Consultations for clinical features of possible cancer and associated urgent referrals before and during the COVID-19 pandemic: an observational cohort study from English primary care.

BACKGROUND: It remains unclear to what extent reductions in urgent referrals for suspected cancer during the COVID-19 pandemic were the result of fewer patients attending primary care compared to GPs referring fewer patients. METHODS: Cohort study including electronic health records data from 8,192,069 patients from 663 English practices. Weekly consultation rates, cumulative consultations and referrals were calculated for 28 clinical features from the NICE suspected cancer guidelines. Clinical feature consultation rate ratios (CRR) and urgent referral rate ratios (RRR) compared time periods in 2020 with 2019. FINDINGS: Consultations for cancer clinical features decreased by 24.19% (95% CI: 24.04-24.34%) between 2019 and 2020, particularly in the 6-12 weeks following the first national lockdown. Urgent referrals for clinical features decreased by 10.47% (95% CI: 9.82-11.12%) between 2019 and 2020. Overall, once patients consulted with primary care, GPs urgently referred a similar or greater proportion of patients compared to previous years. CONCLUSION: Due to the significant fall in patients consulting with clinical features of cancer there was a lower than expected number of urgent referrals in 2020. Sustained efforts should be made throughout the pandemic to encourage the public to consult their GP with cancer clinical features.

Over-use of thyroid testing in Canadian and UK primary care in frequent attenders: A cross-sectional study.

BACKGROUND: Thyroid-stimulating hormone (TSH) is a common test used to detect and monitor clinically significant hypo- and hyperthyroidism. Population-based screening of asymptomatic adults for thyroid disorders is not recommended. OBJECTIVE: The research objectives were to determine patterns of TSH testing in Canadian and English primary care practices, as well as patient and physician practice characteristics associated with testing TSH for primary care patients with no identifiable indication. METHODS: In this 2-year cross-sectional observational study, Canadian and English electronic medical record databases were used to identify patients and physician practices. Cohorts of patients aged 18 years or older, without identifiable indications for TSH testing, were generated from these databases. Analyses were performed using a random-effects logistic regression to determine patient and physician practice characteristics associated with increased testing. We determined the proportion of TSH tests performed concurrently with at least one common screening blood test (lipid profile or hemoglobin A1c). Standardised proportions of TSH test per family practice were used to examine the heterogeneity in the populations. RESULTS: At least one TSH test was performed in 35.97% (N = 489 663) of Canadian patients and 29.36% (N = 1 030 489) of English patients. Almost all TSH tests in Canada and England (95.69% and 99.23% respectively) were within the normal range (0.40-5.00 mU/L). A greater number of patient-physician encounters was the strongest predictor of TSH testing. It was determined that 51.40% of TSH tests in Canada and 76.55% in England were performed on the same day as at least one other screening blood test. There was no association between the practice size and proportion of asymptomatic patients tested. CONCLUSIONS: This comparative binational study found TSH patterns suggestive of over-testing and potentially thyroid disorder screening in both countries. There may be significant opportunities to improve the appropriateness of TSH ordering in Canada and England and therefore improve the allocation of limited system resources.

Linkage of the CHHiP randomised controlled trial with primary care data: a study investigating ways of supplementing cancer trials and improving evidence-based practice.

