Autoimmune conditions and gastric cancer risk in a population-based study in the United Kingdom.

BACKGROUND: Although overall incidence of gastric cancer is decreasing, incidence has been increasing among young people in some Western countries. This trend may stem from the increase in autoimmune conditions. METHODS: A nested case-control study of gastric cancer in UK Clinical Practice Research Datalink. Up to ten cancer-free controls were matched to cases by age and sex. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for associations between analyzable autoimmune conditions (n = 34) and gastric cancer with Bonferroni correction. We evaluated associations between pernicious anaemia and other conditions. A meta-analysis of published prospective studies and ours was conducted. RESULTS: Among 6586 cases (1156 cardia, 1104 non-cardia, and 4334 overlapping/unspecified tumours) and 65,687 controls, any autoimmune condition was associated with gastric cancer (OR = 1.10; 95% CI: 1.01-1.20). Individuals with pernicious anaemia had higher gastric cancer risk than those without (OR = 2.75; 2.19-3.44). Among controls, pernicious anaemia was associated with seven other conditions (OR range: 2.21-29.80). The pooled estimate for any autoimmune condition and gastric cancer was 1.17 (1.14-1.21; n = 47,126 cases). CONCLUSION: Autoimmunity increases gastric cancer risk. Some autoimmune conditions may be indirectly associated with gastric cancer via pernicious anaemia. Pernicious anaemia could be considered for gastric cancer risk stratification and screening.

Assessment and report of individual symptoms in studies of delirium in postoperative populations: a systematic review.

OBJECTIVES: Delirium is most often reported as present or absent. Patients with symptoms falling short of the diagnostic criteria for delirium fall into 'no delirium' or 'control' groups. This binary classification neglects individual symptoms and may be hindering identification of the pathophysiology underlying delirium. This systematic review investigates which individual symptoms of delirium are reported by studies of postoperative delirium in adults. METHODS: Medline, EMBASE and Web of Science databases were searched on 03 June 2021 and 06 April 2023. Two reviewers independently examined titles and abstracts. Each paper was screened in duplicate and conflicting decisions settled by consensus discussion. Data were extracted, qualitatively synthesised and narratively reported. All included studies were quality assessed. RESULTS: These searches yielded 4,367 results. After title and abstract screening, 694 full-text studies were reviewed, and 62 deemed eligible for inclusion. This review details 11,377 patients including 2,049 patients with delirium. In total, 78 differently described delirium symptoms were reported. The most reported symptoms were inattention (N = 29), disorientation (N = 27), psychomotor agitation/retardation (N = 22), hallucination (N = 22) and memory impairment (N = 18). Notably, psychomotor agitation and hallucinations are not listed in the current Diagnostic and Statistical Manual for Mental Disorders-5-Text Revision delirium definition. CONCLUSIONS: The 78 symptoms reported in this systematic review cover domains of attention, awareness, disorientation and other cognitive changes. There is a lack of standardisation of terms, and many recorded symptoms are synonyms of each other. This systematic review provides a library of individual delirium symptoms, which may be used to inform future reporting.

Oral prednisolone and warfarin and risk of oesophageal cancer: A case-control study.

BACKGROUND: A recent epidemiological study systematically screened 250 prescription medications for associations with oesophageal cancer risk, using Scottish data, and identified an increased risk with use of prednisolone and warfarin. We investigated whether oral prednisolone or warfarin use was associated with increased oesophageal cancer risk. METHODS: A case-control study was conducted within the Clinical Practice Research Datalink. In the primary analysis oesophageal cancer cases were identified from linked cancer registry records. Up to 5 cancer-free controls were matched to each case (based upon sex, birth year, GP practice and year of GP registration). Prednisolone and warfarin medications were identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression after adjusting for covariates including demographics, comorbidities and medication use. RESULTS: There were 4552 oesophageal cancer cases and 22,601 matched control participants. Overall, there was no evidence of an increased risk of oesophageal cancer with oral prednisolone use (unadjusted OR=1.16 95% CI 1.06, 1.27 and adjusted OR=0.99 95% CI 0.89, 1.11) or warfarin use (unadjusted OR=1.12 95% CI 0.99, 1.28 and adjusted OR=1.08 95% CI 0.92, 1.27). CONCLUSIONS: In this large population-based study, oral prednisolone and warfarin were not associated with oesophageal cancer risk.

Use of 5-alpha reductase inhibitors and risk of gastrointestinal cancers in men with benign prostatic hyperplasia: A population-based cohort study.

Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.

Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer.

Importance: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer. Objective: To determine whether the risk of breast cancer-specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT). Design, Setting, and Participants: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer-specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023. Exposure: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort. Main Outcomes and Measures: The primary outcome was time to breast cancer-specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer-specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade. Results: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer-specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer-specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94). Conclusions and Relevance: Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

Interventions to improve the appropriate use of polypharmacy for older people.

BACKGROUND: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, so that many medicines may be used to achieve better clinical outcomes for patients. This is the third update of this Cochrane Review. OBJECTIVES: To assess the effects of interventions, alone or in combination, in improving the appropriate use of polypharmacy and reducing medication-related problems in older people. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and two trials registers up until 13 January 2021, together with handsearching of reference lists to identify additional studies. We ran updated searches in February 2023 and have added potentially eligible studies to 'Characteristics of studies awaiting classification'. SELECTION CRITERIA: For this update, we included randomised trials only. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy (four or more medicines) in people aged 65 years and older, which used a validated tool to assess prescribing appropriateness. These tools can be classified as either implicit tools (judgement-based/based on expert professional judgement) or explicit tools (criterion-based, comprising lists of drugs to be avoided in older people). DATA COLLECTION AND ANALYSIS: Four review authors independently reviewed abstracts of eligible studies, and two authors extracted data and assessed the risk of bias of the included studies. We pooled study-specific estimates, and used a random-effects model to yield summary estimates of effect and 95% confidence intervals (CIs). We assessed the overall certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: We identified 38 studies, which includes an additional 10 in this update. The included studies consisted of 24 randomised trials and 14 cluster-randomised trials. Thirty-six studies examined complex, multi-faceted interventions of pharmaceutical care (i.e. the responsible provision of medicines to improve patients' outcomes), in a variety of settings. Interventions were delivered by healthcare professionals such as general physicians, pharmacists, nurses and geriatricians, and most were conducted in high-income countries. Assessments using the Cochrane risk of bias tool found that there was a high and/or unclear risk of bias across a number of domains. Based on the GRADE approach, the overall certainty of evidence for each pooled outcome ranged from low to very low. It is uncertain whether pharmaceutical care improves medication appropriateness (as measured by an implicit tool) (mean difference (MD) -5.66, 95% confidence interval (CI) -9.26 to -2.06; I2 = 97%; 8 studies, 947 participants; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the number of potentially inappropriate medications (PIMs) (standardised mean difference (SMD) -0.19, 95% CI -0.34 to -0.05; I2 = 67%; 9 studies, 2404 participants; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PIM (risk ratio (RR) 0.81, 95% CI 0.68 to 0.98; I2 = 84%; 13 studies, 4534 participants; very low-certainty evidence). Pharmaceutical care may slightly reduce the number of potential prescribing omissions (PPOs) (SMD -0.48, 95% CI -1.05 to 0.09; I2 = 92%; 3 studies, 691 participants; low-certainty evidence), however it must be noted that this effect estimate is based on only three studies, which had serious limitations in terms of risk of bias. Likewise, it is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PPO (RR 0.50, 95% CI 0.27 to 0.91; I2 = 95%; 7 studies, 2765 participants; very low-certainty evidence). Pharmaceutical care may make little or no difference to hospital admissions (data not pooled; 14 studies, 4797 participants; low-certainty evidence). Pharmaceutical care may make little or no difference to quality of life (data not pooled; 16 studies, 7458 participants; low-certainty evidence). Medication-related problems were reported in 10 studies (6740 participants) using different terms (e.g. adverse drug reactions, drug-drug interactions). No consistent intervention effect on medication-related problems was noted across studies. This also applied to studies examining adherence to medication (nine studies, 3848 participants). AUTHORS' CONCLUSIONS: It is unclear whether interventions to improve appropriate polypharmacy resulted in clinically significant improvement. Since the last update of this review in 2018, there appears to have been an increase in the number of studies seeking to address potential prescribing omissions and more interventions being delivered by multidisciplinary teams.

Exposure to weak opioids and risk of gastrointestinal tract cancers: A series of nested case-control studies.

