A Comparison of Sodium-Glucose Co-Transporter 2 Inhibitor Kidney Outcome Trial Participants with a Real-World Chronic Kidney Disease Primary Care Population.

BACKGROUND/HYPOTHESIS: Observational studies suggest sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalisability to those without co-existing type 2 diabetes (T2D), and the representativeness of the EMPA-KIDNEY trial has not been adequately explored. We hypothesised that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. METHODS: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Information Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. RESULTS: Of 6,670,829 adults, 516,491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2%, and 8.0% met the CREDENCE, DAPA-CKD, and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared to the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared to less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. CONCLUSION: SGLT2 inhibitor kidney outcome trials represent a sub-group of people with CKD at high risk of adverse kidney events. Out study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD.

Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales.

BACKGROUND: Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, we aimed to identify risk factors for severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine. METHODS: We constructed prospective cohorts across all four UK nations through linkages of primary care, RT-PCR testing, vaccination, hospitalisation, and mortality data on 30 million people. We included individuals who received primary vaccine doses of BNT162b2 (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our initial analyses. We then restricted analyses to those given a BNT162b2 or mRNA-1273 (elasomeran; Moderna) booster and had a severe COVID-19 outcome between Dec 20, 2021, and Feb 28, 2022 (when the omicron (B.1.1.529) variant was dominant). We fitted time-dependent Poisson regression models and calculated adjusted rate ratios (aRRs) and 95% CIs for the associations between risk factors and COVID-19-related hospitalisation or death. We adjusted for a range of potential covariates, including age, sex, comorbidities, and previous SARS-CoV-2 infection. Stratified analyses were conducted by vaccine type. We then did pooled analyses across UK nations using fixed-effect meta-analyses. FINDINGS: Between Dec 8, 2020, and Feb 28, 2022, 16 208 600 individuals completed their primary vaccine schedule and 13 836 390 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·4%) of the primary vaccine group and 26 100 (0·2%) of those who received their booster had severe COVID-19 outcomes. The risk of severe COVID-19 outcomes reduced after receiving the booster (rate change: 8·8 events per 1000 person-years to 7·6 events per 1000 person-years). Older adults (≥80 years vs 18-49 years; aRR 3·60 [95% CI 3·45-3·75]), those with comorbidities (≥5 comorbidities vs none; 9·51 [9·07-9·97]), being male (male vs female; 1·23 [1·20-1·26]), and those with certain underlying health conditions-in particular, individuals receiving immunosuppressants (yes vs no; 5·80 [5·53-6·09])-and those with chronic kidney disease (stage 5 vs no; 3·71 [2·90-4·74]) remained at high risk despite the initial booster. Individuals with a history of COVID-19 infection were at reduced risk (infected ≥9 months before booster dose vs no previous infection; aRR 0·41 [95% CI 0·29-0·58]). INTERPRETATION: Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster and should, therefore, be prioritised for additional boosters, including novel optimised versions, and the increasing array of COVID-19 therapeutics. FUNDING: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

Mortality from angiotensin-converting enzyme-inhibitors and angiotensin receptor blockers in people infected with COVID-19: a cohort study of 3.7 million people.

BACKGROUND: Concerns have been raised that angiotensin-converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) might facilitate transmission of severe acute respiratory syndrome coronavirus 2 leading to more severe coronavirus disease (COVID-19) disease and an increased risk of mortality. We aimed to investigate the association between ACE-I/ARB treatment and risk of death amongst people with COVID-19 in the first 6 months of the pandemic. METHODS: We identified a cohort of adults diagnosed with either confirmed or probable COVID-19 (from 1 January to 21 June 2020) using computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. This comprised 465 general practices in England, United Kingdom with a nationally representative population of 3.7 million people. We constructed mixed-effects logistic regression models to quantify the association between ACE-I/ARBs and all-cause mortality among people with COVID-19, adjusted for sociodemographic factors, comorbidities, concurrent medication, smoking status, practice clustering, and household number. RESULTS: There were 9,586 COVID-19 cases in the sample and 1,463 (15.3%) died during the study period between 1 January 2020 and 21 June 2020. In adjusted analysis ACE-I and ARBs were not associated with all-cause mortality (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85-1.21 and OR 0.84, 95% CI 0.67-1.07, respectively). CONCLUSION: Use of ACE-I/ARB, which are commonly used drugs, did not alter the odds of all-cause mortality amongst people diagnosed with COVID-19. Our findings should inform patient and prescriber decisions concerning continued use of these medications during the pandemic.

