George Hickman

Master transcription factor reprograming unleashes selective translation promoting castration resistance and immune evasion in lethal prostate cancer.

Publisher: American Association for Cancer Research (AACR)

Date: 07-09-2023

DOI: 10.1158/2159-8290.CD-23-0306

Changes in COVID-19-related mortality across key demographic and clinical subgroups: an observational cohort study using the OpenSAFELY platform on 18 million adults in England

Publisher: Cold Spring Harbor Laboratory

Date: 02-08-2022

DOI: 10.1101/2022.07.30.22278161

Abstract: To quantify in absolute and relative terms how population-level COVID-19 death rates have changed in demographic and clinical subgroups. Retrospective cohort study on behalf of NHS England. Linked primary care and death registry data from the OpenSAFELY-TPP platform, covering the first three pandemic waves in England (wave 1: March 23 to May 30, 2020 wave 2: September 7, 2020 to April 24, 2021 and wave 3, delta: May 28 to December 14, 2021). In total, 18.7, 18.8, and 18.7 million adults were included for waves 1, 2, and 3 respectively. COVID-19-related mortality based on linked death registry records. The crude absolute COVID-19-related death rate per 1,000 person-years decreased from 4.48 in wave 1 (95%CI 4.41 .55), to 2.70 in wave 2 (95%CI 2.67 .73), to 0.64 in wave 3 (95%CI 0.63 .66). The absolute death rate decreased by 90% between waves 1 and 3 in patients aged 80+, but by only 20% in patients aged 18-39. This higher proportional reduction in age- and sex-standardised death rates was also seen for other groups, such as neurological disease, learning disability and severe mental illness. Conversely, standardised death rates in transplant recipients stayed constant across successive waves at 10 per 1,000 person-years. There was also only a small decrease in death rates between waves in people with kidney disease, haematological malignancies or conditions associated with immunosuppression. Consequently, the relative hazard of COVID-19-related death decreased over time for some variables (e.g. age), remained similar for some (e.g. sex, ethnicity), and increased for others (e.g. transplant). COVID-19 death rates decreased over the first three pandemic waves. An especially large decrease was seen in older age groups and people with neurological disease, learning disability or severe mental illness. Some demographic inequalities in death rates persisted over time. Groups more likely to experience impaired vaccine effectiveness did not see the same benefit in COVID-19 mortality reduction.

Comparative effectiveness of ChAdOx1 versus BNT162b2 covid-19 vaccines in health and social care workers in England: cohort study using OpenSAFELY

Publisher: BMJ

Date: 20-07-2022

DOI: 10.1136/BMJ-2021-068946

Abstract: To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) covid-19 vaccines against infection and covid-19 disease in health and social care workers. Cohort study, emulating a comparative effectiveness trial, on behalf of NHS England. Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 Alpha variant was dominant. 317 341 health and social care workers vaccinated between 4 January and 28 February 2021, registered with a general practice using the TPP SystmOne clinical information system in England, and not clinically extremely vulnerable. Vaccination with either BNT162b2 or ChAdOx1 administered as part of the national covid-19 vaccine roll-out. Recorded SARS-CoV-2 positive test, or covid-19 related attendance at an accident and emergency (A& E) department or hospital admission occurring within 20 weeks of receipt of the first vaccine dose. Over the duration of 118 771 person-years of follow-up there were 6962 positive SARS-CoV-2 tests, 282 covid-19 related A& E attendances, and 166 covid-19 related hospital admissions. The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks after vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 20 weeks after first-dose vaccination with BNT162b2 was 21.7 per 1000 people (95% confidence interval 20.9 to 22.4) and with ChAdOx1 was 23.7 (21.8 to 25.6), representing a difference of 2.04 per 1000 people (0.04 to 4.04). The difference in the cumulative incidence per 1000 people of covid-19 related A& E attendance at 20 weeks was 0.06 per 1000 people (95% CI −0.31 to 0.43). For covid-19 related hospital admission, this difference was 0.11 per 1000 people (−0.22 to 0.44). In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or covid-19 disease up to 20 weeks after vaccination. Incidence dropped sharply at 3-4 weeks after vaccination, and there were few covid-19 related hospital attendance and admission events after this period. This is in line with expected onset of vaccine induced immunity and suggests strong protection against Alpha variant covid-19 disease for both vaccines in this relatively young and healthy population of healthcare workers.