AIMS: There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. We aim to assess the association between weak opioids and cancers of the GI tract. METHODS: A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n = 2432), gastric (n = 1443) and colorectal cancer (n = 8750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. RESULTS: There was no association between weak opioids and colorectal cancer (adjusted OR = 0.96, CI 0.90, 1.02, P = 0.15). There was an increased risk of oesophageal (adjusted OR = 1.16, CI 1.04, 1.29, P = 0.01) and gastric cancer (adjusted OR = 1.26, CI 1.10, 1.45, P = 0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR = 1.03 CI 0.86, 1.22, P = 0.76 and adjusted OR = 1.29 CI 1.02, 1.64, P = 0.04 respectively). CONCLUSIONS: In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication.

5α-Reductase Inhibitors and Risk of Kidney and Bladder Cancers in Men with Benign Prostatic Hyperplasia: A Population-Based Cohort Study.

BACKGROUND: Preclinical evidence suggests that 5α-reductase inhibitors (5ARi), commonly used to treat benign prostatic hyperplasia (BPH), are associated with reduced incidence of certain urologic cancers, yet epidemiologic studies are conflicting. This study aimed to determine whether 5ARi's are associated with a reduced risk of kidney and bladder cancers. METHODS: We conducted a new-user active-comparator cohort study in the United Kingdom Clinical Practice Research Datalink. From a base cohort of patients with incident BPH, new users of 5ARi's and α-blockers were identified. Patients were followed up until a first ever diagnosis of kidney or bladder cancer, death from any cause, end of registration, or December 31, 2017. Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (CI) for incident kidney and bladder cancer. RESULTS: There were 5,414 and 37,681 new users of 5ARi's and α-blockers, respectively. During a mean follow-up of 6.3 years, we found no association between the use of 5ARi's and kidney (adjusted HR, 1.26; 95% CI, 0.74-2.12; n = 23) or bladder (adjusted HR, 0.89; 95% CI, 0.64-1.23; n = 57) cancer risk compared with α-blockers. Similar results were observed across sensitivity analyses. CONCLUSIONS: In this study, we found no association between the use of 5ARi's and kidney or bladder cancer incidence in men with BPH when compared with α-blocker use. IMPACT: The findings of this study indicate that 5ARi's are unlikely to reduce kidney or bladder cancer risk.

PROtein enriched MEDiterranean diet to combat undernutrition and promote healthy neuroCOGnitive ageing in older adults: The PROMED-COG consortium project.

Dementia is a major public health challenge owing to its increasing prevalence and recognised impact on disability among older adults. Observational data indicate that weight loss is associated with increased dementia risk of 30%-40% and precedes a diagnosis of cognitive impairment or dementia by at least one decade. Although relatively little is known about the mechanisms of unintentional weight loss in dementia, this provides a window of opportunity to intervene with strategies to counteract undernutrition and delay, or prevent, the onset of dementia. This article provides an overview of the PROMED-COG project and associated work packages. The project aimes to (1) strengthen the epidemiologic evidence to better understand the potential benefits of combating undernutrition for healthy neurocognitive ageing; (2) increase scientific knowledge on the balance between a protein enriched Mediterranean diet (PROMED) and physical exercise to prevent undernutrition and promote healthy neurocognitive ageing, and generate data on mechanistic pathways; (3) stimulate collaboration and capacity building for nutrition and neurocognitive ageing research in Europe; and (4) develop public and practice recommendations to combat undernutrition and promote healthy neurocognitive ageing in older adults. Findings will provide new and critical insights into the role of undernutrition in neurocognitive ageing, how this role can differ by sex, genetic risk and timing of undernutrition exposure, and how modifications of dietary and physical activity behaviour can reduce the burden of undernutrition and neurodegeneration. The research outcomes will be useful to inform policy and practice about the dietary guidelines of older people and provide insight to industry for the development of food-based solutions to prevent undernutrition.

Identification of Drug-Cancer Associations: A Nationwide Screening Study.

The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case-control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time. ORs were estimated using conditional logistic regression accounting for matching factors, educational level, and selected comorbidities. A total of 13,577 drug-cancer associations were examined for individual drugs and 8,996 for drug classes. We reviewed 274 drug-cancer pairs where an association with high use and a cumulative dose-response pattern was present. We classified 65 associations as not readily attributable to bias of which 20 were established as carcinogens by the International Agency for Research on Cancer and the remaining 45 associations may warrant further study. The screening program identified drugs with known carcinogenic effects and highlighted a number of drugs that were not established as carcinogens and warrant further study. The effect estimates in this study should be interpreted cautiously and will need confirmation targeted epidemiologic and translational studies. Significance: This study provides a screening tool for drug carcinogenicity aimed at hypothesis generation and explorative purposes. As such, the study may help to identify drugs with unknown carcinogenic effects and, ultimately, improve drug safety as part of the ongoing safety monitoring of drugs.

