Sex steroid hormones and risk of breast cancer:a two-sample Mendelian randomization study

BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association. METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses. RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09–1.21, OR 1.19, 95% CI 1.07–1.33 and OR 1.03, 95% CI 1.01–1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12–1.27, OR 1.25, 95% CI 1.11–1.40 and OR 1.06, 95% CI 1.03–1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03–1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC. CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-022-01553-9

Homeopathy in the treatment of depression: a systematic review

Introduction: Depression is a common reason for patients to consult homeopaths. This review aims to assess the efficacy, effectiveness and safety of homeopathy in depression. Methods: Thirty databases/sources were used to identify studies reporting on homeopathy in depression, published between 1982 and 2016. Studies were assessed for their risk of bias, model validity, aspect of homeopathy and comparator. Results: Eighteen studies assessing homeopathy in depression were identified. Two double-blind placebo-controlled trials of homeopathic medicinal products (HMPs) for depression were assessed. The first trial (N = 91) with high risk of bias found HMPs were non-inferior to fluoxetine at 4 (p = 0.654) and 8 weeks (p = 0.965); whereas the second trial (N = 133), with low risk of bias, found HMPs was comparable to fluoxetine (p = 0.082) and superior to placebo (p < 0.005) at 6 weeks. The remaining research had unclear/high risk of bias. A non-placebo-controlled RCT found standardised treatment by homeopaths comparable to fluvoxamine; a cohort study of patients receiving treatment provided by GPs practising homeopathy reported significantly lower consumption of psychotropic drugs and improved depression; and patient-reported outcomes showed at least moderate improvement in 10 of 12 uncontrolled studies. Fourteen trials provided safety data. All adverse events were mild or moderate, and transient. No evidence suggested treatment was unsafe. Conclusions: Limited evidence from two placebo-controlled double-blinded trials suggests HMPs might be comparable to antidepressants and superior to placebo in depression, and patients treated by homeopaths report improvement in depression. Overall, the evidence gives a potentially promising risk benefit ratio. There is a need for additional high quality studies

Rethinking ADHD intervention trials: feasibility testing of two treatments and a methodology

Attention deficit hyperactivity disorder (ADHD) is a lifelong condition associated with considerable costs. The long-term effectiveness and acceptability of treatments to improve outcomes remains in doubt. Long-term trials are needed comparing interventions with standard care and each other. The Sheffield Treatments for ADHD Research (STAR) project used the Trials within Cohorts (TwiCs) approach. A cohort of children with ADHD was recruited and outcomes collected from carers and teachers. A random selection was offered treatment by homoeopaths (hom) or nutritional therapists (NT). Their outcomes (Conners Global ADHD Index) were compared with those not offered interventions. The feasibility of the methods and interventions was assessed. The TwiCs approach was feasible with modifications. 144 participants were recruited to the cohort, 83 offered treatment, 72 accepted, and 50 attended 1+ appointments. Results according to carers assessments at 6 months were as follows: t = 1.08, p = .28 (− 1.48, 4.81) SMD .425 (hom); t = 1.71, p = .09 (− .347, 5.89), SMD = .388 (NT). Teachers’ responses were too few and unstable. No serious treatment adverse events occurred. Conclusion: the STAR project demonstrated the feasibility of the TwiCs approach for testing interventions for children with ADHD

Deprivation, clubs and drugs: results of a UK regional population-based cross-sectional study of weight management strategies