Adverse events following first and second dose COVID-19 vaccination in England, October 2020 to September 2021: a national vaccine surveillance platform self-controlled case series study.

BackgroundPost-authorisation vaccine safety surveillance is well established for reporting common adverse events of interest (AEIs) following influenza vaccines, but not for COVID-19 vaccines.AimTo estimate the incidence of AEIs presenting to primary care following COVID-19 vaccination in England, and report safety profile differences between vaccine brands.MethodsWe used a self-controlled case series design to estimate relative incidence (RI) of AEIs reported to the national sentinel network, the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. We compared AEIs (overall and by clinical category) 7 days pre- and post-vaccination to background levels between 1 October 2020 and 12 September 2021.ResultsWithin 7,952,861 records, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs, 4.85% within 7 days post-vaccination. Overall, medically attended AEIs decreased post-vaccination against background levels. There was a 3-7% decrease in incidence within 7 days after both doses of Comirnaty (RI: 0.93; 95% CI: 0.91-0.94 and RI: 0.96; 95% CI: 0.94-0.98, respectively) and Vaxzevria (RI: 0.97; 95% CI: 0.95-0.98). A 20% increase was observed after one dose of Spikevax (RI: 1.20; 95% CI: 1.00-1.44). Fewer AEIs were reported as age increased. Types of AEIs, e.g. increased neurological and psychiatric conditions, varied between brands following two doses of Comirnaty (RI: 1.41; 95% CI: 1.28-1.56) and Vaxzevria (RI: 1.07; 95% CI: 0.97-1.78).ConclusionCOVID-19 vaccines are associated with a small decrease in medically attended AEI incidence. Sentinel networks could routinely report common AEI rates, contributing to reporting vaccine safety.

First dose ChAdOx1 and BNT162b2 COVID-19 vaccinations and cerebral venous sinus thrombosis: A pooled self-controlled case series study of 11.6 million individuals in England, Scotland, and Wales.

BACKGROUND: Several countries restricted the administration of ChAdOx1 to older age groups in 2021 over safety concerns following case reports and observed versus expected analyses suggesting a possible association with cerebral venous sinus thrombosis (CVST). Large datasets are required to precisely estimate the association between Coronavirus Disease 2019 (COVID-19) vaccination and CVST due to the extreme rarity of this event. We aimed to accomplish this by combining national data from England, Scotland, and Wales. METHODS AND FINDINGS: We created data platforms consisting of linked primary care, secondary care, mortality, and virological testing data in each of England, Scotland, and Wales, with a combined cohort of 11,637,157 people and 6,808,293 person years of follow-up. The cohort start date was December 8, 2020, and the end date was June 30, 2021. The outcome measure we examined was incident CVST events recorded in either primary or secondary care records. We carried out a self-controlled case series (SCCS) analysis of this outcome following first dose vaccination with ChAdOx1 and BNT162b2. The observation period consisted of an initial 90-day reference period, followed by a 2-week prerisk period directly prior to vaccination, and a 4-week risk period following vaccination. Counts of CVST cases from each country were tallied, then expanded into a full dataset with 1 row for each individual and observation time period. There was a combined total of 201 incident CVST events in the cohorts (29.5 per million person years). There were 81 CVST events in the observation period among those who a received first dose of ChAdOx1 (approximately 16.34 per million doses) and 40 for those who received a first dose of BNT162b2 (approximately 12.60 per million doses). We fitted conditional Poisson models to estimate incidence rate ratios (IRRs). Vaccination with ChAdOx1 was associated with an elevated risk of incident CVST events in the 28 days following vaccination, IRR = 1.93 (95% confidence interval (CI) 1.20 to 3.11). We did not find an association between BNT162b2 and CVST in the 28 days following vaccination, IRR = 0.78 (95% CI 0.34 to 1.77). Our study had some limitations. The SCCS study design implicitly controls for variables that are constant over the observation period, but also assumes that outcome events are independent of exposure. This assumption may not be satisfied in the case of CVST, firstly because it is a serious adverse event, and secondly because the vaccination programme in the United Kingdom prioritised the clinically extremely vulnerable and those with underlying health conditions, which may have caused a selection effect for individuals more prone to CVST. Although we pooled data from several large datasets, there was still a low number of events, which may have caused imprecision in our estimates. CONCLUSIONS: In this study, we observed a small elevated risk of CVST events following vaccination with ChAdOx1, but not BNT162b2. Our analysis pooled information from large datasets from England, Scotland, and Wales. This evidence may be useful in risk-benefit analyses of vaccine policies and in providing quantification of risks associated with vaccination to the general public.