BACKGROUND: Randomised controlled trials (RCTs) are the gold standard for evidence-based practice. However, RCTs can have limitations. For example, translation of findings into practice can be limited by design features, such as inclusion criteria, not accurately reflecting clinical populations. In addition, it is expensive to recruit and follow-up participants in RCTs. Linkage with routinely collected data could offer a cost-effective way to enhance the conduct and generalisability of RCTs. The aim of this study is to investigate how primary care data can support RCTs. METHODS: Secondary analysis following linkage of two datasets: 1) multicentre CHHiP radiotherapy trial (ISRCTN97182923) and 2) primary care database from the Royal College of General Practitioners Research and Surveillance Centre. Comorbidities and medications recorded in CHHiP at baseline, and radiotherapy-related toxicity recorded in CHHiP over time were compared with primary care records. The association of comorbidities and medications with toxicity was analysed with mixed-effects logistic regression. RESULTS: Primary care records were extracted for 106 out of 2811 CHHiP participants recruited from sites in England (median age 70, range 44 to 82). Complementary information included longitudinal body mass index, blood pressure and cholesterol, as well as baseline smoking and alcohol usage but was limited by the considerable missing data. In the linked sample, 9 (8%) participants were recorded in CHHiP as having a history of diabetes and 38 (36%) hypertension, whereas primary care records indicated incidence prior to trial entry of 11 (10%) and 40 (38%) respectively. Concomitant medications were not collected in CHHiP but available in primary care records. This indicated that 44 (41.5%) men took aspirin, 65 (61.3%) statins, 14 (13.2%) metformin and 46 (43.4%) phosphodiesterase-5-inhibitors at some point before or after trial entry. CONCLUSIONS: We provide a set of recommendations on linkage and supplementation of trials. Data recorded in primary care are a rich resource and linkage could provide near real-time information to supplement trials and an efficient and cost-effective mechanism for long-term follow-up. In addition, standardised primary care data extracts could form part of RCT recruitment and conduct. However, this is at present limited by the variable quality and fragmentation of primary care data.

Clinical Ontologies Improve Case Finding of Primary Biliary Cholangitis in UK Primary and Secondary Care.

INTRODUCTION: PBC registries in the UK focus on data from secondary care without clear coordinated contribution from primary care. The Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) receives data from > 500 primary care practices (PCPs). Notably, the Lancet commissioning group is extracting data from the RCGP RSC database to shape UK policy on liver disease. AIMS: To create a novel ontology to facilitate PBC case finding from primary care provider (PCP) records. METHODS: RCGP RSC data were collected from participating PCPs in the county of Surrey, UK. PBC diagnostic criteria of the AASLD and EASL guidelines were used to develop 725 data codes to facilitate patient record searches. A scoring system built into the ontology allowed categorization of cases as PBC definite, PBC probable, and PBC unlikely. RESULTS: A total of 218,099 records were searched from participating PCPs. Of these, there were 58 PBC definite, 2317 PBC probable, and 215,724 PBC unlikely patients. There were 32 PBC definite patients who did not match to our regional PBC database and were henceforth included as new-found cases. Two of these cases were not labeled as PBC by the PCP. From the PBC unlikely group, 7/215,724 (0.003%) patients were labeled as PBC in secondary care records; however, none of them were coded as having PBC by their PCPs. CONCLUSIONS: Utilization of the UK National RCGP RSC database supported by novel ontology score has successfully helped us identify (i) new cases of PBC not known to local/regional secondary care providers and (ii) de novo PBC cases. There are many PBC probable cases whose data merit further careful evaluation.

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.

Using an Ontology to Facilitate More Accurate Coding of Social Prescriptions Addressing Social Determinants of Health: Feasibility Study.

