Robust and sensitive amplicon-based whole-genome sequencing assay of respiratory syncytial virus subtype A and B.

Prevention of respiratory syncytial virus (RSV) infection is now a global health priority, with a long-acting monoclonal antibody and two RSV vaccines recently licenced for clinical use. Most licenced and candidate interventions target the RSV fusion (RSV-F) protein. New interventions may be associated with the spread of mutations, reducing susceptibility to antibody neutralization in RSV-F. There is a need for ongoing longitudinal global surveillance of circulating RSV strains. To achieve this large-scale genomic surveillance, a reliable, high-throughput RSV sequencing assay is required. Here we report an improved high-throughput RSV whole-genome sequencing (WGS) assay performed directly on clinical samples without additional enrichment, using a 4-primer-pool, short-amplicon PCR-tiling approach that is suitable for short-read sequencing platforms. Using upper respiratory tract (URT) RSV-positive clinical samples obtained from a sentinel network of primary care providers and from hospital patients (29.7% and 70.2%, respectively; n = 1,037), collected over the period 2019 to 2023, this assay had a threshold of approximately 4 × 103 to 8 × 103 copies/mL (RSV-B and RSV-A sub-types, respectively) as the lowest amount of virus needed in the sample to achieve >96% of whole-genome coverage at a high-quality level. Using a Ct value of 31 as an empirical cut-off, the overall assay success rate of obtaining >90% genome coverage at a read depth minimum of 20 was 96.83% for clinical specimens successfully sequenced from a total of 1,071. The RSV WGS approach described in this study has increased sensitivity compared to previous approaches and can be applied to clinical specimens without the requirement for enrichment. The updated approach produces sequences of high quality consistently and cost-effectively, suitable for implementation to underpin national programs for the surveillance of RSV genomic variation. IMPORTANCE: In this paper, we report an improved high-throughput respiratory syncytial virus (RSV) whole-genome sequencing (WGS) assay performed directly on clinical samples, using a 4-primer-pool, short-amplicon PCR-tiling approach that is suitable for short-read sequencing platforms. The RSV WGS approach described in this study has increased sensitivity compared to previous approaches and can be applied to clinical specimens without the requirement for enrichment. The updated approach produces sequences of high quality consistently and cost-effectively, suitable for implementation to underpin national and global programs for the surveillance of RSV genomic variation. The quality of sequence produced is essential for preparedness for new interventions in monitoring antigenic escape, where a single point mutation might lead to a reduction in antibody binding effectiveness and neutralizing activity, or indeed in the monitoring of retaining susceptibility to neutralization by existing and new interventions.

Adverse events after first and second doses of COVID-19 vaccination in England: a national vaccine surveillance platform self-controlled case series study.

OBJECTIVES: To estimate the incidence of adverse events of interest (AEIs) after receiving their first and second doses of coronavirus disease 2019 (COVID-19) vaccinations, and to report the safety profile differences between the different COVID-19 vaccines. DESIGN: We used a self-controlled case series design to estimate the relative incidence (RI) of AEIs reported to the Oxford-Royal College of General Practitioners national sentinel network. We compared the AEIs that occurred seven days before and after receiving the COVID-19 vaccinations to background levels between 1 October 2020 and 12 September 2021. SETTING: England, UK. PARTICIPANTS: Individuals experiencing AEIs after receiving first and second doses of COVID-19 vaccines. MAIN OUTCOME MEASURES: AEIs determined based on events reported in clinical trials and in primary care during post-license surveillance. RESULTS: A total of 7,952,861 individuals were vaccinated with COVID-19 vaccines within the study period. Among them, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs. Within the first seven days post-vaccination, 4.85% of all the AEIs were reported. There was a 3-7% decrease in the overall RI of AEIs in the seven days after receiving both doses of Pfizer-BioNTech BNT162b2 (RI = 0.93; 95% CI: 0.91-0.94) and 0.96; 95% CI: 0.94-0.98), respectively) and Oxford-AstraZeneca ChAdOx1 (RI = 0.97; 95% CI: 0.95-0.98) for both doses), but a 20% increase after receiving the first dose of Moderna mRNA-1273 (RI = 1.20; 95% CI: 1.00-1.44)). CONCLUSIONS: COVID-19 vaccines are associated with a small decrease in the incidence of medically attended AEIs. Sentinel networks could routinely report common AEI rates, which could contribute to reporting vaccine safety.

Trends in SARS-CoV-2 infection and vaccination in school staff, students and their household members from 2020 to 2022 in Wales, UK: an electronic cohort study.