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study.

BACKGROUND: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) COVID-19 vaccines have shown high efficacy against disease in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. Studying the real-world effects of these vaccines is an urgent requirement. The aim of our study was to investigate the association between the mass roll-out of the first doses of these COVID-19 vaccines and hospital admissions for COVID-19. METHODS: We did a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19-EAVE II-database comprising linked vaccination, primary care, real-time reverse transcription-PCR testing, and hospital admission patient records for 5·4 million people in Scotland (about 99% of the population) registered at 940 general practices. Individuals who had previously tested positive were excluded from the analysis. A time-dependent Cox model and Poisson regression models with inverse propensity weights were fitted to estimate effectiveness against COVID-19 hospital admission (defined as 1-adjusted rate ratio) following the first dose of vaccine. FINDINGS: Between Dec 8, 2020, and Feb 22, 2021, a total of 1 331 993 people were vaccinated over the study period. The mean age of those vaccinated was 65·0 years (SD 16·2). The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85-94) for reduced COVID-19 hospital admission at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 88% (95% CI 75-94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar when restricting the analysis to those aged 80 years and older (83%, 95% CI 72-89 at 28-34 days post-vaccination). INTERPRETATION: Mass roll-out of the first doses of the BNT162b2 mRNA and ChAdOx1 vaccines was associated with substantial reductions in the risk of hospital admission due to COVID-19 in Scotland. There remains the possibility that some of the observed effects might have been due to residual confounding. FUNDING: UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK.

Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events in people with type 2 diabetes: A primary care cohort study.

AIM: To determine whether achieving early glycaemic control, and any subsequent glycaemic variability, was associated with any change in the risk of major adverse cardiovascular events (MACE). MATERIALS AND METHODS: A retrospective cohort analysis from the Oxford-Royal College of General Practitioners Research and Surveillance Centre database-a large, English primary care network-was conducted. We followed newly diagnosed patients with type 2 diabetes, on or after 1 January 2005, aged 25 years or older at diagnosis, with HbA1c measurements at both diagnosis and after 1 year, plus five or more measurements of HbA1c thereafter. Three glycaemic bands were created: groups A (HbA1c < 58 mmol/mol [<7.5%]), B (HbA1c ≥ 58 to 75 mmol/mol [7.5%-9.0%]) and C (HbA1c ≥ 75 mmol/mol [≥9.0%]). Movement between bands was determined from diagnosis to 1 year. Additionally, for data after the first 12 months, a glycaemic variability score was calculated from the number of successive HbA1c readings differing by 0.5% or higher (≥5.5 mmol/mol). Risk of MACE from 1 year postdiagnosis was assessed using time-varying Cox proportional hazards models, which included the first-year transition and the glycaemic variability score. RESULTS: From 26 180 patients, there were 2300 MACE. Compared with group A->A transition over 1 year, those with C->A transition had a reduced risk of MACE (HR 0.75; 95% CI 0.60-0.94; P = .014), whereas group C->C had HR 1.21 (0.81-1.81; P = .34). Compared with the lowest glycaemic variability score, the greatest variability increased the risk of MACE (HR 1.51; 1.11-2.06; P = .0096). CONCLUSION: Early control of HbA1c improved cardiovascular outcomes in type 2 diabetes, although subsequent glycaemic variability had a negative effect on an individual's risk.

Valproate prescription to women of childbearing age in English primary care: repeated cross-sectional analyses and retrospective cohort study.