Exposure to Ranitidine and Risk of Bladder Cancer: A Nested Case-Control Study.

INTRODUCTION: Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. METHODS: A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. RESULTS: There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR = 1.22; 95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR = 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR = 0.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR = 0.98; 95% CI 0.80-1.20). DISCUSSION: In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings.

The effects of vitamin E supplementation on malondialdehyde as a biomarker of oxidative stress in haemodialysis patients: a systematic review and meta-analysis.

BACKGROUND: Haemodialysis (HD) patients tend to have higher levels of oxidative stress (OS), associated with increased morbidity and premature mortality, compared to the general population. Levels of malondialdehyde (MDA), a biomarker of OS, are reduced by the antioxidant properties of vitamin E (VE) but outcomes from randomised control trials of VE supplementation on MDA in HD patients have been inconsistent. METHODS: We undertook a systematic review and meta-analysis of adult HD patients from VE supplementation studies with measures of MDA. The following search criteria of MEDLINE and EMBASE were considered from inception to January 2020: 'dialysis' AND 'Vitamin E OR tocopherol' AND 'malondialdehyde OR MDA'. Two reviewers independently extracted study data and assessed risk of bias. Mean MDA levels and standard deviation were determined before and after VE supplementation. Standardised mean difference (SMD) and standard error were calculated as the within person difference and units of measure were not consistently recorded across all studies. The SMD were pooled using random effects meta-analysis. RESULTS: The SMD of MDA levels from 18 comparisons was significantly lower in HD patients following VE supplementation (- 1.55; confidence interval: - 2.17 to - 0.94, P < 0.00001). There were significant levels of heterogeneity between studies (I2 value = 91%; P < 0.00001) with evidence of potential publication bias toward smaller studies. CONCLUSIONS: Our findings support the use of VE to reduce the effects of OS in HD patients although high levels of heterogeneity and variation in the methodological approaches used by some studies highlight the need for further investigation.

Hormone therapy use and the risk of acute kidney injury in patients with prostate cancer: a population-based cohort study.

BACKGROUND: Hormone therapy is widely used in prostate cancer. However, studies have raised concerns that hormone therapy, particularly the use of gonadotropin-releasing hormone agonists, could increase the risk of acute kidney injury. METHODS: Men newly diagnosed with non-metastatic prostate cancer, from 2012 to 2017, were identified from the Scottish Cancer Registry. A matched comparison cohort of prostate cancer-free men was also identified. Hormone therapy use was determined from the Prescribing Information System in Scotland. The primary outcome was hospitalisations with acute kidney injury taken from Scottish hospital records (SMR01) up to June 2019. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for acute kidney injury by hormone therapy use. RESULTS: The prostate cancer cohort contained 10,751 patients followed for 41,997 person years, during which there were 618 hospitalisations with acute kidney injury. Prostate cancer patients had higher rates of acute kidney injury compared with cancer-free controls (adjusted HR = 1.47 95% CI 1.29, 1.69). However, prostate cancer patients currently using hormone therapy (adjusted HR = 1.14 95% CI 0.92, 1.41), including gonadotropin-releasing hormone (GnRH) agonists (adjusted HR = 1.13 95% CI 0.90, 1.40), did not appear to have a marked increase in acute kidney injury compared with prostate cancer patients not using hormone therapy after adjusting for potential confounders. CONCLUSIONS: In our cohort, there was little evidence that gonadotropin-releasing hormone agonists were associated with marked increases in acute kidney injury.

Hormone replacement therapy in women with cancer and risk of cancer-specific mortality and cardiovascular disease: a protocol for a cohort study from Scotland and Wales.