Background Despite rising levels of obesity in England, little is known about slimming club and weight loss drug (medication) use or users. In order to inform future commissioning, we report the prevalence of various weight management strategies and examine the associations between slimming club and medication use and age, gender, deprivation and body mass index. Methods A population based cross-sectional survey of 26,113 adults was conducted in South Yorkshire using a self-completed health questionnaire. Participants were asked whether they had ever used the following interventions to manage their weight: increasing exercise, healthy eating, controlling portion size, slimming club, over the counter weight loss medication, or meal replacements. Factors associated with slimming club and weight-loss medication use were explored using logistic regression. Results Over half of the sample was either overweight (36.6%) or obese (19.6%). Obesity was more common in the most deprived areas compared to the least deprived (26.3% vs. 12.0%). Healthy eating (49.0%), controlling portion size (43.4%), and increasing exercise (43.0%) were the most commonly reported weight management strategies. Less common strategies were attending a slimming club (17.2%), meal replacements (3.4%) and weight-loss medication (3.2%). Adjusting for BMI, age, deprivation and long standing health conditions, women were significantly more likely to report ever using a slimming club (adjusted OR = 18.63, 95% CI = 16.52–21.00) and more likely to report ever using over the counter weight-loss medications (AOR = 3.73, 95% CI = 3.10-4.48), while respondents from the most deprived areas were less likely to report using slimming clubs (AOR = 0.60, 95% CI = 0.53-0.68), and more likely to reporting using weight loss medications (AOR =1.38, 95% CI = 1.05-1.82). Conclusion A large proportion of individuals report having used weight management strategies. Slimming clubs and over-the-counter weight loss medication account for a smaller proportion of the overall uptake. Those from less deprived areas were more likely to use slimming clubs while those from more deprived areas were more likely to use weight-loss medications. Future NHS and Local Authority commissioning of weight management services must be aware of this varying social gradient in weight management strategies

Alternative Covid-19 mitigation measures in school classrooms:analysis using an agent-based model of SARS-CoV-2 transmission

The SARS-CoV-2 epidemic has impacted children's education, with schools required to implement infection control measures that have led to periods of absence and classroom closures. We developed an agent-based epidemiological model of SARS-CoV-2 transmission in a school classroom that allows us to quantify projected infection patterns within primary school classrooms, and related uncertainties. Our approach is based on a contact model constructed using random networks, informed by structured expert judgement. The effectiveness of mitigation strategies in suppressing infection outbreaks and limiting pupil absence are considered. COVID-19 infections in primary schools in England in autumn 2020 were re-examined and the model was then used to estimate infection levels in autumn 2021, as the Delta variant was emerging and it was thought likely that school transmission would play a major role in an incipient new wave of the epidemic. Our results were in good agreement with available data. These findings indicate that testing-based surveillance is more effective than bubble quarantine, both for reducing transmission and avoiding pupil absence, even accounting for insensitivity of self-administered tests. Bubble quarantine entails large numbers of absences, with only modest impact on classroom infections. However, maintaining reduced contact rates within the classroom can have a major benefit for managing COVID-19 in school settings

Alternative Covid-19 mitigation measures in school classrooms:analysis using an agent-based model of SARS-CoV-2 transmission

The SARS-CoV-2 epidemic has impacted children's education, with schools required to implement infection control measures that have led to periods of absence and classroom closures. We developed an agent-based epidemiological model of SARS-CoV-2 transmission in a school classroom that allows us to quantify projected infection patterns within primary school classrooms, and related uncertainties. Our approach is based on a contact model constructed using random networks, informed by structured expert judgement. The effectiveness of mitigation strategies in suppressing infection outbreaks and limiting pupil absence are considered. COVID-19 infections in primary schools in England in autumn 2020 were re-examined and the model was then used to estimate infection levels in autumn 2021, as the Delta variant was emerging and it was thought likely that school transmission would play a major role in an incipient new wave of the epidemic. Our results were in good agreement with available data. These findings indicate that testing-based surveillance is more effective than bubble quarantine, both for reducing transmission and avoiding pupil absence, even accounting for insensitivity of self-administered tests. Bubble quarantine entails large numbers of absences, with only modest impact on classroom infections. However, maintaining reduced contact rates within the classroom can have a major benefit for managing COVID-19 in school settings

Association Between Genetic Variants on Chromosome 15q25 Locus and Objective Measures of Tobacco Exposure