BACKGROUND: National Health Service (NHS) England supports social prescribing in order to address social determinants of health, which account for approximately 80% of all health outcomes. Nevertheless, data on ongoing social prescribing activities are lacking. Although NHS England has attempted to overcome this problem by recommending 3 standardized primary care codes, these codes do not capture the social prescribing activity to a level of granularity that would allow for fair attribution of outcomes to social prescribing. OBJECTIVE: In this study, we explored whether an alternative approach to coding social prescribing activity, specifically through a social prescribing ontology, can be used to capture the social prescriptions used in primary care in greater detail. METHODS: The social prescribing ontology, implemented according to the Web Ontology Language, was designed to cover several key concepts encompassing social determinants of health. Readv2 and Clinical Terms Version 3 codes were identified using the NHS Terms Browser. The Royal College of General Practitioners Research Surveillance Centre, a sentinel network of over 1000 primary care practices across England covering a population of more than 4,000,000 registered patients, was used for data analyses for a defined period (ie, January 2011 to December 2019). RESULTS: In all, 668 codes capturing social prescriptions addressing different social determinants of health were identified for the social prescribing ontology. For the study period, social prescribing ontology codes were used 5,504,037 times by primary care practices of the Royal College of General Practitioners Research Surveillance Centre as compared to 29,606 instances of use of social prescribing codes, including NHS England's recommended codes. CONCLUSIONS: A social prescribing ontology provides a powerful alternative to the codes currently recommended by NHS England to capture detailed social prescribing activity in England. The more detailed information thus obtained will allow for explorations about whether outputs or outcomes of care delivery can be attributed to social prescriptions, which is essential for demonstrating the overall value that social prescribing can deliver to the NHS and health care systems.

Development of a modified Cambridge Multimorbidity Score for use with SNOMED CT: an observational English primary care sentinel network study.

BACKGROUND: People with multiple health conditions are more likely to have poorer health outcomes and greater care and service needs; a reliable measure of multimorbidity would inform management strategies and resource allocation. AIM: To develop and validate a modified version of the Cambridge Multimorbidity Score in an extended age range, using clinical terms that are routinely used in electronic health records across the world (Systematized Nomenclature of Medicine - Clinical Terms, SNOMED CT). DESIGN AND SETTING: Observational study using diagnosis and prescriptions data from an English primary care sentinel surveillance network between 2014 and 2019. METHOD: In this study new variables describing 37 health conditions were curated and the associations modelled between these and 1-year mortality risk using the Cox proportional hazard model in a development dataset (n = 300 000). Two simplified models were then developed - a 20-condition model as per the original Cambridge Multimorbidity Score and a variable reduction model using backward elimination with Akaike information criterion as the stopping criterion. The results were compared and validated for 1-year mortality in a synchronous validation dataset (n = 150 000), and for 1-year and 5-year mortality in an asynchronous validation dataset (n = 150 000). RESULTS: The final variable reduction model retained 21 conditions, and the conditions mostly overlapped with those in the 20-condition model. The model performed similarly to the 37- and 20-condition models, showing high discrimination and good calibration following recalibration. CONCLUSION: This modified version of the Cambridge Multimorbidity Score allows reliable estimation using clinical terms that can be applied internationally across multiple healthcare settings.

Hepatitis B virus infection in general practice across England: An analysis of the Royal College of General Practitioners Research and Surveillance Centre real-world database.

OBJECTIVES: We analyzed hepatitis B surface antigen (HBsAg) screening and seropositivity within a network of 419 general practices representative of all regions of England. METHODS: Information was extracted using pseudonymized registration data. Predictors of HBsAg seropositivity were explored in models that considered age, gender, ethnicity, time at the current practice, practice location and associated deprivation index, and presence of nationally endorsed screen indicators including pregnancy, men who have sex with men (MSM), history of injecting drug use (IDU), close HBV contact or imprisonment, and diagnosis of blood-borne or sexually transmitted infections. RESULTS: Among 6,975,119 individuals, 192,639 (2.8 %) had a screening record, including 3.6-38.6 % of those with a screen indicator, and 8065 (0.12 %) had a seropositive record. The odds of seropositivity were highest in London, in the most deprived neighborhoods, among minority ethnic groups, and in people with screen indicators. Seroprevalence exceeded 1 % in people from high-prevalence countries, MSM, close HBV contacts, and people with a history of IDU or a recorded diagnosis of HIV, HCV, or syphilis. Overall, 1989/8065 (24.7 %) had a recorded referral to specialist hepatitis care. CONCLUSIONS: In England, HBV infection is associated with poverty. There are unrealized opportunities to promote access to diagnosis and care for those affected.

Safety of routine childhood vaccine coadministration versus separate vaccination.

