Combined MRI, high-resolution manometry and a randomised trial of bisacodyl versus hyoscine show the significance of an enlarged colon in constipation: the RECLAIM study.

BACKGROUND: Colonic motility in constipation can be assessed non-invasively using MRI. OBJECTIVE: To compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response. DESIGN: Part 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500-1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by 'tagging' were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation. RESULTS: Part 1: Total CVs median (range) were significantly greater in IBS-C (776 (595-1033)) and FC (802 (633-951)) vs HV (645 (467-780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03). CONCLUSION: An abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity. TRIAL REGISTRATION NUMBER: The study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

Predicting the risk of pancreatic cancer in adults with new-onset diabetes: development and internal-external validation of a clinical risk prediction model.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) recommends that people aged 60+ years with newly diagnosed diabetes and weight loss undergo abdominal imaging to assess for pancreatic cancer. More nuanced stratification could lead to enrichment of these referral pathways. METHODS: Population-based cohort study of adults aged 30-85 years at type 2 diabetes diagnosis (2010-2021) using the QResearch primary care database in England linked to secondary care data, the national cancer registry and mortality registers. Clinical prediction models were developed to estimate risks of pancreatic cancer diagnosis within 2 years and evaluated using internal-external cross-validation. RESULTS: Seven hundred and sixty-seven of 253,766 individuals were diagnosed with pancreatic cancer within 2 years. Models included age, sex, BMI, prior venous thromboembolism, digoxin prescription, HbA1c, ALT, creatinine, haemoglobin, platelet count; and the presence of abdominal pain, weight loss, jaundice, heartburn, indigestion or nausea (previous 6 months). The Cox model had the highest discrimination (Harrell's C-index 0.802 (95% CI: 0.797-0.817)), the highest clinical utility, and was well calibrated. The model's highest 1% of predicted risks captured 12.51% of pancreatic cancer cases. NICE guidance had 3.95% sensitivity. DISCUSSION: A new prediction model could have clinical utility in identifying individuals with recent onset diabetes suitable for fast-track abdominal imaging.

Hormone replacement therapy and cancer mortality in women with 17 site-specific cancers: a cohort study using linked medical records.

BACKGROUND: There is limited evidence on the safety of Hormone Replacement Therapy (HRT) in women with cancer. Therefore, we systematically examined HRT use and cancer-specific mortality in women with 17 site-specific cancers. METHODS: Women newly diagnosed with 17 site-specific cancers from 1998 to 2019, were identified from general practitioner (GP) records, hospital diagnoses or cancer registries in Scotland, Wales and England. Breast cancer patients were excluded because HRT is contraindicated in breast cancer patients. The primary outcome was time to cancer-specific mortality. Time-dependent Cox regression models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer-specific mortality by systemic HRT use. RESULTS: The combined cancer cohorts contained 182,589 women across 17 cancer sites. Overall 7% of patients used systemic HRT after their cancer diagnosis. There was no evidence that HRT users, compared with non-users, had higher cancer-specific mortality at any cancer site. In particular, no increase was observed in common cancers including lung (adjusted HR = 0.98 95% CI 0.90, 1.07), colorectal (adjusted HR = 0.79 95% CI 0.70, 0.90), and melanoma (adjusted HR = 0.77 95% CI 0.58, 1.02). CONCLUSIONS: We observed no evidence of increased cancer-specific mortality in women with a range of cancers (excluding breast) receiving HRT.

Uptake, effectiveness and safety of COVID-19 vaccines in individuals at clinical risk due to immunosuppressive drug therapy or transplantation procedures: a population-based cohort study in England.