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY

Publisher: OpenSAFELY

Date: 2021

DOI: 10.53764/RPT.3917AB5AC5

Abstract: This OpenSAFELY report is a routine update of our peer-review paper published in the British Journal of General Practice on the Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY. It is a routine update of the analysis described in the paper. The data requires careful interpretation and there are a number of caveats. Please read the full detail about our methods and discussionis and the full analytical methods on this routine report are available on GitHub. OpenSAFELY is a new secure analytics platform for electronic patient records built on behalf of NHS England to deliver urgent academic and operational research during the pandemic. You can read more about OpenSAFELY on our website.

Identifying Care Home Residents in Electronic Health Records - An OpenSAFELY Short Data Report

Publisher: F1000 Research Ltd

Date: 27-04-2021

DOI: 10.12688/WELLCOMEOPENRES.16737.1

Abstract: Background: Care home residents have been severely affected by the COVID-19 pandemic. Electronic Health Records (EHR) hold significant potential for studying the healthcare needs of this vulnerable population however, identifying care home residents in EHR is not straightforward. We describe and compare three different methods for identifying care home residents in the newly created OpenSAFELY-TPP data analytics platform. Methods: Working on behalf of NHS England, we identified in iduals aged 65 years or older potentially living in a care home on the 1st of February 2020 using (1) a complex address linkage, in which cleaned GP registered addresses were matched to old age care home addresses using data from the Care and Quality Commission (CQC) (2) coded events in the EHR (3) household identifiers, age and household size to identify households with more than 3 in iduals aged 65 years or older as potential care home residents. Raw addresses were not available to the investigators. Results: Of 4,437,286 in iduals aged 65 years or older, 2.27% were identified as potential care home residents using the complex address linkage, 1.96% using coded events, 3.13% using household size and age and 3.74% using either of these methods. 53,210 in iduals (32.0% of all potential care home residents) were classified as care home residents using all three methods. Address linkage had the largest overlap with the other methods 93.3% of in iduals identified as care home residents using the address linkage were also identified as such using either coded events or household age and size. Conclusion: We have described the partial overlap between three methods for identifying care home residents in EHR, and provide detailed instructions for how to implement these in OpenSAFELY-TPP to support research into the impact of the COVID-19 pandemic on care home residents.

The impact of COVID-19 on medication reviews in English primary care. An OpenSAFELY-TPP analysis of 20 million adult electronic health records

Publisher: Cold Spring Harbor Laboratory

Date: 31-07-2023

DOI: 10.1101/2023.07.31.23293419

Abstract: The COVID-19 pandemic caused significant disruption to routine activity in primary care. Medication reviews are an important primary care activity to ensure safety and appropriateness of ongoing prescribing and a disruption could have significant negative implications for patient care. Using routinely collected data, our aim was to i) describe the SNOMED CT codes used to report medication review activity ii) report the impact of COVID-19 on the volume and variation of medication reviews. With the approval of NHS England, we conducted a cohort study of 20 million adult patient records in general practice, in-situ using the OpenSAFELY platform. For each month between April 2019 - March 2022, we report the percentage of patients with a medication review coded monthly and in the previous 12 months. These measures were broken down by regional, clinical and demographic subgroups and amongst those prescribed high risk medications. In April 2019, 32.3% of patients had a medication review coded in the previous 12 months. During the first COVID-19 lockdown, monthly activity substantially decreased (−21.1% April 2020), but the rate of patients with a medication review coded in the previous 12 months was not substantially impacted according to our classification (−10.5% March 2021). There was regional and ethnic variation (March 2022 - London 21.9% vs North West 33.6% Chinese 16.8% vs British 33.0%). Following the introduction of “structured medication reviews”, the rate of structured medication review in the last 12 months reached 2.9% by March 2022, with higher percentages in high risk groups (March 2022 - care home residents 34.1%, 90+ years 13.1%, high risk medications 10.2%). The most used SNOMED CT medication review code across the study period was Medication review done - 314530002 (59.5%). We have reported a substantial reduction in the monthly rate of medication reviews during the pandemic but rates recovered by the end of the study period.