INTRODUCTION: As new vaccines are developed more vaccine coadministrations vaccines are being offered to make delivery more practical for health systems and patients. We compared the safety of coadministered vaccines with separate vaccination for 20 coadministrations by considering nine types of adverse events following immunisation (AEFI). METHODS: Real-life immunisation and adverse event data for this observational cohort study were extracted from the Oxford-Royal College of General Practitioners Research and Surveillance Centre for children registered in the database between 2008 and 2018. We applied the self-controlled case series method to calculate relative incidence ratios (RIR) for AEFI. These RIRs compare the RI of AEFI following coadministration with the RI following separate administration of the same vaccines. RESULTS: We assessed 3 518 047 adverse events and included 5 993 290 vaccine doses given to 958 591 children. 17% of AEFI occurred less and 11% more frequently following coadministration than would have been expected based on the RIs following separate vaccinations, while there was no significant difference for 72% of AEFI. We found amplifying interaction effects for AEFI after five coadministrations comprising three vaccines: for fever (RIR 1.93 (95% CI 1.63 to 2.29)), rash (RIR 1.49 (95% CI 1.29 to 1.74)), gastrointestinal events (RIR 1.31 (95% CI 1.14 to 1.49)) and respiratory events (RIR 1.27 (1.17-1.38)) following DTaP/IPV/Hib+MenC+ PCV; gastrointestinal events (RIR 1.65 (95% CI 1.35 to 2.02)) following DTaP/IPV/Hib+MenC+ RV; fever (RIR 1.44 (95% CI 1.09 to 1.90)) and respiratory events (RIR 1.40 (95% CI 1.25 to 1.57)) following DTaP/IPV/Hib+PCV+ RV; gastrointestinal (RIR 1.48 (95% CI 1.20 to 1.82)) and respiratory events (RIR 1.43 (95% CI 1.26 to 1.63)) following MMR+Hib/MenC+PCV; gastrointestinal events (RIR 1.68 (95% CI 1.07 to 2.64)) and general symptoms (RIR 11.83 (95% CI 1.28 to 109.01)) following MMR+MenC+PCV. Coadministration of MMR+PCV led to more fever (RIR 1.91 (95% CI 1.83 to 1.99)), neurological events (RIR 2.04 (95% CI 1.67 to 2.49)) and rash (RIR 1.06 (95% CI 1.01 to 1.11)) compared with separate administration, DTaP/IPV/Hib+MMR to more musculoskeletal events (RIR 3.56 (95% CI 1.21 to 10.50)) and MMR+MenC to more fever (RIR 1.58 (95% CI 1.37 to 1.82)). There was no indication that unscheduled coadministrations are less safe than scheduled coadministrations. CONCLUSION: Real-life RIRs of AEFI justify coadministering routine childhood vaccines according to the immunisation schedule. Further research into the severity of AEFI following coadministration is required for a complete understanding of the burden of these AEFI.

Long term follow up of direct oral anticoagulants and warfarin therapy on stroke, with all-cause mortality as a competing risk, in people with atrial fibrillation: Sentinel network database study.