BACKGROUND: Immunocompromised individuals are at increased risk of severe COVID-19 outcomes, underscoring the importance of COVID-19 vaccination in this population. The lack of comprehensive real-world data on vaccine uptake, effectiveness and safety in these individuals presents a critical knowledge gap, highlighting the urgency to better understand and address the unique challenges faced by immunocompromised individuals in the context of COVID-19 vaccination. METHODS: We analysed data from 12,274,946 people in the UK aged > 12 years from 01/12/2020 to 11/04/2022. Of these, 583,541 (4.8%) were immunocompromised due to immunosuppressive drugs, organ transplants, dialysis or chemotherapy. We undertook a cohort analysis to determine COVID-19 vaccine uptake, nested case-control analyses adjusted for comorbidities and sociodemographic characteristics to determine effectiveness of vaccination against COVID-19 hospitalisation, ICU admission and death, and a self-controlled case series assessing vaccine safety for pre-specified adverse events of interest. RESULTS: Overall, 93.7% of immunocompromised individuals received at least one COVID-19 vaccine dose, with 80.4% having received three or more doses. Uptake reduced with increasing deprivation (hazard ratio [HR] 0.78 [95%CI 0.77-0.79] in the most deprived quintile compared to the least deprived quintile for the first dose). Estimated vaccine effectiveness against COVID-19 hospitalisation 2-6 weeks after the second and third doses compared to unvaccinated was 78% (95%CI 72-83) and 91% (95%CI 88-93) in the immunocompromised population, versus 85% (95%CI 83-86) and 86% (95%CI 85-89), respectively, for the general population. Results showed COVID-19 vaccines were protective against intensive care unit (ICU) admission and death in both populations, with effectiveness of over 92% against COVID-19-related death and up to 95% in reducing ICU admissions for both populations following the third dose. COVID-19 vaccines were generally safe for immunocompromised individuals, though specific doses of ChAdOx1, mRNA-1273 and BNT162b2 raised risks of specific cardiovascular/neurological conditions. CONCLUSIONS: COVID-19 vaccine uptake is high in immunocompromised individuals on immunosuppressive drug therapy or who have undergone transplantation procedures, with documented disparities by deprivation. Findings suggest that COVID-19 vaccines are protective against severe COVID-19 outcomes in this vulnerable population, and show a similar safety profile in immunocompromised individuals and the general population, despite some increased risk of adverse events. These results underscore the importance of ongoing vaccination prioritisation for this clinically at-risk population to maximise protection against severe COVID-19 outcomes.

Fatigue during the COVID-19 pandemic - prevalence and predictors: findings from a prospective cohort study.

The COVID-19 pandemic and consequent lockdowns had a substantial impact on mental health. Distress and fatigue are highly correlated. However, little is known about the determinants of fatigue in the general population during the pandemic. This study aimed to examine the prevalence and predictors of fatigue during the COVID-19 pandemic in the UK population. Online surveys were completed by a UK community cohort in April 2020 (wave 1), July-September 2020 (wave 2) and November-December 2020 (wave 3). In total, 3097 participants completed the wave 1 survey, and 1385 and 1087 participants (85.4% women) completed wave 2 and 3 surveys respectively. Fatigue was assessed using the Chalder Fatigue Scale at waves 2 and 3. Hair samples were provided by 827 participants (90.6% women) at wave 1 and wave 2, which were analyzed to indicate HairE (stress hormone). The mean total fatigue score during wave 2 was 14.7 (SD = 4.7), significantly higher than pre-pandemic levels observed in the community (mean difference 0.50, p = .003). At wave 2, 614 (44.3%) participants met the case definition for fatigue, only 15.6% of whom indicated that fatigue lasted for more than 6 months (suggesting it had started prior to the pandemic). Predictors of fatigue at wave 3 included being in a risk group, depression and belief in having COVID-19, which explained 23.8% of the variability in fatigue scores. Depression at wave 1 was the only significant predictor of remaining a fatigue case at wave 3. Fatigue was highly prevalent in the UK community during the COVID-19 pandemic and limited people's daily function. Depression and sociodemographic variables were significant predictors of fatigue.

Fatigue levels between July-December 2020 were higher compared to pre-pandemic levels.Predictors of fatigue levels 7-8 months later included being a clinical risk group, depression and belief in having had COVID-19.HairE was not associated with fatigue.Depression was the only significant predictor of remaining a fatigue case.

Cost-effectiveness of the 'Stay One Step Ahead' Home Safety programme for the prevention of injuries among children under 5 years.

