log(IgG) was best described by a quadratic function for serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 19A and 23F, whereas a log-dose model was the best fit for serotypes 14, 18C and 19F. For PCV10, a linear relationship was the best fit for serotypes 1, 6B, 7F, 9V and 23F and log-dose model was the best fit for 4, 5, 14, 18C and 19F. CONCLUSION: Our findings suggest that available PCV10/13 could be reformulated to optimize protective responses
Normative growth trajectories of fetal brain regions validated by satisfactory maturation of neurodevelopmental domains at 2 years of age.
Get PDFWe previously constructed a qualitative, 3D ultrasound derived atlas of the normative spatiotemporal dynamics of fetal brain maturation. Here, using the same healthy multi-national cohort, we applied deep learning methods to 4205 fetal brain scans from 18-27 weeks' gestation, to produce an extensive, quantitative description of the growth of 16 fetal brain structures associated with satisfactory domain-specific neurodevelopmental scores at 2 years of age. The methodology, which is publicly available, takes less than 10 seconds per scan. We define 28 region-specific, functionally relevant, normative growth trajectories, a ratio between the relative volumes of the insular (rILV) and parietal (rPLV) lobes reflecting asynchronous maturation of fetal brain regions, and introduce a fetal brain maturation index that quantifies biological age and deviations from chronological age. Finally, the very low percentage of variance explained by between site differences (0.6% to 5.8% of the total variance) reinforces a fundamental biological principle: fetal growth and development across populations with diverse ancestries is similar provided that environmental constraints on growth are minimal
Forty years later: adult health and non-communicable disease following the 1984-1985 Great Ethiopian Famine - a retrospective cohort study.
Get PDFBACKGROUND: As the threat of child malnutrition increases, the focus remains mostly on short-term consequences. Long-term sequelae are increasingly recognised but lack strong evidence, and many studies face methodological limitations. METHOD: A retrospective cohort of survivors of the 1984-1985 Great-Ethiopian Famine was compared with two novel control groups: born post-famine; and age category- and sex-matched controls. Exposure to famine at different age categories was explored (fetal, 0-2, 2-5, 5-10 and 10-18 years). Follow-up was 40 years later. Outcomes included anthropometry, body composition, arterial stiffness, mental health, and risk of cardiometabolic and non-communicable diseases (NCDs). Adjusted differences and 95% CI between exposed and controls were calculated. RESULTS: Compared with matched and post-famine controls, adjusted differences (95% CI) for exposed group were: height, -1.4 cm (-2.4 to -0.3) and -2.4 cm (-3.7 to -1.1); weight, -1.4 kg (-2.7 to -0.1) and -1.7 kg (-3.3 to -0.1); diastolic blood pressure (DBP), -2.8 mm Hg (-4.4 to -1.1) and 2.8 mmHg (0.9 to 4.7); handgrip strength, -1.7 kg (-2.7 to -0.6) and -4.1 kg (-5.5 to -2.7); brachial augmentation index, 5.4% (0.3% to 10.5%) and 16.1% (10.1% to 22.1%); aortic augmentation index, 6.0% (1.5% to 10.4%) and 11.7% (6.1% to 17.3%); subscapular skinfold thickness, 1.1 mm (0.2 to 1.9) and 1.2 mm (0.1 to 2.3); triceps skinfold thickness, 1.8 mm (0.8 to 2.7) and 2.1 mm (1.0 to 3.3) and waist-to-height ratio, 0.01 (0.003 to 0.02) and 0.01 (0.001 to 0.02), respectively. When comparing risk by timing of exposure, individuals exposed during early childhood (0-2 years), preschool age (2-5 years), and late childhood (5-10 years) had reduced adult stature of -2.8 cm (-4.8 to -0.9), -2.8 cm (-4.7 to -0.9) and -2.1 cm (-4.0 to -0.2), respectively, and increased triceps skinfold of 1.7 mm (-0.5 to 3.8), 3.2 mm (0.8 to 5.6) and 3.8 mm (1.6 to 6.02), respectively. CONCLUSIONS: Early-life famine exposure is associated with smaller adult size and several, but not all NCD risks. Lower DBP in survivors compared with matched controls is surprising and might reflect differential susceptibility to specific later-life health risks. Greater arterial stiffness underscores the need to identify both preclinical and clinical risk. In contrast to exposure in utero, risk was higher among those exposed during early childhood (0-2 years), preschool (2-5 years) and late childhood (5-10 years). The study underscores the need for a dual approach in low- and middle-income settings: tackling the immediate undernutrition while also anticipating and mitigating long-term NCD risk in populations exposed to early-life severe malnutrition or famine
Understanding the adult social care market in England
Get PDFThe English adult social care market is a complex system comprising various services, diverse funding sources, and
numerous care providers. Social care, or long-term care as known internationally, primarily aims to support individuals
who struggle to live independently, including older people, people with disabilities, and those with long-term
conditions. Social care services encompass personal care that facilitates independent living, such as assistance with
washing, cooking, dressing, and other activities to help care receivers stay active and engaged in their communities.
There are various social care settings, including care homes, home (or domiciliary) care and other settings such as day
care and community centres. Care homes include residential facilities where individuals receive round-the-clock
support, while home care allows people to remain in their homes with assistance for daily activities. Other social care
services include supported living, community agencies and shared lives, which offer specialised support to those in
need. However, these specialised services have relatively smaller market shares than care homes and home care