Waning effectiveness of BNT162b2 and ChAdOx1 covid-19 vaccines over six months since second dose: OpenSAFELY cohort study using linked electronic health records

Publisher: BMJ

Date: 20-07-2022

DOI: 10.1136/BMJ-2022-071249

Abstract: To estimate waning of covid-19 vaccine effectiveness over six months after second dose. Cohort study, approved by NHS England. Linked primary care, hospital, and covid-19 records within the OpenSAFELY-TPP database. Adults without previous SARS-CoV-2 infection were eligible, excluding care home residents and healthcare professionals. People who had received two doses of BNT162b2 or ChAdOx1 (administered during the national vaccine rollout) were compared with unvaccinated people during six consecutive comparison periods, each of four weeks. Adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, positive SARS-CoV-2 test, and non-covid-19 related death comparing vaccinated with unvaccinated people. Waning vaccine effectiveness was quantified as ratios of adjusted hazard ratios per four week period, separately for subgroups aged ≥65 years, 18-64 years and clinically vulnerable, 40-64 years, and 18-39 years. 1 951 866 and 3 219 349 eligible adults received two doses of BNT162b2 and ChAdOx1, respectively, and 2 422 980 remained unvaccinated. Waning of vaccine effectiveness was estimated to be similar across outcomes and vaccine brands. In the ≥65 years subgroup, ratios of adjusted hazard ratios for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test ranged from 1.19 (95% confidence interval 1.14 to 1.24) to 1.34 (1.09 to 1.64) per four weeks. Despite waning vaccine effectiveness, rates of covid-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2, and ≥75% for ChAdOx1. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than in unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2 and 1.86 (1.79 to 1.93) for ChAdOx1). The rate at which estimated vaccine effectiveness waned was consistent for covid-19 related hospital admission, covid-19 related death, and positive SARS-CoV-2 test and was similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination.

OpenSAFELY: The impact of COVID-19 on azathioprine, leflunomide, and methotrexate monitoring, and factors associated with change in monitoring rate

Publisher: Cold Spring Harbor Laboratory

Date: 07-06-2023

DOI: 10.1101/2023.06.06.23290826

Abstract: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study aimed to investigate if disease-modifying anti-rheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic. A population-based cohort study was conducted with the approval of NHS England, using the OpenSAFELY platform to access electronic health record data from 24·2 million patients registered at general practices using TPP’s SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide, or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations. An acute increase in the rate of missed monitoring occurred across the study population (+12·4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70-79 year-olds: +13·7 percentage points females: +12·8 percentage points), regions (North West: +17·0 percentage points), medications (Leflunomide: +20·7 percentage points), and monitoring tests (Blood Pressure: +24·5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Substantial and consistent differences were observed in overall missed monitoring rates between several groups throughout the study. DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions, and patient groups, highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should aim to evaluate the causes of the differences identified between groups. None. Disease-modifying anti-rheumatic drugs (DMARDs) are immunosuppressive and/or immunomodulatory drugs, which carry risks of serious adverse effects such as gastrointestinal, renal, hepatic, and pulmonary toxicity myelosuppression and increased susceptibility to infection. To mitigate these safety risks, national safety guidance recommends that patients taking these drugs receive regular monitoring. We searched PubMed, Web of Science and Scopus for studies published between database inception and July 28th, 2022, using the terms ([covid-19] AND [monitoring OR shared care OR dmard OR outcome factors] AND [primary care]), with no language restrictions. Studies that investigated the effect of the COVID-19 pandemic on healthcare services were identified. One key study in England showed disruption to various monitoring services in primary care had occurred during the pandemic. Another English study highlighted a disproportionate impact of the COVID-19 pandemic on health outcomes in certain groups. Prior to this study knowledge of how high-risk drugs, such as DMARDs, were affected by the COVID-19 pandemic was limited. This study reports the impact of COVID-19 on the safety monitoring of DMARDs. Moreover, it reports variation in DMARD monitoring rates between demographic, clinical and regional subgroups, which has not yet been described. This is enabled through use of the OpenSAFELY platform, which provides secure access to pseudonymised primary care patient records in England for the purposes of analysing the COVID-19 pandemic impact. DMARD monitoring rates transiently deteriorated during the COVID-19 pandemic, consistent with previous research on other monitoring tests. Deterioration coincided with the onset of lockdown measures, with performance recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between demographic, clinical and regional subgroups highlight opportunities to identify and tackle potential inequalities in the provision or uptake of monitoring services. Further research should aim to evaluate the causes of the differences identified between groups, and establish the clinical relevance of missed monitoring. Several studies have demonstrated the capability of the OpenSAFELY platform as a secure and efficient approach for analysing NHS primary care data at scale, generating meaningful insights on service delivery.

Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP

Publisher: Cold Spring Harbor Laboratory

Date: 06-06-2022

DOI: 10.1101/2022.06.06.22276026

Abstract: The UK COVID-19 vaccination programme delivered its first “booster” doses in September 2021, initially in groups at high risk of severe disease then across the adult population. The BNT162b2 Pfizer-BioNTech vaccine was used initially, with Moderna mRNA-1273 subsequently also used. We used the OpenSAFELY-TPP database, covering 40% of English primary care practices and linked to national coronavirus surveillance, hospital episodes, and death registry data, to estimate the effectiveness of boosting with BNT162b2 compared with no boosting in eligible adults who had received two primary course vaccine doses between 16 September and 16 December 2021 when the Delta variant of SARS-CoV-2 was dominant. Follow up was for up to 10 weeks. Each booster recipient was matched with an unboosted control on factors relating to booster priority status and prior immunisation. Additional factors were adjusted for in Cox models estimating hazard ratios (HRs). Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, COVID-19 death and non-COVID-9 death. Booster vaccine effectiveness was defined as 1−HR. Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was 50.7% (95% CI 50.1-51.3) for positive SARS-CoV-2 test, 80.1% (78.3-81.8) for COVID-19 hospitalisation, 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death. Estimated effectiveness was similar among those who had received a BNT162b2 or ChAdOx1-S two-dose primary vaccination course, but effectiveness against severe COVID-19 was slightly lower in those classified as clinically extremely vulnerable (76.3% (73.1-79.1) for COVID-19 hospitalisation, and 85.1% (79.6-89.1) for COVID-19 death). Estimated effectiveness against each outcome was lower in those aged 18-65 years than in those aged 65 and over. Our findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.

Recording of ’COVID-19 vaccine declined‘: a cohort study on 57.9 million National Health Service patients’ records in situ using OpenSAFELY, England, 8 December 2020 to 25 May 2021

Publisher: European Centre for Disease Control and Prevention (ECDC)

Date: 18-08-2022

DOI: 10.2807/1560-7917.ES.2022.27.33.2100885

Abstract: Priority patients in England were offered COVID-19 vaccination by mid-April 2021. Codes in clinical record systems can denote the vaccine being declined. We describe records of COVID-19 vaccines being declined, according to clinical and demographic factors. With the approval of NHS England, we conducted a retrospective cohort study between 8 December 2020 and 25 May 2021 with primary care records for 57.9 million patients using OpenSAFELY, a secure health analytics platform. COVID-19 vaccination priority patients were those aged ≥ 50 years or ≥ 16 years clinically extremely vulnerable (CEV) or ’at risk’. We describe the proportion recorded as declining vaccination for each group and stratified by clinical and demographic subgroups, subsequent vaccination and distribution of clinical code usage across general practices. Of 24.5 million priority patients, 663,033 (2.7%) had a decline recorded, while 2,155,076 (8.8%) had neither a vaccine nor decline recorded. Those recorded as declining, who were subsequently vaccinated (n = 125,587 18.9%) were overrepresented in the South Asian population (32.3% vs 22.8% for other ethnicities aged ≥ 65 years). The proportion of declining unvaccinated patients was highest in CEV (3.3%), varied strongly with ethnicity (black 15.3%, South Asian 5.6%, white 1.5% for ≥ 80 years) and correlated positively with increasing deprivation. Clinical codes indicative of COVID-19 vaccinations being declined are commonly used in England, but substantially more common among black and South Asian people, and in more deprived areas. Qualitative research is needed to determine typical reasons for recorded declines, including to what extent they reflect patients actively declining.