BACKGROUND: Unintentional injuries are a common cause of morbidity and mortality in the under-5s, but undertaking home safety practices can reduce injury risk. Stay One Step Ahead (SOSA) is an evidence-based standardised home safety programme. This study evaluates the cost-effectiveness of SOSA versus usual care in Nottingham, UK. METHODS: Cost-effectiveness analysis from a National Health Service and personal social services perspective. SOSA activity data, injury occurrence and associated short-term healthcare costs were collected within a controlled before-and-after study from 2017 to 2020. The primary outcome was the incremental cost-effectiveness ratio (ICER) per additional home adopting three key safety practices (working smoke alarm, safe poisons storage and fitted stair gate). Secondary outcomes were ICERs per injury avoided and quality-adjusted life-years (QALYs) gained. RESULTS: SOSA costs £30 per child but reduces short-term healthcare expenditure by £42. SOSA increased the number of homes with three key safety practices by 0.02 per child, reduced injuries per child by 0.15 and gained 0.0036 QALYs per child. SOSA was dominant as it was cheaper and more effective than current practice. ICERs were -£590 per additional home deemed safe, -£77 per injury avoided and -£3225 per QALY gained. Focusing on healthcare expenditure alone, SOSA saved £1.39 for every pound spent. CONCLUSIONS: SOSA is a cost-saving intervention. Commissioners should consider implementing SOSA.

Temporality of body mass index, blood tests, comorbidities and medication use as early markers for pancreatic ductal adenocarcinoma (PDAC): a nested case-control study.

OBJECTIVE: Prior studies identified clinical factors associated with increased risk of pancreatic ductal adenocarcinoma (PDAC). However, little is known regarding their time-varying nature, which could inform earlier diagnosis. This study assessed temporality of body mass index (BMI), blood-based markers, comorbidities and medication use with PDAC risk . DESIGN: We performed a population-based nested case-control study of 28 137 PDAC cases and 261 219 matched-controls in England. We described the associations of biomarkers with risk of PDAC using fractional polynomials and 5-year time trends using joinpoint regression. Associations with comorbidities and medication use were evaluated using conditional logistic regression. RESULTS: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while following a U-shaped relationship for BMI and haemoglobin. Five-year trends showed biphasic BMI decrease and HbA1c increase prior to PDAC; early-gradual changes 2-3 years prior, followed by late-rapid changes 1-2 years prior. Liver markers and blood counts (white blood cell, platelets) showed monophasic rapid-increase approximately 1 year prior. Recent diagnosis of pancreatic cyst, pancreatitis, type 2 diabetes and initiation of certain glucose-lowering and acid-regulating therapies were associated with highest risk of PDAC. CONCLUSION: Risk of PDAC increased with raised HbA1c, liver markers, white blood cell and platelets, while followed a U-shaped relationship for BMI and haemoglobin. BMI and HbA1c derange biphasically approximately 3 years prior while liver markers and blood counts (white blood cell, platelets) derange monophasically approximately 1 year prior to PDAC. Profiling these in combination with their temporality could inform earlier PDAC diagnosis.

Risk of Myocarditis After Sequential Doses of COVID-19 Vaccine and SARS-CoV-2 Infection by Age and Sex.

BACKGROUND: Myocarditis is more common after severe acute respiratory syndrome coronavirus 2 infection than after COVID-19 vaccination, but the risks in younger people and after sequential vaccine doses are less certain. METHODS: A self-controlled case series study of people ages 13 years or older vaccinated for COVID-19 in England between December 1, 2020, and December 15, 2021, evaluated the association between vaccination and myocarditis, stratified by age and sex. The incidence rate ratio and excess number of hospital admissions or deaths from myocarditis per million people were estimated for the 1 to 28 days after sequential doses of adenovirus (ChAdOx1) or mRNA-based (BNT162b2, mRNA-1273) vaccines, or after a positive SARS-CoV-2 test. RESULTS: In 42 842 345 people receiving at least 1 dose of vaccine, 21 242 629 received 3 doses, and 5 934 153 had SARS-CoV-2 infection before or after vaccination. Myocarditis occurred in 2861 (0.007%) people, with 617 events 1 to 28 days after vaccination. Risk of myocarditis was increased in the 1 to 28 days after a first dose of ChAdOx1 (incidence rate ratio, 1.33 [95% CI, 1.09-1.62]) and a first, second, and booster dose of BNT162b2 (1.52 [95% CI, 1.24-1.85]; 1.57 [95% CI, 1.28-1.92], and 1.72 [95% CI, 1.33-2.22], respectively) but was lower than the risks after a positive SARS-CoV-2 test before or after vaccination (11.14 [95% CI, 8.64-14.36] and 5.97 [95% CI, 4.54-7.87], respectively). The risk of myocarditis was higher 1 to 28 days after a second dose of mRNA-1273 (11.76 [95% CI, 7.25-19.08]) and persisted after a booster dose (2.64 [95% CI, 1.25-5.58]). Associations were stronger in men younger than 40 years for all vaccines. In men younger than 40 years old, the number of excess myocarditis events per million people was higher after a second dose of mRNA-1273 than after a positive SARS-CoV-2 test (97 [95% CI, 91-99] versus 16 [95% CI, 12-18]). In women younger than 40 years, the number of excess events per million was similar after a second dose of mRNA-1273 and a positive test (7 [95% CI, 1-9] versus 8 [95% CI, 6-8]). CONCLUSIONS: Overall, the risk of myocarditis is greater after SARS-CoV-2 infection than after COVID-19 vaccination and remains modest after sequential doses including a booster dose of BNT162b2 mRNA vaccine. However, the risk of myocarditis after vaccination is higher in younger men, particularly after a second dose of the mRNA-1273 vaccine.

Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected clinical data. Eligible patients were aged 60 years or older who were receiving aspirin at a daily dose of 325 mg or less (with four or more 28-day prescriptions in the past year) and had a positive C13 urea breath test for H pylori at screening. Patients receiving ulcerogenic or gastroprotective medication were excluded. Participants were randomly assigned (1:1) to receive either a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (active eradication), or oral placebo (control), twice daily for 1 week. Participants, their general practitioners and health-care providers, and the research nurses, trial team, adjudication committee, and analysis team were all masked to group allocation throughout the trial. Follow-up was by scrutiny of electronic data in primary and secondary care. The primary outcome was time to hospitalisation or death due to definite or probable peptic ulcer bleeding, and was analysed by Cox proportional hazards methods in the intention-to-treat population. This trial is registered with EudraCT, 2011-003425-96. FINDINGS: Between Sept 14, 2012, and Nov 22, 2017, 30 166 patients had breath testing for H pylori, 5367 had a positive result, and 5352 were randomly assigned to receive active eradication (n=2677) or placebo (n=2675) and were followed up for a median of 5·0 years (IQR 3·9-6·4). Analysis of the primary outcome showed a significant departure from proportional hazards assumptions (p=0·0068), requiring analysis over separate time periods. There was a significant reduction in incidence of the primary outcome in the active eradication group in the first 2·5 years of follow-up compared with the control group (six episodes adjudicated as definite or probable peptic ulcer bleeds, rate 0·92 [95% CI 0·41-2·04] per 1000 person-years vs 17 episodes, rate 2·61 [1·62-4·19] per 1000 person-years; hazard ratio [HR] 0·35 [95% CI 0·14-0·89]; p=0·028). This advantage remained significant after adjusting for the competing risk of death (p=0·028) but was lost with longer follow-up (HR 1·31 [95% CI 0·55-3·11] in the period after the first 2·5 years; p=0·54). Reports of adverse events were actively solicited; taste disturbance was the most common event (787 patients). INTERPRETATION: H pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term. FUNDING: National Institute for Health and Care Research Health Technology Assessment.

Cost-effectiveness of England's national 'Safe At Home' scheme for reducing hospital admissions for unintentional injury in children aged under 5.

BACKGROUND: Injuries in children aged under 5 years most commonly occur in the home and disproportionately affect those living in the most disadvantaged communities. The 'Safe at Home' (SAH) national home safety equipment scheme, which ran in England between 2009 and 2011, has been shown to reduce injury-related hospital admissions, but there is little evidence of cost-effectiveness. MATERIALS AND METHODS: Cost-effectiveness analysis from a health and local government perspective. Measures were the incremental cost-effectiveness ratio per hospital admission averted (ICER) and cost-offset ratio (COR), comparing SAH expenditure to savings in admission expenditure. The study period was split into three periods: T1 (years 0-2, implementation); T2 (years 3-4) and T3 (years 5-6). Analyses were conducted for T2 versus T1 and T3 versus T1. RESULTS: Total cost of SAH was £9 518 066. 202 223 hospital admissions in the children occurred during T1-3, costing £3 320 000. Comparing T3 to T1 SAH reduced admission expenditure by £924 per month per local authority and monthly admission rates by 0.5 per local authority per month compared with control areas. ICER per admission averted was £4209 for T3 versus T1, with a COR of £0.29, suggesting that 29p was returned in savings on admission expenditure for every pound spent on SAH. CONCLUSION: SAH was effective at reducing hospital admissions due to injury and did result in some cost recovery when taking into admissions only. Further analysis of its cost-effectiveness, including emergency healthcare, primary care attendances and wider societal costs, is likely to improve the return on investment further.