BACKGROUND: Valproate is a teratogenic drug that should be avoided during the preconception period and pregnancy. The aim was to explore general practitioners' (GPs) prescription patterns over time, describe trends, and explore inter-practice variation within primary care. METHODS: We identified women of childbearing age (12-46 years old) in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network. We performed repeated cross-sectional analyses from 2004 to 2018 to determine rates of prescription and a retrospective cohort estimated the prevalence of use of valproate during pregnancy. RESULTS: In 2004, 0.31% (95% Confidence Interval (95%CI):0.18 to 0.44%) women were prescribed valproate, decreasing to 0.16% (95%CI:0.07 to 0.24%) by 2018. Among women with epilepsy, the rate fell from 15.2% (95%CI:14.4 to 16.0%) to 8.8% (95% CI:8.2 to 9.7%) over the same period. In 2018, almost two thirds (62.2%) of women who were prescribed valproate had epilepsy only, whereas bipolar disorder and migraine accounted for 15.8% and 7.4% respectively. Contraceptive prescriptions did not increase over time, and only in 2018 was there greater odds of being prescribed contraception (OR 1.41, 95%CI:1.08 to 1.45). Just under a fifth (19.7%) of women were prescribed valproate during their pregnancy; two out of three of these pregnancies were preceded by folic acid prescription (5 mg). While some practices reduced their rate of valproate prescription, others did not. CONCLUSIONS: Regulatory guidelines have changed GPs' prescription patterns in women of childbearing potential for valproate but not for contraception. Further research is needed to identify the barriers of GPs and women of childbearing potential to undertaking contraception.

Mortality in COVID-19 among women on hormone replacement therapy: a retrospective cohort study.

BACKGROUND: Limited recent observational data have suggested that there may be a protective effect of oestrogen on the severity of COVID-19 disease. Our aim was to investigate the association between hormone replacement therapy (HRT) or combined oral contraceptive pill (COCP) use and the likelihood of death in women with COVID-19. METHODS: We undertook a retrospective cohort study using routinely collected computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. We identified a cohort of 1,863,478 women over 18 years of age from 465 general practices in England. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use and all-cause mortality among women diagnosed with confirmed or suspected COVID-19 in unadjusted and adjusted models. RESULTS: There were 5,451 COVID-19 cases within the cohort. HRT was associated with a reduction in all-cause mortality in COVID-19 (adjusted OR 0.22, 95% CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP. CONCLUSIONS: We found that HRT prescription within 6 months of a recorded diagnosis of COVID-19 infection was associated with a reduction in all-cause mortality. Further work is needed in larger cohorts to examine the association of COCP in COVID-19, and to further investigate the hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

Prescribing sodium-glucose co-transporter-2 inhibitors for type 2 diabetes in primary care: influence of renal function and heart failure diagnosis.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are licenced for initiation for glucose lowering in people with type 2 diabetes (T2DM) with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2). However, recent trial data have shown that these medications have renal and cardio-protective effects, even for impaired kidney function. The extent to which trial evidence and updated guidelines have influenced real-world prescribing of SGLT-2is is not known, particularly with co-administration of diuretics. METHODS: We performed a cross-sectional analysis of people with T2DM registered with practices in the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database on the 31st July 2019. We calculated the percentage of people prescribed SGLT-2is according to eGFR categories (< 45, 45-59, and ≥ 60 mL/min/1.73m2), with a heart failure diagnosis and stratified by body mass index categories (underweight, normal weight, overweight, obese), and with concomitant prescription of a diuretic. Multilevel logistic regression analysis was performed to determine whether heart failure diagnosis and renal function were associated with SGLT-2i prescribing. RESULTS: From a population of 242,624 people with T2DM across 419 practices, 11.0% (n = 26,700) had been prescribed SGLT-2is. The majority of people initiated SGLT-2is had an eGFR ≥ 60 mL/min/1.73m2 (93.2%), and 4.3% had a heart failure diagnosis. 9,226 (3.8%) people were prescribed SGLT-2is as an add-on to their diuretic prescription. People in the highest eGFR category (≥ 60 mL/min/1.73m2) were more likely to be prescribed SGLT-2is than those in eGFR lower categories. Overweight (OR 2.05, 95% CI 1.841-2.274) and obese people (OR 3.84, 95% CI 3.472-4.250) were also more likely to be prescribed these medications, whilst use of diuretics (OR 0.74, 95% CI 0.682-0.804) and heart failure (OR 0.81, 95% CI 0.653-0.998) were associated with lower odds of being prescribed SGLT-2is. CONCLUSIONS: Prescribing patterns of SGLT-2is for glucose lowering in T2DM in primary care generally concur with licenced indications according to recommended renal thresholds. A small percentage of people with heart failure were prescribed SGLT-2is for T2DM. An updated analysis is merited should UK National Institute for Health Care and Excellence prescribing guidelines for T2DM be revised to incorporate new data on the benefits for those with reduced renal function or with heart failure.