Comparative effectiveness of ChAdOx1 versus BNT162b2 COVID-19 vaccines in Health and Social Care workers in England: a cohort study using OpenSAFELY

Publisher: Cold Spring Harbor Laboratory

Date: 18-10-2021

DOI: 10.1101/2021.10.13.21264937

Abstract: To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) COVID-19 vaccines against infection and COVID-19 disease in health and social care workers. Cohort study, emulating a comparative effectiveness trial. Linked primary care, hospital, and COVID-19 surveillance records available within the OpenSAFELY-TPP research platform. 317,341 health and social care workers vaccinated between 4 January and 28 February 2021, registered with a GP practice using the TPP SystmOne clinical information system in England, and not clinically extremely vulnerable. Vaccination with either BNT162b2 or ChAdOx1 administered as part of the national COVID-19 vaccine roll-out. Recorded SARS-CoV-2 positive test, or COVID-19 related Accident and Emergency attendance or hospital admission occurring within 20 weeks of vaccination. The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks post-vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 6 weeks after vaccination with BNT162b2 was 19.2 per 1000 people (95%CI 18.6 to 19.7) and with ChAdOx1 was 18.9 (95%CI 17.6 to 20.3), representing a difference of -0.24 per 1000 people (95%CI -1.71 to 1.22). The difference in the cumulative incidence per 1000 people of COVID-19 accident and emergency attendance at 6 weeks was 0.01 per 1000 people (95%CI -0.27 to 0.28). For COVID-19 hospital admission, this difference was 0.03 per 1000 people (95%CI -0.22 to 0.27). In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or COVID-19 disease up to 20 weeks after vaccination. Incidence dropped sharply after 3-4 weeks and there were very few COVID-19 hospital attendance and admission events after this period. This is in line with expected onset of vaccine-induced immunity, and suggests strong protection against COVID-19 disease for both vaccines.

Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: A cohort study from OpenSAFELY

Publisher: Cold Spring Harbor Laboratory

Date: 08-11-2021

DOI: 10.1101/2021.11.08.21265380

Abstract: While the vaccines against COVID-19 are considered to be highly effective, COVID-19 vaccine breakthrough is likely and a small number of people will still fall ill, be hospitalised, or die from COVID-19, despite being fully vaccinated. With the continued increase in numbers of positive SARS-CoV-2 tests, describing the characters of in iduals who have experienced a COVID-19 vaccine breakthrough could be hugely important in helping to determine who may be at greatest risk. With the approval of NHS England we conducted a retrospective cohort study using routine clinical data from the OpenSAFELY TPP database of fully vaccinated in iduals, linked to secondary care and death registry data, and described the characteristics of those experiencing a COVID-19 vaccine breakthrough. As of 01 st November 2021, a total of 15,436,455 in iduals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: 107-179). From within this population, a total of 577245 ( %) in iduals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate was 98.02 (95% CI 97.9-98.15). There were 16,120 COVID-19-related hospital admissions, 1,100 COVID-19 critical care admission patients and 3,925 COVID-19-related deaths corresponding incidence rates of 2.72 (95% C 2.7-2.74), 0.19 (95% C 0.18-0.19) and 0.66 (95% C 0.65-0.67), respectively. When broken down by the initial priority group, higher rates of hospitalisation and death were seen in those in care homes and those over 80 years of age. Comorbidities with the highest rates of breakthrough COVID-19 included chronic kidney disease, dialysis, transplant, haematological malignancy, and immunocompromised. The majority of COVID-19 vaccine breakthrough cases in England were mild with relatively few fully vaccinated in iduals being hospitalised or dying as a result. However, some concerning differences in rates of breakthrough cases were identified in several clinical and demographic groups. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the continued increase in numbers of positive SARS-CoV-2 tests are concerning. As numbers of fully vaccinated in iduals increases and follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, aimed at identifying in iduals at higher risk, are therefore required.