Effectiveness of systematically delivered evidence-based home safety promotion to improve child home safety practices: a controlled before-and-after study.

OBJECTIVE: Evaluate the effectiveness of systematically delivered evidence-based home safety promotion for improving child home safety practices. DESIGN: Controlled before-and-after study. SETTING: Nine electoral wards in Nottingham, UK. PARTICIPANTS: 361 families with children aged 2-7 months at recruitment living in four intervention wards with high health, education and social need; and 401 in five matched control wards. INTERVENTION: Evidence-based home safety promotion delivered by health visiting teams, family mentors and children's centres including 24 monthly safety messages; home safety activity sessions; quarterly 'safety weeks'; home safety checklists. OUTCOMES: Primary: composite measure comprising having a working smoke alarm, storing poisons out of reach and having a stairgate. Secondary: other home safety practices; medically attended injuries. Parents completed questionnaires at 12 and 24 months after recruitment plus optional three monthly injury questionnaires. RESULTS: At 24 months there was no significant difference between groups in the primary outcome (55.8% vs 48.8%; OR 1.58, 95% CI 0.98 to 2.55) or medically attended injury rates (incidence rate ratio 0.89, 95% CI 0.51 to 1.56), but intervention families were more likely to store poisons safely (OR 1.81, 95% CI 1.06 to 3.07), have a fire escape plan (OR 1.81, 95% CI 1.06 to 3.08), use a fireguard or have no fire (OR 3.17, 95% CI 1.63 to 6.16) and perform more safety practices (ß 0.46, 95% CI 0.13 to 0.79). CONCLUSIONS: Systematic evidence-based home safety promotion in areas with substantial need increases adoption of some safety practices. Funders should consider commissioning evidence-based multicomponent child home safety interventions. TRIAL REGISTRATION NUMBER: ISRCTN31210493.

Frequency and impact of medication reviews for people aged 65 years or above in UK primary care: an observational study using electronic health records.

BACKGROUND: Medication reviews in primary care provide an opportunity to review and discuss the safety and appropriateness of a person's medicines. However, there is limited evidence about access to and the impact of routine medication reviews for older adults in the general population, particularly in the UK. We aimed to quantify the proportion of people aged 65 years and over with a medication review recorded in 2019 and describe changes in the numbers and types of medicines prescribed following a review. METHODS: We used anonymised primary care electronic health records from the UK's Clinical Practice Research Datalink (CPRD GOLD) to define a population of people aged 65 years or over in 2019. We counted people with a medication review record in 2019 and used Cox regression to estimate associations between demographic characteristics, diagnoses, and prescribed medicines and having a medication review. We used linear regression to compare the number of medicines prescribed as repeat prescriptions in the three months before and after a medication review. Specifically, we compared the 'prescription count' - the maximum number of different medicines with overlapping prescriptions people had in each period. RESULTS: Of 591,726 people prescribed one or more medicines at baseline, 305,526 (51.6%) had a recorded medication review in 2019. Living in a care home (hazard ratio 1.51, 95% confidence interval 1.40-1.62), medication review in the previous year (1.83, 1.69-1.98), and baseline prescription count (e.g. 5-9 vs 1 medicine 1.41, 1.37-1.46) were strongly associated with having a medication review in 2019. Overall, the prescription count tended to increase after a review (mean change 0.13 medicines, 95% CI 0.12-0.14). CONCLUSIONS: Although medication reviews were commonly recorded for people aged 65 years or over, there was little change overall in the numbers and types of medicines prescribed following a review. This study did not examine whether the prescriptions were appropriate or other metrics, such as dose or medicine changes within the same class. However, by examining the impact of medication reviews before the introduction of structured medication review requirements in England in 2020, it provides a useful benchmark which these new reviews can be compared with.

Ethnic disparities in COVID-19 outcomes: a multinational cohort study of 20 million individuals from England and Canada.