Background: Two single-nucleotide polymorphisms, rs1051730 and rs16969968, located within the nicotinic acetylcholine receptor gene cluster on chromosome 15q25 locus, are associated with heaviness of smoking, risk for lung cancer, and other smoking-related health outcomes. Previous studies have typically relied on self-reported smoking behavior, which may not fully capture interindividual variation in tobacco exposure. / Methods: We investigated the association of rs1051730 and rs16969968 genotype (referred to as rs1051730–rs16969968, because these are in perfect linkage disequilibrium and interchangeable) with both self-reported daily cigarette consumption and biochemically measured plasma or serum cotinine levels among cigarette smokers. Summary estimates and descriptive statistical data for 12 364 subjects were obtained from six independent studies, and 2932 smokers were included in the analyses. Linear regression was used to calculate the per-allele association of rs1051730–rs16969968 genotype with cigarette consumption and cotinine levels in current smokers for each study. Meta-analysis of per-allele associations was conducted using a random effects method. The likely resulting association between genotype and lung cancer risk was assessed using published data on the association between cotinine levels and lung cancer risk. All statistical tests were two-sided. / Results: Pooled per-allele associations showed that current smokers with one or two copies of the rs1051730–rs16969968 risk allele had increased self-reported cigarette consumption (mean increase in unadjusted number of cigarettes per day per allele = 1.0 cigarette, 95% confidence interval [CI] = 0.57 to 1.43 cigarettes, P = 5.22 × 10−6) and cotinine levels (mean increase in unadjusted cotinine levels per allele = 138.72 nmol/L, 95% CI = 97.91 to 179.53 nmol/L, P = 2.71 × 10−11). The increase in cotinine levels indicated an increased risk of lung cancer with each additional copy of the rs1051730–rs16969968 risk allele (per-allele odds ratio = 1.31, 95% CI = 1.21 to 1.42). / Conclusions: Our data show a stronger association of rs1051730–rs16969968 genotype with objective measures of tobacco exposure compared with self-reported cigarette consumption. The association of these variants with lung cancer risk is likely to be mediated largely, if not wholly, via tobacco exposure

Optimised patient information materials and recruitment to a study of behavioural activation in older adults : an embedded study within a trial [version 1; peer review: awaiting peer review]

YesPrinted participant information about randomised controlled trials is often long, technical and difficult to navigate. Improving information materials is possible through optimisation and user-testing, and may impact on participant understanding and rates of recruitment. Methods: A study within a trial (SWAT) was undertaken within the CASPER trial. Potential CASPER participants were randomised to receive either the standard trial information or revised information that had been optimised through information design and user testing. Results: A total of 11,531 patients were randomised in the SWAT. Rates of recruitment to the CASPER trial were 2.0% in the optimised information group and 1.9% in the standard information group (odds ratio 1.027; 95% CI 0.79 to 1.33; p=0.202). Conclusions: Participant information that had been optimised through information design and user testing did not result in any change to rate of recruitment to the host trial. Registration: ISRCTN ID ISRCTN02202951; registered on 3 June 2009.UK National Institute of Health Research Health Technology Assessment Programme (project number 08/19/04)This article is included in the Studies Within A Trial (SWAT) collection (https://f1000research.com/collections/swat

Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception

Abstract Background The well-established association of chronological age with changes in DNA methylation is primarily founded on the analysis of large sets of blood samples, while conclusions regarding tissue-specificity are typically based on small number of samples, tissues and CpGs. Here, we systematically investigate the tissue-specific character of age-related DNA methylation changes at the level of the CpG, functional genomic region and nearest gene in a large dataset. Results We assembled a compendium of public data, encompassing genome-wide DNA methylation data (Illumina 450k array) on 8092 samples from 16 different tissues, including 7 tissues with moderate to high sample numbers (Dataset size range 96–1202, N total = 2858). In the 7 tissues (brain, buccal, liver, kidney, subcutaneous fat, monocytes and T-helper cells), we identified 7850 differentially methylated positions that gained (gain-aDMPs; cut-offs: P bonf ≤ 0.05, effect size ≥ 2%/10 years) and 4,287 that lost DNA methylation with age (loss-aDMPs), 92% of which had not previously been reported for whole blood. The majority of all aDMPs identified occurred in one tissue only (gain-aDMPs: 85.2%; loss-aDMPs: 97.4%), an effect independent of statistical power. This striking tissue-specificity extended to both the functional genomic regions (defined by chromatin state segmentation) and the nearest gene. However, aDMPs did accumulate in regions with the same functional annotation across tissues, namely polycomb-repressed CpG islands for gain-aDMPs and regions marked by active histone modifications for loss-aDMPs. Conclusion Our analysis shows that age-related DNA methylation changes are highly tissue-specific. These results may guide the development of improved tissue-specific markers of chronological and, perhaps, biological age