A comprehensive high cost drugs dataset from the NHS in England - An OpenSAFELY-TPP Short Data Report

Publisher: F1000 Research Ltd

Date: 22-12-2021

DOI: 10.12688/WELLCOMEOPENRES.17360.1

Abstract: Background: At the outset of the COVID-19 pandemic, there was no routine comprehensive hospital medicines data from the UK available to researchers. These records can be important for many analyses including the effect of certain medicines on the risk of severe COVID-19 outcomes. With the approval of NHS England, we set out to obtain data on one specific group of medicines, “high-cost drugs” (HCD) which are typically specialist medicines for the management of long-term conditions, prescribed by hospitals to patients. Additionally, we aimed to make these data available to all approved researchers in OpenSAFELY-TPP. This report is intended to support all studies carried out in OpenSAFELY-TPP, and those elsewhere, working with this dataset or similar data. Methods: Working with the North East Commissioning Support Unit and NHS Digital, we arranged for collation of a single national HCD dataset to help inform responses to the COVID-19 pandemic. The dataset was developed from payment submissions from hospitals to commissioners. Results: In the financial year (FY) 2018/19 there were 2.8 million submissions for 1.1 million unique patient IDs recorded in the HCD. The average number of submissions per patient over the year was 2.6. In FY 2019/20 there were 4.0 million submissions for 1.3 million unique patient IDs. The average number of submissions per patient over the year was 3.1. Of the 21 variables in the dataset, three are now available for analysis in OpenSafely-TPP: Financial year and month of drug being dispensed drug name and a description of the drug dispensed. Conclusions: We have described the process for sourcing a national HCD dataset, making these data available for COVID-19-related analysis through OpenSAFELY-TPP and provided information on the variables included in the dataset, data coverage and an initial descriptive analysis.

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment

Publisher: American Society for Clinical Investigation

Date: 04-2022

DOI: 10.1172/JCI148667

Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.CELL.2012.02.030

Rates of serious clinical outcomes in survivors of hospitalisation with COVID-19 in England: a descriptive cohort study within the OpenSAFELY platform

Publisher: F1000 Research Ltd

Date: 29-04-2022

DOI: 10.12688/WELLCOMEOPENRES.17735.1

Abstract: Background: Patients surviving hospitalisation for COVID-19 are thought to be at high risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in people after discharge from hospital with COVID-19. Methods: Working on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following pre-pandemic hospitalisation with pneumonia, and a frequency-matched cohort from the general population in 2019. We studied seven outcomes: deep vein thrombosis (DVT), pulmonary embolism (PE), ischaemic stroke, myocardial infarction (MI), heart failure, AKI and new type 2 diabetes mellitus (T2DM) diagnosis. Absolute rates were measured in each cohort and Fine and Gray models were used to estimate age/sex adjusted subdistribution hazard ratios comparing outcome risk between discharged COVID-19 patients and the two comparator cohorts. Results: Amongst the population of 77,347 patients discharged following hospitalisation with COVID-19, rates for the majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly higher risk of all outcomes compared to matched controls from the 2019 general population. Across the whole study period, the risk of outcomes was more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had higher risk of T2DM (15.2 versus 37.2 [rate per 1,000-person-years for COVID-19 versus pneumonia, respectively] SHR, 1.46 [95% CI: 1.31 - 1.63]). Conclusions: Risk of cardiometabolic and pulmonary adverse outcomes is markedly raised following discharge from hospitalisation with COVID-19 compared to the general population. However, excess risks were similar to those seen following discharge post-pneumonia. Overall, this suggests a large additional burden on healthcare resources.