BACKGROUND: Heterogeneous studies have demonstrated ethnic inequalities in the risk of SARS-CoV-2 infection and adverse COVID-19 outcomes. This study evaluates the association between ethnicity and COVID-19 outcomes in two large population-based cohorts from England and Canada and investigates potential explanatory factors for ethnic patterning of severe outcomes. METHODS: We identified adults aged 18 to 99 years in the QResearch primary care (England) and Ontario (Canada) healthcare administrative population-based datasets (start of follow-up: 24th and 25th Jan 2020 in England and Canada, respectively; end of follow-up: 31st Oct and 30th Sept 2020, respectively). We harmonised the definitions and the design of two cohorts to investigate associations between ethnicity and COVID-19-related death, hospitalisation, and intensive care (ICU) admission, adjusted for confounders, and combined the estimates obtained from survival analyses. We calculated the 'percentage of excess risk mediated' by these risk factors in the QResearch cohort. RESULTS: There were 9.83 million adults in the QResearch cohort (11,597 deaths; 21,917 hospitalisations; 2932 ICU admissions) and 10.27 million adults in the Ontario cohort (951 deaths; 5132 hospitalisations; 1191 ICU admissions). Compared to the general population, pooled random-effects estimates showed that South Asian ethnicity was associated with an increased risk of COVID-19 death (hazard ratio: 1.63, 95% CI: 1.09-2.44), hospitalisation (1.53; 1.32-1.76), and ICU admission (1.67; 1.23-2.28). Associations with ethnic groups were consistent across levels of deprivation. In QResearch, sociodemographic, lifestyle, and clinical factors accounted for 42.9% (South Asian) and 39.4% (Black) of the excess risk of COVID-19 death. CONCLUSION: International population-level analyses demonstrate clear ethnic inequalities in COVID-19 risks. Policymakers should be cognisant of the increased risks in some ethnic populations and design equitable health policy as the pandemic continues.

Relationship Between Anxiety, Depression, and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Proof of Concept.

BACKGROUND: Psychological factors can influence susceptibility to viral infections. We examined whether such influences are evident in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Participants (n = 102) completed measures of anxiety, depression, positive mood, and loneliness and provided a blood sample for the measurement of antibodies to the SARS-CoV-2 spike and nucleocapsid proteins. RESULTS: SARS-CoV-2 was significantly negatively associated with anxiety and depression. The model remained significant after adjustment for age and gender, although anxiety and depression were no longer significant independent predictors. CONCLUSIONS: These findings offer early support for the hypothesis that psychological factors may influence susceptibility to SARS-CoV-2 infection.

Smoking and COVID-19 outcomes: an observational and Mendelian randomisation study using the UK Biobank cohort.

BACKGROUND: Conflicting evidence has emerged regarding the relevance of smoking on risk of COVID-19 and its severity. METHODS: We undertook large-scale observational and Mendelian randomisation (MR) analyses using UK Biobank. Most recent smoking status was determined from primary care records (70.8%) and UK Biobank questionnaire data (29.2%). COVID-19 outcomes were derived from Public Health England SARS-CoV-2 testing data, hospital admissions data, and death certificates (until 18 August 2020). Logistic regression was used to estimate associations between smoking status and confirmed SARS-CoV-2 infection, COVID-19-related hospitalisation, and COVID-19-related death. Inverse variance-weighted MR analyses using established genetic instruments for smoking initiation and smoking heaviness were undertaken (reported per SD increase). RESULTS: There were 421 469 eligible participants, 1649 confirmed infections, 968 COVID-19-related hospitalisations and 444 COVID-19-related deaths. Compared with never-smokers, current smokers had higher risks of hospitalisation (OR 1.80, 95% CI 1.26 to 2.29) and mortality (smoking 1-9/day: OR 2.14, 95% CI 0.87 to 5.24; 10-19/day: OR 5.91, 95% CI 3.66 to 9.54; 20+/day: OR 6.11, 95% CI 3.59 to 10.42). In MR analyses of 281 105 White British participants, genetically predicted propensity to initiate smoking was associated with higher risks of infection (OR 1.45, 95% CI 1.10 to 1.91) and hospitalisation (OR 1.60, 95% CI 1.13 to 2.27). Genetically predicted higher number of cigarettes smoked per day was associated with higher risks of all outcomes (infection OR 2.51, 95% CI 1.20 to 5.24; hospitalisation OR 5.08, 95% CI 2.04 to 12.66; and death OR 10.02, 95% CI 2.53 to 39.72). INTERPRETATION: Congruent results from two analytical approaches support a causal effect of smoking on risk of severe COVID-19.

The risk of all-cause and cause-specific mortality in people prescribed mirtazapine: an active comparator cohort study using electronic health records.