The impact of social and physical distancing measures on COVID-19 activity in England: findings from a multi-tiered surveillance system.

BackgroundA multi-tiered surveillance system based on influenza surveillance was adopted in the United Kingdom in the early stages of the coronavirus disease (COVID-19) epidemic to monitor different stages of the disease. Mandatory social and physical distancing measures (SPDM) were introduced on 23 March 2020 to attempt to limit transmission.AimTo describe the impact of SPDM on COVID-19 activity as detected through the different surveillance systems.MethodsData from national population surveys, web-based indicators, syndromic surveillance, sentinel swabbing, respiratory outbreaks, secondary care admissions and mortality indicators from the start of the epidemic to week 18 2020 were used to identify the timing of peaks in surveillance indicators relative to the introduction of SPDM. This timing was compared with median time from symptom onset to different stages of illness and levels of care or interactions with healthcare services.ResultsThe impact of SPDM was detected within 1 week through population surveys, web search indicators and sentinel swabbing reported by onset date. There were detectable impacts on syndromic surveillance indicators for difficulty breathing, influenza-like illness and COVID-19 coding at 2, 7 and 12 days respectively, hospitalisations and critical care admissions (both 12 days), laboratory positivity (14 days), deaths (17 days) and nursing home outbreaks (4 weeks).ConclusionThe impact of SPDM on COVID-19 activity was detectable within 1 week through community surveillance indicators, highlighting their importance in early detection of changes in activity. Community swabbing surveillance may be increasingly important as a specific indicator, should circulation of seasonal respiratory viruses increase.

Household presentation of acute gastroenteritis in a primary care sentinel network: retrospective database studies.

BACKGROUND: Acute gastroenteritis (AGE) is a highly transmissible condition spreading rapidly between individuals and within households. Rotavirus vaccination was introduced in the UK in 2013. The study objectives were to investigate how acute gastroenteritis incidence changed over 25 years and household incidence of AGE since 2013. METHODS: Repeated cross-sectional study of Royal College of General Practitioners Research and Surveillance Centre network. We used a negative binomial model to report incidence rate ratio (IRR) using the last 5 years data. We also conducted a retrospective cohort analysis, using a shared gamma frailty model (2013-2017). We explored the impact of child under 5- years, household size, socioeconomic status quintile, and rurality. RESULTS: In the cross-sectional analysis, the IRR of AGE in households with a child of under 5 years was 12.20 (95%CI 11.08-13.45-, p < 0.001) compared with households without; the IRR fell across IMD quintiles, for example there is a 37% decrease in incidence comparing IMD quintile 1 to quintile 5 (95%CI -0.52-0.76, p < 0.001), The cohort study revealed that the presence of an under 5 in the household was associated with a higher risk of household presentation (HR = 6.29, 95% CI 5.61-7.06, p < 0.001). In addition, we observe a reduction in risk of presentation from the most to the least deprived socioeconomic quintile (second quintile: HR = 0.74 (95%CI 0.59-0.92), to least deprived quintile, HR = 0.55 (95%CI 0.41-0.74). We saw a lower association with male gender, white ethnicity and living outside London, but an increased association with increasing household size. CONCLUSIONS: The incidence of AGE has changed over time: pre-school children, larger households, and living in London were associated with higher rates, and male gender and higher economic status associated with lower rates.

Household presentation of influenza and acute respiratory illnesses to a primary care sentinel network: retrospective database studies (2013-2018).