Stromal Oncostatin M axis promotes breast cancer progression

Publisher: Cold Spring Harbor Laboratory

Date: 30-10-2020

DOI: 10.1101/2020.10.30.356774

Abstract: Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression 1,2 . However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform

Publisher: Cold Spring Harbor Laboratory

Date: 10-09-2021

DOI: 10.1101/2021.09.03.21262888

Abstract: It is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes. With the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysingroutinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate). We identified 17,672,065 adults of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in in iduals with IMIDs overall compared to in iduals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56) however, this finding may relate to confounding. COVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics. We searched PubMed on May 19 th , 2021, using the terms “COVID-19”, “SARS-CoV-2” and “rheumatoid arthritis”, “psoriatic arthritis” “ankylosing spondylitis”, “Crohn’s disease” “ulcerative colitis” “hidradenitis suppurativa” and “psoriasis”, to identify primary research articles examining severe COVID-19 outcome risk in in iduals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small s le sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease-specific registries are subject to selection bias and lack denominator populations. In our large population-based study of 17 million in iduals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35). Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small. This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medications Our study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for in iduals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records

Publisher: Cold Spring Harbor Laboratory

Date: 23-03-2022

DOI: 10.1101/2022.03.23.22272804

Abstract: The rate at which COVID-19 vaccine effectiveness wanes over time is crucial for vaccination policies, but is incompletely understood with conflicting results from different studies. This cohort study, using the OpenSAFELY-TPP database and approved by NHS England, included in iduals without prior SARS-CoV-2 infection assigned to vaccines priority groups 2-12 defined by the UK Joint Committee on Vaccination and Immunisation. We compared in iduals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated in iduals during six 4-week comparison periods, separately for subgroups aged 65+ years 16-64 years and clinically vulnerable 40-64 years and 18-39 years. We used Cox regression, stratified by first dose eligibility and geographical region and controlled for calendar time, to estimate adjusted hazard ratios (aHRs) comparing vaccinated with unvaccinated in iduals, and quantified waning vaccine effectiveness as ratios of aHRs per-4-week period. The outcomes were COVID-19 hospitalisation, COVID-19 death, positive SARS-CoV-2 test, and non-COVID-19 death. The BNT162b2, ChAdOx1 and unvaccinated groups comprised 1,773,970, 2,961,011 and 2,433,988 in iduals, respectively. Waning of vaccine effectiveness was similar across outcomes and vaccine brands: e.g. in the 65+ years subgroup ratios of aHRs versus unvaccinated for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test ranged from 1.23 (95% CI 1.15-1.32) to 1.27 (1.20-1.34) for BNT162b2 and 1.16 (0.98-1.37) to 1.20 (1.14-1.27) for ChAdOx1. Despite waning, rates of COVID-19 hospitalisation and COVID-19 death were substantially lower among vaccinated in iduals compared to unvaccinated in iduals up to 26 weeks after second dose, with estimated aHRs .20 ( % vaccine effectiveness) for BNT162b2, and .26 ( %) for ChAdOx1. By weeks 23-26, rates of SARS-CoV-2 infection in fully vaccinated in iduals were similar to or higher than those in unvaccinated in iduals: aHRs ranged from 0.85 (0.78-0.92) to 1.53 (1.07-2.18) for BNT162b2, and 1.21 (1.13-1.30) to 1.99 (1.94-2.05) for ChAdOx1. The rate at which estimated vaccine effectiveness waned was strikingly consistent for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test, and similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the Omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination doses.

University Of Oxford University College Oxford

Location: United Kingdom of Great Britain and Northern Ireland

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University Of Oxford

Location: United Kingdom of Great Britain and Northern Ireland

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Universidad Del País Vasco Facultad De Ciencia Y Tecnología

Location: Spain

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Beth Israel Deaconess Medical Center

Location: United States of America

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Centro De Investigación Cooperativa En Biociencias

Location: Spain

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Fomento De Construcciones Y Contratas SA

Location: Spain

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Ikerbasque, Basque Foundation For Science

Location: Spain

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Memorial Sloan Kettering Cancer Center

Location: United States of America

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Universidad Complutense De Madrid

Location: Spain

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Universidad Del País Vasco

Location: Spain

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Ikerbasque, Basque Foundation For Science

Location: No location found

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