BACKGROUND: We investigated differences in risk of stroke, with all-cause mortality as a competing risk, in people newly diagnosed with atrial fibrillation (AF) who were commenced on either direct oral anticoagulants (DOACs) or warfarin treatment. METHODS AND RESULTS: We conducted a retrospective cohort study of the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database (a network of 500 English general practices). We compared long term exposure to DOAC (n = 5,168) and warfarin (n = 7,451) in new cases of AF not previously treated with oral anticoagulants. Analyses included: survival analysis, estimating cause specific hazard ratios (CSHR), Fine-Gray analysis for factors affecting cumulative incidence of events occurring over time and a cumulative risk regression with time varying effects.We found no difference in CSHR between stroke 1.08 (0.72-1.63, p = 0.69) and all-cause mortality 0.93 (0.81-1.08, p = 0.37), or between the anticoagulant groups. Fine-Gray analysis produced similar results 1.07 (0.71-1.6 p = 0.75) for stroke and 0.93 (0.8-1.07, p = 0.3) mortality. The cumulative risk of mortality with DOAC was significantly elevated in early follow-up (67 days), with cumulative risk decreasing until 1,537 days and all-cause mortality risk significantly decreased coefficient estimate:: -0.23 (-0.38-0.01, p = 0.001); which persisted over seven years of follow-up. CONCLUSIONS: In this large, contemporary, real world primary care study with longer follow-up, we found no overall difference in the hazard of stroke between warfarin and DOAC treatment for AF. However, there was a significant time-varying effect between anti-coagulant regimen on all-cause mortality, with DOACs showing better survival. This is a key methodological observation for future follow-up studies, and reassuring for patients and health care professionals for longer duration of therapy.

Mental Health Presentations Across Health Care Settings During the First 9 Months of the COVID-19 Pandemic in England: Retrospective Observational Study.

BACKGROUND: The COVID-19 pandemic has resulted in an unprecedented impact on the day-to-day lives of people, with several features potentially adversely affecting mental health. There is growing evidence of the size of the impact of COVID-19 on mental health, but much of this is from ongoing population surveys using validated mental health scores. OBJECTIVE: This study investigated the impact of the pandemic and control measures on mental health conditions presenting to a spectrum of national health care services monitored using real-time syndromic surveillance in England. METHODS: We conducted a retrospective observational descriptive study of mental health presentations (those calling the national medical helpline, National Health Service [NHS] 111; consulting general practitioners [GPs] in and out-of-hours; calling ambulance services; and attending emergency departments) from January 1, 2019, to September 30, 2020. Estimates for the impact of lockdown measures were provided using an interrupted time series analysis. RESULTS: Mental health presentations showed a marked decrease during the early stages of the pandemic. Postlockdown, attendances for mental health conditions reached higher than prepandemic levels across most systems-a rise of 10% compared to that expected for NHS 111 and 21% for GP out-of-hours service-while the number of consultations to GP in-hours service was 13% lower compared to the same time previous year. Increases were observed in calls to NHS 111 for sleep problems. CONCLUSIONS: These analyses showed marked changes in the health care attendances and prescribing for common mental health conditions across a spectrum of health care provision, with some of these changes persisting. The reasons for such changes are likely to be complex and multifactorial. The impact of the pandemic on mental health may not be fully understood for some time, and therefore, these syndromic indicators should continue to be monitored.

National rates and disparities in childhood vaccination and vaccine-preventable disease during the COVID-19 pandemic: English sentinel network retrospective database study.

OBJECTIVES: To describe rates and variation in uptake of pneumococcal and measles, mumps and rubella (MMR) vaccines in children and associated change in vaccine-preventable diseases (VPDs) across the first and second waves of the COVID-19 pandemic. METHODS: Retrospective database study of all children aged <19 registered with a general practice in the Oxford Royal College of General Practitioners Research and Surveillance Centre English national sentinel surveillance network between 2 November 2015 and 18 July 2021. RESULTS: Coverage of booster dose of pneumococcal vaccine decreased from 94.5% (95% CI 94.3% to 94.7%) at its height on International Organization for Standardization (ISO) week 47 (2020) to 93.6% (95% CI 93.4% to 93.8%) by the end of the study. Coverage of second dose of MMR decreased from 85.0% (95% CI 84.7% to 85.3%) at its height on ISO week 37 (2020) to 84.1% (95% CI 83.8% to 84.4%) by the end of the study. The break point in trends for MMR was at ISO week 34 (2020) (95% CI weeks 32-37 (2020)), while for pneumococcal vaccine the break point was later at ISO week 3 (2021) (95% CI week 53 (2020) to week 8 (2021)). Vaccination coverage for children of white ethnicity was less likely to decrease than other ethnicities. Rates of consultation for VPDs fell and remained low since August 2020. CONCLUSION: Childhood vaccination rates started to fall ahead of the onset of the second wave; this fall is accentuating ethnic, socioeconomic and geographical disparities in vaccine uptake and risks widening health disparities. Social distancing and school closures may have contributed to lower rates of associated VPDs, but there may be increased risk as these measures are removed.