OBJECTIVES: We investigated SARS-CoV-2 infection trends, risk of SARS-CoV-2 infection and COVID-19 vaccination uptake among school staff, students and their household members in Wales, UK. DESIGN: Seven-day average of SARS-CoV-2 infections and polymerase chain reaction tests per 1000 people daily, cumulative incidence of COVID-19 vaccination uptake and multi-level Poisson models with time-varying covariates. SETTING: National electronic cohort between September 2020 and May 2022 when several variants were predominant in the UK (Alpha, Delta and Omicron). PARTICIPANTS: School students aged 4 to 10/11 years (primary school and younger middle school, n = 238,163), and 11 to 15/16 years (secondary school and older middle school, n = 182,775), school staff in Wales (n = 47,963) and the household members of students and staff (n = 697,659). MAIN OUTCOME MEASURES: SARS-CoV-2 infection and COVID-19 vaccination uptake. RESULTS: School students had a sustained period of high infection rates compared with household members after August 2021. Primary schedule vaccination uptake was highest among staff (96.3%) but lower for household members (72.2%), secondary and older middle school students (59.8%), and primary and younger middle school students (3.3%). Multi-level Poisson models showed that vaccination was associated with a lower risk of SARS-CoV-2 infection. The Delta variant posed a greater infection risk for students than the Alpha variant. However, Omicron was a larger risk for staff and household members. CONCLUSIONS: Public health bodies should be informed of the protection COVID-19 vaccines afford, with more research being required for younger populations. Furthermore, schools require additional support in managing new, highly transmissible variants. Further research should examine the mechanisms between child deprivation and SARS-CoV-2 infection.

Forecasting the 2017/2018 seasonal influenza epidemic in England using multiple dynamic transmission models: a case study.

BACKGROUND: Since the 2009 A/H1N1 pandemic, Public Health England have developed a suite of real-time statistical models utilising enhanced pandemic surveillance data to nowcast and forecast a future pandemic. Their ability to track seasonal influenza and predict heightened winter healthcare burden in the light of high activity in Australia in 2017 was untested. METHODS: Four transmission models were used in forecasting the 2017/2018 seasonal influenza epidemic in England: a stratified primary care model using daily, region-specific, counts and virological swab positivity of influenza-like illness consultations in general practice (GP); a strain-specific (SS) model using weekly, national GP ILI and virological data; an intensive care model (ICU) using reports of ICU influenza admissions; and a synthesis model that included all data sources. For the first 12 weeks of 2018, each model was applied to the latest data to provide estimates of epidemic parameters and short-term influenza forecasts. The added value of pre-season population susceptibility data was explored. RESULTS: The combined results provided valuable nowcasts of the state of the epidemic. Short-term predictions of burden on primary and secondary health services were initially highly variable before reaching consensus beyond the observed peaks in activity between weeks 3-4 of 2018. Estimates for R0 were consistent over time for three of the four models until week 12 of 2018, and there was consistency in the estimation of R0 across the SPC and SS models, and in the ICU attack rates estimated by the ICU and the synthesis model. Estimation and predictions varied according to the assumed levels of pre-season immunity. CONCLUSIONS: This exercise successfully applied a range of pandemic models to seasonal influenza. Forecasting early in the season remains challenging but represents a crucially important activity to inform planning. Improved knowledge of pre-existing levels of immunity would be valuable.

End of season influenza vaccine effectiveness in primary care in adults and children in the United Kingdom in 2018/19.

2018/19 was the first season of introduction of a newly licensed adjuvanted influenza vaccine (aTIV) for adults aged 65 years and over and the sixth season in the roll-out of a childhood influenza vaccination programme with a quadrivalent live attenuated influenza vaccine (LAIV). The season saw mainly A(H1N1)pdm09 and latterly A(H3N2) circulation. End-of-season adjusted vaccine effectiveness (aVE) estimates against laboratory confirmed influenza infection in primary care were calculated using the test negative case control method adjusting for key confounders. End-of-season aVE was 44.3% (95% CI: 26.8, 57.7) against all laboratory-confirmed influenza; 45.7% (95% CI: 26.0, 60.1) against influenza A(H1N1)pdm09 and 35.1% (95% CI: -3.7,59.3) against A(H3N2). Overall aVE was 49.9% (95%CI: -13.7, 77.9) for all those ≥ 65 years of age and 62.0% (95% CI: 3.4, 85.0) for those who received aTIV. Overall aVE for 2-17 year olds receiving LAIV was 48.6% (95% CI: -4.4, 74.7). The paper provides evidence of overall significant influenza VE in 2018/19, most notably against influenza A(H1N1)pdm09, however, as seen in 2017/18, there was reduced, non-significant VE against A(H3N2). aTIV provided significant protection for those 65 years of age and over.

Determinants of inter-practice variation in ADHD diagnosis and stimulant prescribing: cross-sectional database study of a national surveillance network.