BACKGROUND: Direct observation of the household spread of influenza and respiratory infections is limited; much of our understanding comes from mathematical models. The study aims to determine household incidence of influenza-like illness (ILI), lower (LRTI) and upper (URTI) respiratory infections within a primary care routine data and identify factors associated with the diseases' incidence. METHODS: We conducted two five-year retrospective analyses of influenza-like illness (ILI), lower (LRTI) and upper (URTI) respiratory infections using the England Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care sentinel network database; a cross-sectional study reporting incident rate ratio (IRR) from a negative binomial model and a retrospective cohort study, using a shared gamma frailty survival model, reporting hazard ratios (HR). We reported the following household characteristics: children < 5 years old, each extra household member, gender, ethnicity (reference white), chronic disease, pregnancy, and rurality. RESULTS: The IRR where there was a child < 5 years were 1·62 (1·38-1·89, p < 0·0001), 2·40 (2.04-2.83, p < 0·0001) and 4·46 (3.79-5.255, p < 0·0001) for ILI, LRTI and URTI respectively. IRR also increased with household size, rurality and presentations and by female gender, compared to male. Household incidence of URTI and LRTI changed little between years whereas influenza did and were greater in years with lower vaccine effectiveness. The HR where there was a child < 5 years were 2·34 (95%CI 1·88-2·90, p < 0·0001), 2·97 (95%CI 2·76-3·2, p < 0·0001) and 10·32 (95%CI 10.04-10.62, p < 0·0001) for ILI, LRTI and URTI respectively. HR were increased with female gender, rurality, and increasing household size. CONCLUSIONS: Patterns of household incidence can be measured from routine data and may provide insights for the modelling of disease transmission and public health policy.

Prehabilitation for adults diagnosed with cancer: A systematic review of long-term physical function, nutrition and patient-reported outcomes.

OBJECTIVE: Prehabilitation is increasingly being used to mitigate treatment-related complications and enhance recovery. An individual's state of health at diagnosis, including obesity, physical fitness and comorbidities, are influencing factors for the occurrence of adverse effects. This review explores whether prehabilitation works in improving health outcomes at or beyond the initial 30 days post-treatment and considers the utility of prehabilitation before cancer treatment. METHODS: A database search was conducted for articles published with prehabilitation as a pre-cancer treatment intervention between 2009 and 2017. Studies with no 30 days post-treatment data were excluded. Outcomes post-prehabilitation were extracted for physical function, nutrition and patient-reported outcomes. RESULTS: Sixteen randomised controlled trials with a combined 2017 participants and six observational studies with 289 participants were included. Prehabilitation interventions provided multi-modality components including exercise, nutrition and psychoeducational aspects. Prehabilitation improved gait, cardiopulmonary function, urinary continence, lung function and mood 30 days post-treatment but was not consistent across studies. CONCLUSION: When combined with rehabilitation, greater benefits were seen in 30-day gait and physical functioning compared to prehabilitation alone. Large-scale randomised studies are required to translate what is already known from feasibility studies to improve overall health and increase long-term cancer patient outcomes.

Defining and Risk-Stratifying Immunosuppression (the DESTINIES Study): Protocol for an Electronic Delphi Study.