Adverse Events of Interest Following Influenza Vaccination in the First Season of Adjuvanted Trivalent Immunization: Retrospective Cohort Study.

BACKGROUND: Vaccination is the most effective form of prevention of seasonal influenza; the United Kingdom has a national influenza vaccination program to cover targeted population groups. Influenza vaccines are known to be associated with some common minor adverse events of interest (AEIs), but it is not known if the adjuvanted trivalent influenza vaccine (aTIV), first offered in the 2018/2019 season, would be associated with more AEIs than other types of vaccines. OBJECTIVE: We aim to compare the incidence of AEIs associated with different types of seasonal influenza vaccines offered in the 2018/2019 season. METHODS: We carried out a retrospective cohort study using computerized medical record data from the Royal College of General Practitioners Research and Surveillance Centre sentinel network database. We extracted data on vaccine exposure and consultations for European Medicines Agency-specified AEIs for the 2018/2019 influenza season. We used a self-controlled case series design; computed relative incidence (RI) of AEIs following vaccination; and compared the incidence of AEIs associated with aTIV, the quadrivalent influenza vaccine, and the live attenuated influenza vaccine. We also compared the incidence of AEIs for vaccinations that took place in a practice with those that took place elsewhere. RESULTS: A total of 1,024,160 individuals received a seasonal influenza vaccine, of which 165,723 individuals reported a total of 283,355 compatible symptoms in the 2018/2019 season. Most AEIs occurred within 7 days following vaccination, with a seasonal effect observed. Using aTIV as the reference group, the quadrivalent influenza vaccine was associated with a higher incidence of AEIs (RI 1.46, 95% CI 1.41-1.52), whereas the live attenuated influenza vaccine was associated with a lower incidence of AEIs (RI 0.79, 95% CI 0.73-0.83). No effect of vaccination setting on the incidence of AEIs was observed. CONCLUSIONS: Routine sentinel network data offer an opportunity to make comparisons between safety profiles of different vaccines. Evidence that supports the safety of newer types of vaccines may be reassuring for patients and could help improve uptake in the future.

Pfizer-BioNTech and Oxford AstraZeneca COVID-19 vaccine effectiveness and immune response amongst individuals in clinical risk groups.

Background COVID-19 vaccines approved in the UK are highly effective in general population cohorts, however, data on effectiveness amongst individuals with clinical conditions that place them at increased risk of severe disease are limited. Methods We used GP electronic health record data, sentinel virology swabbing and antibody testing within a cohort of 712 general practices across England to estimate vaccine antibody response and vaccine effectiveness against medically attended COVID-19 amongst individuals in clinical risk groups using cohort and test-negative case control designs. Findings There was no reduction in S-antibody positivity in most clinical risk groups, however reduced S-antibody positivity and response was significant in the immunosuppressed group. Reduced vaccine effectiveness against clinical disease was also noted in the immunosuppressed group; after a second dose, effectiveness was moderate (Pfizer: 59.6%, 95%CI 18.0-80.1%; AstraZeneca 60.0%, 95%CI -63.6-90.2%). Interpretation In most clinical risk groups, immune response to primary vaccination was maintained and high levels of vaccine effectiveness were seen. Reduced antibody response and vaccine effectiveness were seen after 1 dose of vaccine amongst a broad immunosuppressed group, and second dose vaccine effectiveness was moderate. These findings support maximising coverage in immunosuppressed individuals and the policy of prioritisation of this group for third doses.

Sociodemographic disparities in COVID-19 seroprevalence across England in the Oxford RCGP primary care sentinel network.