BACKGROUND: Studies have reported an increased risk of mortality among people prescribed mirtazapine compared to other antidepressants. The study aimed to compare all-cause and cause-specific mortality between adults prescribed mirtazapine or other second-line antidepressants. METHODS: This cohort study used English primary care electronic medical records, hospital admission records, and mortality data from the Clinical Practice Research Datalink (CPRD), for the period 01 January 2005 to 30 November 2018. It included people aged 18-99 years with depression first prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine (5081), a different SSRI (15,032), amitriptyline (3905), or venlafaxine (1580). Follow-up was from starting to stopping the second antidepressant, with a 6-month wash-out window, censoring at the end of CPRD follow-up or 30 November 2018. Age-sex standardised rates of all-cause mortality and death due to circulatory system disease, cancer, or respiratory system disease were calculated. Survival analyses were performed, accounting for baseline characteristics using inverse probability of treatment weighting. RESULTS: The cohort contained 25,598 people (median age 41 years). The mirtazapine group had the highest standardised mortality rate, with an additional 7.8 (95% confidence interval (CI) 5.9-9.7) deaths/1000 person-years compared to the SSRI group. Within 2 years of follow-up, the risk of all-cause mortality was statistically significantly higher in the mirtazapine group than in the SSRI group (weighted hazard ratio (HR) 1.62, 95% CI 1.28-2.06). No significant difference was found between the mirtazapine group and the amitriptyline (HR 1.18, 95% CI 0.85-1.63) or venlafaxine (HR 1.11, 95% CI 0.60-2.05) groups. After 2 years, the risk was significantly higher in the mirtazapine group compared to the SSRI (HR 1.51, 95% CI 1.04-2.19), amitriptyline (HR 2.59, 95% CI 1.38-4.86), and venlafaxine (HR 2.35, 95% CI 1.02-5.44) groups. The risks of death due to cancer (HR 1.74, 95% CI 1.06-2.85) and respiratory system disease (HR 1.72, 95% CI 1.07-2.77) were significantly higher in the mirtazapine than in the SSRI group. CONCLUSIONS: Mortality was higher in people prescribed mirtazapine than people prescribed a second SSRI, possibly reflecting residual differences in other risk factors between the groups. Identifying these potential health risks when prescribing mirtazapine may help reduce the risk of mortality.

Risk models for recurrence and survival after kidney cancer: a systematic review.

OBJECTIVE: To systematically identify and compare the performance of prognostic models providing estimates of survival or recurrence of localized renal cell cancer (RCC) in patients treated with surgery with curative intent. MATERIALS AND METHODS: We performed a systematic review (PROSPERO CRD42019162349). We searched Medline, EMBASE and the Cochrane Library from 1 January 2000 to 12 December 2019 to identify studies reporting the performance of one or more prognostic model(s) that predict recurrence-free survival (RFS), cancer-specific survival (CSS) or overall survival (OS) in patients who have undergone surgical resection for localized RCC. For each outcome we summarized the discrimination of each model using the C-statistic and performed multivariate random-effects meta-analysis of the logit transformed C-statistic to rank the models. RESULTS: Of a total of 13 549 articles, 57 included data on the performance of 22 models in external populations. C-statistics ranged from 0.59 to 0.90. Several risk models were assessed in two or more external populations and had similarly high discriminative performance. For RFS, these were the Sorbellini, Karakiewicz, Leibovich and Kattan models, with the UCLA Integrated Staging System model also having similar performance in European/US populations. All had C-statistics ≥0.75 in at least half of the validations. For CSS, they the models with the highest discriminative performance in two or more external validation studies were the Zisman, Stage, Size, Grade and Necrosis (SSIGN), Karakiewicz, Leibovich and Sorbellini models (C-statistic ≥0.80 in at least half of the validations), and for OS they were the Leibovich, Karakiewicz, Sorbellini and SSIGN models. For all outcomes, the models based on clinical features at presentation alone (Cindolo and Yaycioglu) had consistently lower discrimination. Estimates of model calibration were only infrequently included but most underestimated survival. CONCLUSION: Several models had good discriminative ability, with there being no single 'best' model. The choice from these models for each setting should be informed by both the comparative performance and availability of factors included in the models. All would need recalibration if used to provide absolute survival estimates.

Psychological Predictors of Self-reported COVID-19 Outcomes: Results From a Prospective Cohort Study.