BACKGROUND: Globally, there are marked inconsistencies in how immunosuppression is characterized and subdivided into clinical risk groups. This is detrimental to the precision and comparability of disease surveillance efforts-which has negative implications for the care of those who are immunosuppressed and their health outcomes. This was particularly apparent during the COVID-19 pandemic; despite collective motivation to protect these patients, conflicting clinical definitions created international rifts in how those who were immunosuppressed were monitored and managed during this period. We propose that international clinical consensus be built around the conditions that lead to immunosuppression and their gradations of severity concerning COVID-19. Such information can then be formalized into a digital phenotype to enhance disease surveillance and provide much-needed intelligence on risk-prioritizing these patients. OBJECTIVE: We aim to demonstrate how electronic Delphi objectives, methodology, and statistical approaches will help address this lack of consensus internationally and deliver a COVID-19 risk-stratified phenotype for "adult immunosuppression." METHODS: Leveraging existing evidence for heterogeneous COVID-19 outcomes in adults who are immunosuppressed, this work will recruit over 50 world-leading clinical, research, or policy experts in the area of immunology or clinical risk prioritization. After 2 rounds of clinical consensus building and 1 round of concluding debate, these panelists will confirm the medical conditions that should be classed as immunosuppressed and their differential vulnerability to COVID-19. Consensus statements on the time and dose dependencies of these risks will also be presented. This work will be conducted iteratively, with opportunities for panelists to ask clarifying questions between rounds and provide ongoing feedback to improve questionnaire items. Statistical analysis will focus on levels of agreement between responses. RESULTS: This protocol outlines a robust method for improving consensus on the definition and meaningful subdivision of adult immunosuppression concerning COVID-19. Panelist recruitment took place between April and May of 2024; the target set for over 50 panelists was achieved. The study launched at the end of May and data collection is projected to end in July 2024. CONCLUSIONS: This protocol, if fully implemented, will deliver a universally acceptable, clinically relevant, and electronic health record-compatible phenotype for adult immunosuppression. As well as having immediate value for COVID-19 resource prioritization, this exercise and its output hold prospective value for clinical decision-making across all diseases that disproportionately affect those who are immunosuppressed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56271.

Disparities in COVID-19 mortality amongst the immunosuppressed: A systematic review and meta-analysis for enhanced disease surveillance.

BACKGROUND: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. METHODS: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. FINDINGS: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. INTERPRETATION: Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission.

Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study.

Background: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. Methods: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). Findings: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). Interpretation: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. Funding: None.

A Profile of Influenza Vaccine Coverage for 2019-2020: Database Study of the English Primary Care Sentinel Cohort.

BACKGROUND: Innovation in seasonal influenza vaccine development has resulted in a wider range of formulations becoming available. Understanding vaccine coverage across populations including the timing of administration is important when evaluating vaccine benefits and risks. OBJECTIVE: This study aims to report the representativeness, uptake of influenza vaccines, different formulations of influenza vaccines, and timing of administration within the English Primary Care Sentinel Cohort (PCSC). METHODS: We used the PCSC of the Oxford-Royal College of General Practitioners Research and Surveillance Centre. We included patients of all ages registered with PCSC member general practices, reporting influenza vaccine coverage between September 1, 2019, and January 29, 2020. We identified influenza vaccination recipients and characterized them by age, clinical risk groups, and vaccine type. We reported the date of influenza vaccination within the PCSC by International Standard Organization (ISO) week. The representativeness of the PCSC population was compared with population data provided by the Office for National Statistics. PCSC influenza vaccine coverage was compared with published UK Health Security Agency's national data. We used paired t tests to compare populations, reported with 95% CI. RESULTS: The PCSC comprised 7,010,627 people from 693 general practices. The study population included a greater proportion of people aged 18-49 years (2,982,390/7,010,627, 42.5%; 95% CI 42.5%-42.6%) compared with the Office for National Statistics 2019 midyear population estimates (23,219,730/56,286,961, 41.3%; 95% CI 4.12%-41.3%; P<.001). People who are more deprived were underrepresented and those in the least deprived quintile were overrepresented. Within the study population, 24.7% (1,731,062/7,010,627; 95% CI 24.7%-24.7%) of people of all ages received an influenza vaccine compared with 24.2% (14,468,665/59,764,928; 95% CI 24.2%-24.2%; P<.001) in national data. The highest coverage was in people aged ≥65 years (913,695/1,264,700, 72.3%; 95% CI 72.2%-72.3%). The proportion of people in risk groups who received an influenza vaccine was also higher; for example, 69.8% (284,280/407,228; 95% CI 69.7%-70%) of people with diabetes in the PCSC received an influenza vaccine compared with 61.2% (983,727/1,607,996; 95% CI 61.1%-61.3%; P<.001) in national data. In the PCSC, vaccine type and brand information were available for 71.8% (358,365/498,923; 95% CI 71.7%-72%) of people aged 16-64 years and 81.9% (748,312/913,695; 95% CI 81.8%-82%) of people aged ≥65 years, compared with 23.6% (696,880/2,900,000) and 17.8% (1,385,888/7,700,000), respectively, of the same age groups in national data. Vaccination commenced during ISO week 35, continued until ISO week 3, and peaked during ISO week 41. The in-week peak in vaccination administration was on Saturdays. CONCLUSIONS: The PCSC's sociodemographic profile was similar to the national population and captured more data about risk groups, vaccine brands, and batches. This may reflect higher data quality. Its capabilities included reporting precise dates of administration. The PCSC is suitable for undertaking studies of influenza vaccine coverage.