Early recognition, identification and treatment of children with attention deficit hyperactivity disorder (ADHD) can reduce detrimental outcomes and redirect their developmental trajectory. We aimed to describe variations in age of ADHD diagnosis and stimulant prescribing among general practitioner practices in a nationwide network and identify child, parental, household and general practice factors that might account for these variations. Cross-sectional study of children aged under 19 years registered within a general practice in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network in 2016, RCGP RSC has a household key allowing parent and child details to be linked. Data from 158 general practices and 353 774 children under 19 were included. The mean age of first ADHD diagnosis was 10.5 years (95% CI 10.1 to 10.9, median 10, IQR 9.0-11.9) and the mean percentage of children with ADHD prescribed stimulant medications among RCGP RSC practices was 41.2% (95% CI 38.7 to 43.6). There was wide inter-practice variation in the prevalence of diagnosis of ADHD, the age of diagnosis and stimulant prescribing. ADHD diagnosis is more likely to be made later in households with a greater number of children and with a larger age difference between adults and children. Stimulant prescribing for children with ADHD was higher in less deprived practices. Older parents and families with more children fail to recognise ADHD and may need more support. Practices in areas of higher socio-economic status are associated with greater prescribing of stimulants for children with ADHD.

Improving Collaborative Behaviour Planning in Adult Auditory Rehabilitation: Development of the I-PLAN Intervention Using the Behaviour Change Wheel.

Background: The consequences of poorly managed hearing loss can be ameliorated with hearing aid use but rates of use are sub-optimal. The impact of audiologist behaviour on subsequent use, particularly over the long term, is unknown. Purpose: This study aimed to describe the role of the behaviour change wheel in developing an intervention to introduce and embed particular clinical behaviours into adult hearing aid fitting consultations, within the framework of the Medical Research Council guidance on complex interventions. Methods: Following the steps of the behaviour change wheel, audiologist behaviours that might influence hearing aid use were identified based on a systematic review and qualitative work with audiologists. An analysis, using the COM-B model, identified potential drivers of the target behaviours. This was used to select intervention functions and behaviour change techniques likely to influence behaviour in this context. Results: The target behaviours were as follows: giving information about the benefits of hearing aid use and the negative consequences of non-use, providing prompts for use and engaging in collaborative behavioural planning for use. The behavioural analysis suggested that psychological capability, opportunity and motivation were potential drivers of these behaviours. The intervention functions of education, coercion, training, environmental restructuring, modelling and enablement were selected and combined to develop a single complex intervention that seeks to address the target behaviours.

Socioeconomic and geographical variation in general practitioner consultations for allergic rhinitis in England, 2003-2014: an observational study.

OBJECTIVE: Allergic rhinitis (AR) is a global health problem, potentially impacting individuals' sleep, work and social life. We aimed to use a surveillance network of general practitioners (GPs) to describe the epidemiology of AR consultations in England. SETTING: A large GP surveillance network covering approximately 53% of the English population. METHODS: GP consultations for AR across England between 30 December 2002 and 31 December 2014 were analysed. Using more granular data available between 2 April 2012 and 31 December 2014 rates and rate ratios (RR) of AR were further analysed in different age groups, gender, rural-urban classification and index of multiple deprivation score quintile of location of GP. RESULTS: The mean weekly rate for AR consultations was 19.8 consultations per 100 000 GP registered patients (range 1.13-207), with a regular peak occurring during June (weeks 24-26), and a smaller peak during April. Between 1 April 2012 and 31 December 2014, the highest mean daily rates of consultations per 1 00 000 were: in age group 5-14 years (rate=8.02, RR 6.65, 95% CI 6.38 to 6.93); females (rate=4.57, RR 1.12 95% CI 1.12 to 1.13); persons registered at a GP in the most socioeconomically deprived quintile local authority (rate=5.69, RR 1.48, 95% CI 1.47 to 1.49) or in an urban area with major conurbation (rate=5.91, RR 1.78, 95% CI 1.69 to 1.87). CONCLUSIONS: AR rates were higher in those aged 5-14 years, females and in urban and socioeconomically deprived areas. This needs to be viewed in the context of this study's limitations but should be considered in health promotion and service planning.

Audit-based education lowers systolic blood pressure in chronic kidney disease: the Quality Improvement in CKD (QICKD) trial results.

Strict control of systolic blood pressure is known to slow progression of chronic kidney disease (CKD). Here we compared audit-based education (ABE) to guidelines and prompts or usual practice in lowering systolic blood pressure in people with CKD. This 2-year cluster randomized trial included 93 volunteer general practices randomized into three arms with 30 ABE practices, 32 with guidelines and prompts, and 31 usual practices. An intervention effect on the primary outcome, systolic blood pressure, was calculated using a multilevel model to predict changes after the intervention. The prevalence of CKD was 7.29% (41,183 of 565,016 patients) with all cardiovascular comorbidities more common in those with CKD. Our models showed that the systolic blood pressure was significantly lowered by 2.41 mm Hg (CI 0.59-4.29 mm Hg), in the ABE practices with an odds ratio of achieving at least a 5 mm Hg reduction in systolic blood pressure of 1.24 (CI 1.05-1.45). Practices exposed to guidelines and prompts produced no significant change compared to usual practice. Male gender, ABE, ischemic heart disease, and congestive heart failure were independently associated with a greater lowering of systolic blood pressure but the converse applied to hypertension and age over 75 years. There were no reports of harm. Thus, individuals receiving ABE are more likely to achieve a lower blood pressure than those receiving only usual practice. The findings should be interpreted with caution due to the wide confidence intervals.