BACKGROUND: Previous research has shown that psychological factors, such as stress and social support, are associated with greater susceptibility to viral respiratory illnesses and more severe symptoms. During the COVID-19 pandemic there has been a well-documented deterioration in psychological well-being and increased social isolation. This raises questions as to whether those experiencing psychological adversity during the pandemic are more at risk of contracting and/or experiencing COVID-19 symptoms. PURPOSE: To examine the relationship between psychological factors and the risk of COVID-19 self-reported infection and the symptomatic experience of SARS-CoV-2 (indicated by the number and severity of symptoms). METHODS: As part of a longitudinal prospective observational cohort study, 1,087 adults completed validated measures of psychological well-being during April 2020 and self-reported incidence of COVID-19 infection and symptom experience across the pandemic through to December 2020. Regression models were used to explore these relationships controlling for demographic and occupational factors. RESULTS: Greater psychological distress during the early phase of the pandemic was significantly associated with subsequent self-reported SARS-CoV-2 infection as well as the experience of a greater number and more severe symptoms. CONCLUSIONS: COVID-19 infection and symptoms may be more common among those experiencing elevated psychological distress. Further research to elucidate the mechanisms underlying these associations is needed.

'It is designed for everybody to find their own level and to improve themselves'; views of older people and instructors of the Falls Management Exercise (FaME) programme.

BACKGROUND: Older adults are at increased risk of falls due to ageing, decreased muscle strength and impaired balance. Clinical trials have demonstrated the efficacy and effectiveness of the Falls Management Exercise (FaME) programme in improving functioning and preventing falls. However, programme completion is often low, impacting the potential benefits of FaME. OBJECTIVE: To explore the barriers and facilitators for participation and completion of the FaME programme from an instructor and participant perspective. METHODS: Semi-structured interviews were conducted with 20 FaME users and seven Postural Stability Instructors from the East Midlands region of England, UK. Interviews were conducted using a topic guide and explored their views of the programme, intended benefits, reasons for participating, instructor's approach and venue facilities. Data were transcribed verbatim and analysed using thematic analysis. Written informed consent was obtained from all participants and instructors. RESULTS: Common themes identified by participants and instructors for adherence related to perceived health benefits, psychological well-being, intervention characteristics, cost, instructors' qualities, opportunity to socialise, venue accessibility and facilities. Further factors such as maintaining independence, discipline, relationship with peers and caring responsibilities influenced participants' engagement with the programme. Instructor factors such as progression were also reported as important predictors. CONCLUSIONS: Instructor and participant factors influence uptake, attendance and adherence of FaME. The findings from this study can inform the development and improvement of additional falls-prevention programmes. It can also guide marketing strategies to promote uptake of exercise-based falls-prevention programmes among older adults.

Design decisions and data completeness for experience sampling methods used in psychosis: systematic review.

BACKGROUND: The experience sampling method (ESM) is an intensive longitudinal research method.  Participants complete questionnaires at multiple times about their current or very recent state. The design of ESM studies is complex. People with psychosis have been shown to be less adherent to ESM study protocols than the general population. It is not known how to design studies that increase adherence to study protocols. A lack of typology makes it is hard for researchers to decide how to collect data in a way that allows for methodological rigour, quality of reporting, and the ability to synthesise findings. The aims of this systematic review were to characterise the design choices made in ESM studies monitoring the daily lives of people with psychosis, and to synthesise evidence relating the data completeness to different design choices. METHODS: A systematic review was conducted of published literature on studies using ESM with people with psychosis. Studies were included if they used digital technology for data collection and reported the completeness of the data set. The constant comparative method was used to identify design decisions, using inductive identification of design decisions with simultaneous comparison of design decisions observed. Weighted regression was used to identify design decisions that predicted data completeness. The review was pre-registered (PROSPERO CRD42019125545). RESULTS: Thirty-eight studies were included. A typology of design choices used in ESM studies was developed, which comprised three superordinate categories of design choice: Study context, ESM approach and ESM implementation. Design decisions that predict data completeness include type of ESM protocol used, length of time participants are enrolled in the study, and if there is contact with the research team during data collection. CONCLUSIONS: This review identified a range of design decisions used in studies using ESM in the context of psychosis. Design decisions that influence data completeness were identified. Findings will help the design and reporting of future ESM studies. Results are presented with the focus on psychosis, but the findings can be applied across different mental health populations.