Risk of severe COVID-19 outcomes after autumn 2022 COVID-19 booster vaccinations: a pooled analysis of national prospective cohort studies involving 7.4 million adults in England, Northern Ireland, Scotland and Wales.

Background: UK COVID-19 vaccination policy has evolved to offering COVID-19 booster doses to individuals at increased risk of severe Illness from COVID-19. Building on our analyses of vaccine effectiveness of first, second and initial booster doses, we aimed to identify individuals at increased risk of severe outcomes (i.e., COVID-19 related hospitalisation or death) post the autumn 2022 booster dose. Methods: We undertook a national population-based cohort analysis across all four UK nations through linked primary care, vaccination, hospitalisation and mortality data. We included individuals who received autumn 2022 booster doses of BNT162b2 (Comirnaty) or mRNA-1273 (Spikevax) during the period September 1, 2022 to December 31, 2022 to investigate the risk of severe COVID-19 outcomes. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for the association between demographic and clinical factors and severe COVID-19 outcomes after the autumn booster dose. Analyses were adjusted for age, sex, body mass index (BMI), deprivation, urban/rural areas and comorbidities. Stratified analyses were conducted by vaccine type. We then conducted a fixed-effect meta-analysis to combine results across the four UK nations. Findings: Between September 1, 2022 and December 31, 2022, 7,451,890 individuals ≥18 years received an autumn booster dose. 3500 had severe COVID-19 outcomes (2.9 events per 1000 person-years). Being male (male vs female, aHR 1.41 (1.32-1.51)), older adults (≥80 years vs 18-49 years; 10.43 (8.06-13.50)), underweight (BMI <18.5 vs BMI 25.0-29.9; 2.94 (2.51-3.44)), those with comorbidities (≥5 comorbidities vs none; 9.45 (8.15-10.96)) had a higher risk of COVID-19 hospitalisation or death after the autumn booster dose. Those with a larger household size (≥11 people within household vs 2 people; 1.56 (1.23-1.98)) and from more deprived areas (most deprived vs least deprived quintile; 1.35 (1.21-1.51)) had modestly higher risks. We also observed at least a two-fold increase in risk for those with various chronic neurological conditions, including Down's syndrome, immunodeficiency, chronic kidney disease, cancer, chronic respiratory disease, or cardiovascular disease. Interpretation: Males, older individuals, underweight individuals, those with an increasing number of comorbidities, from a larger household or more deprived areas, and those with specific underlying health conditions remained at increased risk of COVID-19 hospitalisation and death after the autumn 2022 vaccine booster dose. There is now a need to focus on these risk groups for investigating immunogenicity and efficacy of further booster doses or therapeutics. Funding: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council and Economic and Social Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

Uptake of COVID-19 vaccinations amongst 3,433,483 children and young people: meta-analysis of UK prospective cohorts.

SARS-CoV-2 infection in children and young people (CYP) can lead to life-threatening COVID-19, transmission within households and schools, and the development of long COVID. Using linked health and administrative data, we investigated vaccine uptake among 3,433,483 CYP aged 5-17 years across all UK nations between 4th August 2021 and 31st May 2022. We constructed national cohorts and undertook multi-state modelling and meta-analysis to identify associations between demographic variables and vaccine uptake. We found that uptake of the first COVID-19 vaccine among CYP was low across all four nations compared to other age groups and diminished with subsequent doses. Age and vaccination status of adults living in the same household were identified as important risk factors associated with vaccine uptake in CYP. For example, 5-11 year-olds were less likely to receive their first vaccine compared to 16-17 year-olds (adjusted Hazard Ratio [aHR]: 0.10 (95%CI: 0.06-0.19)), and CYP in unvaccinated households were less likely to receive their first vaccine compared to CYP in partially vaccinated households (aHR: 0.19, 95%CI 0.13-0.29).