Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

National data about mortality in people with ID provides a basis for public health interventions. Linked data using GP records to identify people with ID could provide comprehensive population-based monitoring in England, unbiased by the circumstances of illnesses or death; to date information governance constraints have prevented this. However, GPs in England currently identify only around 0.5% of the population as having ID, suggesting that individuals with mild, non-syndromic ID are largely missed. Notably common causes of death suggest control of cardiovascular risk factors, epilepsy and dysphagia, management of thrombotic risks and colorectal screening are important areas for health promotion initiatives.

A prospective validation study was conducted in 171 consenting patients from oncology and palliative care outpatient clinics to validate the Distress Thermometer (DT) against the Hospital Anxiety and Depression Scale (HADS), General Health Questionnaire-12 (GHQ-12) and Brief Symptom Inventory-18 (BSI-18) at baseline, four weeks and eight weeks. Receiver Operating Characteristic analysis was used to examine the sensitivity and specificity of the DT scores against the clinically significant cut-off scores of the criterion measures reporting 95% confidence intervals. Standardised response means were used to compare DT scores with criterion measures over time. For a cut-off of 4 vs 5, sensitivity against HADS was 79%, specificity 81%; against GHQ-12, sensitivity was 63%, specificity 83%; and against BSI-18, sensitivity was 88%, specificity 74%. At both four and eight weeks, DT scores tended to change significantly in the same direction as the criterion measures. Ninety-five percent of patients found completing the DT acceptable. The DT is valid and acceptable for use as a rapid screening instrument for patients in the UK with cancer. Our results indicate that it can be used to monitor change in psychological distress over time, but further work is needed to confirm this.

LMO4 belongs to a family of LIM-only transcriptional regulators, the first two members of which are oncoproteins in acute T cell leukemia. We have explored a role for LMO4, initially described as a human breast tumor autoantigen, in developing mammary epithelium and breast oncogenesis. Lmo4 was expressed predominantly in the lobuloalveoli of the mammary gland during pregnancy. Consistent with a role in proliferation, forced expression of this gene inhibited differentiation of mammary epithelial cells. Overexpression of LMO4 mRNA was observed in 5 of 10 human breast cancer cell lines. Moreover, in situ hybridization analysis of 177 primary invasive breast carcinomas revealed overexpression of LMO4 in 56% of specimens. Immunohistochemistry confirmed overexpression in a high percentage (62%) of tumors. These studies imply a role for LMO4 in maintaining proliferation of mammary epithelium and suggest that deregulation of this gene may contribute to breast tumorigenesis.

BackgroundWe aimed to systematically review the evidence on adverse mental health outcomes in breast cancer survivors (≥1 year) compared with women with no history of cancer.MethodsStudies were identified by searching MEDLINE, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and the Social Sciences Citation Index, and through backward citation tracking. Two researchers selected the studies, extracted data, and assessed the risk of bias.ResultsSixty studies were included. Of 38 studies of depression, 33 observed more depression in breast cancer survivors; this was statistically significant in 19 studies overall, including six of seven where depression was ascertained clinically, three of four studies of antidepressants, and 13 of 31 that quantified depressive symptoms. Of 21 studies of anxiety, 17 observed more anxiety in breast cancer survivors, statistically significant in 11 studies overall, including two of four with clinical/prescription-based outcomes, and in eight of 17 of anxiety symptoms. Breast cancer survivors also had statistically significantly increased symptoms/frequency of neurocognitive dysfunction (18 of 24 studies), sexual dysfunctions (5 of 6 studies), sleep disturbance (5 of 5 studies), stress-related disorders/PTSD (2 of 3 studies), suicide (2 of 2 studies), somatisation (2 of 2 studies), and bipolar and obsessive-compulsive disorders (1 of 1 study each). Studies were heterogeneous in terms of participants’ characteristics, time since diagnosis, ascertainment of outcomes, and measures reported. Approximately one-half of the studies were at high risk of selection bias and confounding by socio-economic status.ConclusionsThere is compelling evidence of an increased risk of anxiety, depression and suicide, and neurocognitive and sexual dysfunctions in breast cancer survivors compared with women with no prior cancer. This information can be used to support evidence-based prevention and management strategies. Further population-based and longitudinal research would help to better characterize these associations.