BACKGROUND: Hormone replacement therapy (HRT) is widely used and has proven benefits for women with menopausal symptoms. An increasing number of women with cancer experience menopausal symptoms but the safety of HRT use in women with cancer is unclear. There are particular concerns that HRT could accelerate cancer progression in women with cancer, and also that HRT could increase the risk of cardiovascular disease in such women. Therefore, our primary aim is to determine whether HRT use alters the risk of cancer-specific mortality in women with a range of common cancers. Our secondary objectives are to investigate whether HRT alters the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality. METHODS: The study will utilise independent population-based data from Wales using the SAIL databank and Scotland based upon the national Prescribing Information System. The study will include women newly diagnosed with common cancers from 2000 to 2016, identified from cancer registries. Women with breast cancers will be excluded. HRT will be ascertained using electronic prescribing in Wales or dispensing records in Scotland. The primary outcome will be time to cancer-specific mortality from national mortality records. Time-dependent cox regression models will be used to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) for cancer specific death in HRT users compared with non-users after cancer diagnosis after adjusting for relevant confounders, stratified by cancer site. Analysis will be repeated investigating the impact of HRT use immediately before cancer diagnosis. Secondary analyses will be conducted on the risk of second cancers, cardiovascular disease, venous thromboembolism and all-cause mortality. Analyses will be conducted within each cohort and pooled across cohorts. DISCUSSION: Our study will provide evidence to inform guidance given to women diagnosed with cancer on the safety of HRT use and/or guide modifications to clinical practice.

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria.

Do interviewer attitudes to data linkage influence respondents' consent to linkage? Analysis of Understanding Society.

BACKGROUND: Variable consent rates threaten the validity of linked datasets. One modifiable element is the interviewer-respondent relationship. We examine interviewer attitudes to consent to linkage and the effect on respondent consent. METHODS: Subjects were 27 380 respondents from the Wave 1 Understanding Society (US) survey in Great Britain and 449 interviewers who completed the US Interviewer Survey. Two types of consent were considered: (i) whether the interviewer would hypothetically agree to having their data linked if he/she was an US respondent and (ii) whether the respondent consented to have their data linked. Factors influencing the interviewer's propensity to link data were examined using logistic regression. The association between interviewer consent and respondent consent to health record linkage was assessed using multi-level logistic regression models. RESULTS: The interviewer's propensity to consent to data linkage was strongly positively associated with its perceived usefulness: those that found it somewhat useful were 57% less likely to consent [adjusted odds ratio (AOR) 0.43, 95% CI: 0.22-0.82] compared to those who thought it was very useful. Positive beliefs about data security and their ability to understand the data linkage information were also associated. Respondents were 17% less likely to consent when interviewed by an interviewer who would not consent to record linkage (AOR 0.83, 95% CI: 0.71-0.97). CONCLUSIONS: The interviewer's propensity to consent was influenced by their beliefs about data linkage, which in turn influenced respondent consent. We recommend using interviewer training to emphasize the usefulness of data linkage and the measures around data security.

Food environment intervention improves food knowledge, wellbeing and dietary habits in primary school children: Project Daire, a randomised-controlled, factorial design cluster trial.

BACKGROUND: Evidence suggests that dietary intake of UK children is suboptimal. As schools provide an ideal natural environment for public health interventions, effective and sustainable methods of improving food knowledge and dietary habits in this population must be identified. Project Daire aimed to improve children's health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions. METHODS: Daire was a randomised-controlled, factorial design trial evaluating two interventions across four arms. Primary schools in Northern Ireland were randomised to one of four 6-month intervention arms: i) 'Nourish', ii) 'Engage', iii) 'Nourish' and 'Engage' and iv) Control (Delayed). 'Nourish' was an intervention aiming to alter the whole-school food environment, provide food-related experiences and exposure to locally produced foods. 'Engage' was an age-appropriate, cross-curricular educational intervention on food, agriculture, nutrition science and related careers. Primary outcomes were emotional and behavioural wellbeing and health-related quality of life. A number of secondary outcomes, including dietary intake, cooking competence and food-related knowledge, were also measured. RESULTS: Fifteen schools from areas of varying socio-economic status participated in the randomised trial. A total of 903 (n = 445 aged 6-7 years and n = 458 aged 10-11 years) primary school pupils took part. Total Difficulties Score improved in all pupils (6-7 and 10-11 year old pupils) who received the 'Nourish' intervention compared with those that did not (adjusted difference in mean = - 0.82; 95% CI -1.46, - 0.17; P < 0.02). No statistically significant difference in Health-Related Quality of Life was observed. The 'Nourish' intervention also produced some changes in school-based dietary behaviour, which were most apparent in the 10-11 year old pupils. The 'Nourish' intervention also produced improvements in understanding of food labels (adjusted difference in mean = 0.15; 95% CI 0.05, 0.25; P < 0.01) and knowledge of vegetables in season (adjusted difference in mean = 0.29; 95% CI 0.01,0.56; P = 0.04) whilst an increased willingness to try new foods and improved perceived cooking competence was also observed. CONCLUSIONS: Improvements in childhood emotional and behavioural wellbeing, dietary intake, knowledge about food, cooking skills and willingness to try new foods were associated with the 'Nourish' whole-school food environment intervention. Exploration of the sustainability and long-term effectiveness of such whole-school food interventions should be conducted. TRIAL REGISTRATION: National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312 ).