OBJECTIVES: To monitor changes in seroprevalence of SARS-CoV-2 antibodies in populations over time and between different demographic groups. METHODS: A subset of practices in the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) sentinel network provided serum samples, collected when volunteer patients had routine blood tests. We tested these samples for SARS-CoV-2 antibodies using Abbott (Chicago, USA), Roche (Basel, Switzerland) and/or Euroimmun (Luebeck, Germany) assays, and linked the results to the patients' primary care computerised medical records. We report seropositivity by region and age group, and additionally examined the effects of gender, ethnicity, deprivation, rurality, shielding recommendation and smoking status. RESULTS: We estimated seropositivity from patients aged 18-100 years old, which ranged from 4.1% (95% CI 3.1-5.3%) to 8.9% (95% CI 7.8-10.2%) across the different assays and time periods. We found higher Euroimmun seropositivity in younger age groups, people of Black and Asian ethnicity (compared to white), major conurbations, and non-smokers. We did not observe any significant effect by region, gender, deprivation, or shielding recommendation. CONCLUSIONS: Our results suggest that prior to the vaccination programme, most of the population remained unexposed to SARS-CoV-2.

Co-administration of routine paediatric vaccines in England often deviates from the immunisation schedule.

Vaccine co-administration can facilitate the introduction of new vaccines in immunisation schedules and improve coverage. We analysed real life data to quantify the extent of routine paediatric vaccine co-administrations as recommended and as never recommended in the immunisation schedule in England, and assessed factors for recommended and never recommended vaccine co-administrations. Immunisation data for all scheduled routine paediatric vaccines between 2008 and 2018 was obtained from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We included 6'257'828 doses administered to 1'005'827 children. Twenty-one percent of vaccines were given separately, 79% were co-administered. Sixty-four percent of vaccines scheduled for co-administration were co-administered as recommended while 15% were administered separately. Among all vaccine co-administrations, 75% happened as recommended in the schedule, 4% were never recommended, while 21% deviated from the schedule. Vaccine co-administration according to the schedule varied greatly between vaccines. Forty-eight percent of English children received at least one of their vaccine co-administrations not as recommended in the immunisation schedule, with 19% of children receiving none of their co-administered vaccines as recommended. Late administration of one or more vaccines increased the odds for deviated co-administrations (OR 1.60) and strongly increased the odds for never recommended co-administrations (OR 5.34). Differences between genders, NHS regions, and IMD quintiles were statistically significant but small. Suboptimal co-administration rates for routine paediatric vaccines are a missed opportunity and should be optimised by concerted public health action.

Adherence to the paediatric immunisation schedule in England.

Both adequate coverage and adherence to paediatric immunisation schedules are required for optimal protection against vaccine preventable diseases. We studied the timeliness of routine paediatric vaccinations according to the NHS's immunisation schedule and potential factors of schedule adherence. Immunisation data was obtained from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). We collected vaccine types, doses, and dates for all routine paediatric vaccines between 2008 and 2018: DTaP/IPV/Hib/HepB, DTaP/IPV/Hib, DTaP/IPV, dTaP/IPV, Td/IPV, MMR, PCV, MenB, MenC, MenACWY, Hib/MenC, RV, HPV. Adherence to the immunisation schedule was calculated for each vaccine and dose. Differences in adherence between genders, NHS regions, and IMD quintiles were analysed. Our study included 6'257'828 vaccinations in 1'005'827 children. Seventy-five percent of first doses were administered within one (for vaccines scheduled in the first year of life) or two months (for vaccines scheduled later in life) following the recommended age, 19% too late and 6% too early. About half of the subsequent doses were given timely. The time between first and second doses was too short for 36% of vaccinations while 13% of second doses were administered too long after the first dose. Third doses were administered timely for 45%, too short for 37%, and too long for 18% of vaccinations. Differences in immunisation schedule adherence between girls and boys were negligible, except for HPV, and differences between the four main NHS regions were small. Overall, immunisation schedule adherence improved slightly with decreasing deprivation according to the Index of Multiple Deprivation. Efforts are required to improve the timeliness of paediatric vaccinations and to assure adequate protection against vaccine preventable diseases. We propose developing a compound measure combining coverage and adherence to provide a better indication of the protection against vaccine preventable diseases in a community.

PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship: a retrospective sentinel network cohort study.

BACKGROUND: The Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) has provided in-pandemic evidence that azithromycin and doxycycline were not beneficial in the early primary care management of coronavirus 2019 disease (COVID-19). AIM: To explore the extent of in-pandemic azithromycin and doxycycline use, and the scope for trial findings impacting on practice. DESIGN & SETTING: Crude rates of prescribing and respiratory tract infections (RTI) in 2020 were compared with 2019, using the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). METHOD: Negative binomial models were used to compare azithromycin and doxycycline prescribing, lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), and influenza-like illness (ILI) in 2020 with 2019; reporting incident rate ratios (IRR) between years, and 95% confidence intervals (95% CI). RESULTS: Azithromycin prescriptions increased 7% in 2020 compared with 2019, whereas doxycycline decreased by 7%. Concurrently, LRTI and URTI incidence fell by over half (58.3% and 54.4%, respectively) while ILI rose slightly (6.4%). The overall percentage of RTI-prescribed azithromycin rose from 0.51% in 2019 to 0.72% in 2020 (risk difference 0.214%; 95% CI = 0.211 to 0.217); doxycycline rose from 11.86% in 2019 to 15.79% in 2020 (risk difference 3.93%; 95% CI = 3.73 to 4.14). The adjusted IRR showed azithromycin prescribing was 22% higher in 2020 (IRR = 1.22; 95% CI = 1.19 to 1.26; P<0.0001). For every unit rise in confirmed COVID-19 there was an associated 3% rise in prescription (IRR = 1.03; 95% CI = 1.02 to 1.03; P<0.0001); whereas these measures were static for doxycycline. CONCLUSION: PRINCIPLE demonstrates scope for improved antimicrobial stewardship during a pandemic.

Diabetic retinopathy in newly diagnosed Type 2 diabetes mellitus: Prevalence and predictors of progression; a national primary network study.

AIMS: To determine, inreal-world primary care settings, the prevalence of, and risk factors for, retinopathy atType 2 diabetes mellitus diagnosis and report cumulative incidence and progression of retinopathy seven years after diabetes diagnosis. METHODS: Retrospective cohort analysis of people with newly diagnosed Type 2 diabetesrecorded bythe Royal College of General Practitioners Research and Surveillance Centre(between 2005 and 2009, n=11,399).Outcomes included; retinopathy prevalence atdiabetesdiagnosis (baseline) and cumulative incidence or progression of retinopathy at seven years. Retinopathy prevalence was compared with the United Kingdom Prospective Diabetes Study (UKPDS-1998). Factors influencing retinopathy incidence and progression were analysed using logistic regression. RESULTS: Baseline retinopathy prevalencewas 18% (n=2,048) versus 37% in UKPDS. At seven years, 11.6% (n=237) of those with baseline retinopathyhad progression of retinopathy. In those without baseline retinopathy, 46.4% (n=4,337/9,351) developed retinopathy by seven years. Retinopathy development (OR: 1.05 [95%CI: 1.02-1.07] per mmol/mol increase) and progression (OR: 1.05 [1.04-1.06]) at seven years was associated with higher HbA1catdiabetesdiagnosis. Obesity (OR: 0.88 [0.79-0.98]) and high socioeconomic status (OR: 0.63 [0.53-0.74]) were negatively associated with retinopathy development at seven years. CONCLUSIONS: Baseline retinopathy prevalence has declined since UKPDS. Additionally, HbA1c at diabetes diagnosis remains important for retinopathy development and progression.