Record linkage is increasingly used to expand the information available for public health research. An understanding of record linkage methods and the relevant strengths and limitations is important for robust analysis and interpretation of linked data. Here, we describe the approach used by Clinical Practice Research Datalink (CPRD) to link primary care data to other patient level datasets, and the potential implications of this approach for CPRD data analysis. General practice electronic health record software providers separately submit de-identified data to CPRD and patient identifiers to NHS Digital, excluding patients who have opted-out from contributing data. Data custodians for external datasets also send patient identifiers to NHS Digital. NHS Digital uses identifiers to link the datasets using an 8-stage deterministic methodology. CPRD subsequently receives a de-identified linked cohort file and provides researchers with anonymised linked data and metadata detailing the linkage process. This methodology has been used to generate routine primary care linked datasets, including data from Hospital Episode Statistics, Office for National Statistics and National Cancer Registration and Analysis Service. 10.6 million (M) patients from 411 English general practices were included in record linkage in June 2018. 9.1M (86%) patients were of research quality, of which 8.0M (88%) had a valid NHS number and were eligible for linkage in the CPRD standard linked dataset release. Linking CPRD data to other sources improves the range and validity of research studies. This manuscript, together with metadata generated on match strength and linkage eligibility, can be used to inform study design and explore potential linkage-related selection and misclassification biases.

Purpose Primary care databases are increasingly used for researching pregnancy, eg, the effects of maternal drug exposures. However, ascertaining pregnancies, their timing, and outcomes in these data is challenging. While individual studies have adopted different methods, no systematic approach to characterise all pregnancies in a primary care database has yet been published. Therefore, we developed a new algorithm to establish a Pregnancy Register in the UK Clinical Practice Research Datalink (CPRD) GOLD primary care database. Methods We compiled over 4000 read and entity codes to identify pregnancy‐related records among women aged 11 to 49 years in CPRD GOLD. Codes were categorised by the stage or outcome of pregnancy to facilitate delineation of pregnancy episodes. We constructed hierarchical rule systems to handle information from multiple sources. We assessed the validity of the Register to identify pregnancy outcomes by comparing our results to linked hospitalisation records and Office for National Statistics population rates. Results Our algorithm identified 5.8 million pregnancies among 2.4 million women (January 1987‐February 2018). We observed close agreement with hospitalisation data regarding completeness of pregnancy outcomes (91% sensitivity for deliveries and 77% for pregnancy losses) and their timing (median 0 days difference, interquartile range 0‐2 days). Miscarriage and prematurity rates were consistent with population figures, although termination and, to a lesser extent, live birth rates were underestimated in the Register. Conclusions The Pregnancy Register offers huge research potential because of its large size, high completeness, and availability. Further validation work is underway to enhance this data resource and identify optimal approaches for its use.

Objective To evaluate the association between pioglitazone use and bladder cancer risk in patients with type 2 diabetes.Design Retrospective cohort study using propensity score matched cohorts.Settings Healthcare databases from Finland, the Netherlands, Sweden, and the United Kingdom. Data comprised country specific datasets of linked records on prescriptions, hospitals, general practitioners, cancer, and deaths.Participants Patients with type 2 diabetes who initiated pioglitazone (n=56 337) matched with patients with type 2 diabetes in the same country exposed to diabetes drug treatments other than pioglitazone (n=317 109). Two matched cohorts were created, using a 1:1 fixed ratio (nearest match cohort) and a 1:10 variable ratio (multiple match cohort). Patients were matched on treatment history and propensity scores accounting for several variables associated with pioglitazone initiation.Main outcome measures Hazard ratios and 95% confidence intervals were estimated by Cox’s proportional hazards model with adjustments for relevant confounders. To assess the robustness of the findings, several sensitivity and stratified analyses were performed.Results In the cohort exposed to pioglitazone treatment, 130 bladder cancers occurred over a mean follow-up time of 2.9 years. In the nearest match and multiple match cohorts not exposed to pioglitazone treatment, 153 and 970 bladder cancers were recorded, with a mean follow‑up time of 2.8 and 2.9 years, respectively. With regards to bladder cancer risk, the adjusted hazard ratio for patients ever exposed versus never exposed to pioglitazone was 0.99 (95% confidence interval 0.75 to 1.30) and 1.00 (0.83 to 1.21) in the nearest and multiple match cohorts, respectively. Increasing duration of pioglitazone use and increasing cumulative dose were not associated with risk of bladder cancer (>48 months of pioglitazone use, adjusted hazard ratio 0.86 (0.44 to 1.66); >40 000 mg cumulative dose, 0.65 (0.33 to 1.26) in the nearest match cohort).Conclusions This study shows no evidence of an association between ever use of pioglitzone and risk of bladder cancer compared with never use, which is consistent with results from other recent studies that also included a long follow-up period.Trial registration Registered to the European Union electronic register of post-authorisation studies (EU PAS register no EUPAS3626).