Circulating Sex Hormones Are Associated With Gastric and Colorectal Cancers but Not Esophageal Adenocarcinoma in the UK Biobank.

INTRODUCTION: Gastrointestinal cancers show an unexplained male predominance, but few prospective studies have investigated sex hormones and gastrointestinal cancer risk. This study aimed to determine the impact of circulating sex hormones on risk of esophageal, gastric, and colorectal cancers in men and women. METHODS: We included 219,425 men and 147,180 women from the UK Biobank. Sex hormones were quantified using chemiluminescent immunoassay. Gastrointestinal cancers were identified from cancer registry linkages. Sex hormone concentrations and risk of gastrointestinal cancers were investigated using Cox proportional hazards regression. RESULTS: During the 10 years of follow-up, 376 esophageal adenocarcinoma, 108 esophageal squamous cell carcinoma, and 333 gastric and 2,868 colorectal cancer cases were identified. Increased hazard ratios (HRs) were found for sex hormone-binding globulin (SHBG) and risk of gastric cancer in men (Q4 vs Q1 HR 1.43, 95% confidence interval [CI] 0.95-2.17, Ptrend = 0.01). Free testosterone was inversely associated with esophageal squamous cell carcinoma in women (Q4 vs Q1 HR 0.32, 95% CI 0.11-0.98, Ptrend = 0.05). For colorectal cancer, SHBG was associated with a reduced risk among men (Q4 vs Q1 HR 0.89, 95% CI 0.77-1.03, Ptrend = 0.04) and free testosterone concentrations was associated with a reduction in risk among women (Q4 vs Q1 HR 0.80, 95% CI 0.66-0.97, Ptrend = 0.01). No associations were found for esophageal adenocarcinoma. DISCUSSION: In this large prospective investigation of prediagnostic sex hormones and risk of gastrointestinal cancers, men with higher SHBG concentrations had higher gastric, yet lower colorectal, cancer risks, whereas women with higher free testosterone levels had a lower risk of esophageal squamous cell carcinoma and colorectal cancer.

Post-diagnostic antipsychotic use and cancer mortality: a population based cohort study.

BACKGROUND: Many antipsychotics elevate prolactin, a hormone implicated in breast cancer aetiology however no studies have investigated antipsychotic use in patients with breast cancer. This study investigated if antipsychotic use is associated with an increased risk of cancer-specific mortality among breast cancer patients. METHODS: A cohort of 23,695 women newly diagnosed with a primary breast cancer between 1st January 1998 and 31st December 2012 was identified from the UK Clinical Practice Research Datalink linked to English cancer-registries and followed for until 30th September 2015. Time-dependent Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer-specific mortality comparing use of antipsychotics with non-use, overall, and by prolactin elevating activitiy. Analyses were repeated restricting to patients with a history of severe mental illness to control for potential confounding by indication. RESULTS: In total 848 patients were prescribed an antipsychotic and of which 162 died due to their breast cancer. Compared with non-use, antipsychotic use was associated with an increased risk of breast-cancer specific mortality (HR 2.25, 95%CI 1.90-2.67), but this did not follow a dose response relation. Restricting the cohort to patients with severe mental illness attenuated the association between antipsychotic use and breast cancer-specific mortality (HR 1.11, 95%CI 0.58-2.14). CONCLUSIONS: In this population-based cohort of breast cancer patients, while the use of antipsychotics was associated with increased breast cancer-specific mortality, there was a lack of a dose response, and importantly null associations were observed in patients with severe mental illness, suggesting the observed association is likely a result of confounding by indication. This study provides an exemplar of confounding by indication, highlighting the importance of consideration of this important bias in studies of drug effects in cancer patients.

Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis.

BACKGROUND: CGRP Antibodies are high-cost newly licensed migraine preventatives. OBJECTIVE: To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment. METHODS: Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed. RESULTS: 21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I2  = 69%, Phetereogeneity  < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I2  = 15%, Phetereogeneity  = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59,0.75; I2  = 64%, Phetereogeneity  = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I2  = 20%, Phetereogeneity  = .280). Industry funded every study, but risk of bias was low. CONCLUSIONS: CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.