[This corrects the article DOI: 10.1371/journal.pone.0338907.].

BackgroundThe Bristol IVF Study (BRIST-IVF) is a longitudinal clinical cohort, established to determine factors related to successful live birth and other outcomes following conception by assisted reproductive technologies (ART). This cohort profile describes recruitment, data collection and planned research.MethodsThe study gathered comprehensive sociodemographic, lifestyle, anthropometric, and clinical data from women and their partners before and during treatment, as well as during pregnancy and after birth. Biological samples, including blood, urine, and saliva, were collected at initial recruitment and at pregnancy clinics, with cord blood and placental tissue obtained at birth. Participants consented to NHS record linkage, allowing access to pregnancy and birth outcomes from obstetric notes. Data collection during pregnancy and after birth followed the same protocols as a naturally conceived cohort, the second generation of the Avon Longitudinal Study of Parents and Children (ALSPAC-G2).ResultsBetween 3rd September 2019 and 30th June 2023, 502 couples or single women were recruited (967 individuals in total). Of these, 490 women underwent 1,055 ART treatment cycles during the study follow-up (up to 31st March 2024). Recruited women had a mean age of 35.8 years (SD = 4.4) and a mean BMI of 25.1 (SD = 4.4). At the time of recruitment, 251 women (50%) had never been pregnant, and 374 (75%) had not had a previous live birth. Women and their partners with a confirmed viable pregnancy at a scan performed at 7 weeks of gestation were invited to participate in the pregnancy follow-up study, with 305 women (for 324 pregnancies) invited. Data were collected from pregnancy questionnaires (n = 246, 76%), pregnancy clinic data (n = 119, 37%), and birth questionnaires (n = 223, 69%). Collection of obstetric data from health records is ongoing.ConclusionThe BRIST-IVF cohort enables novel research into the predictors and consequences of ART conception, with comparison to ALSPAC-G2.

BACKGROUND:Observational studies have suggested that a younger age at menarche is associated with increased risks of adverse pregnancy and perinatal outcomes. However, it is unclear whether these relationships are causal. METHODS:We estimated the associations between age at menarche and 13 pre-specified pregnancy outcomes by using two approaches. We estimated observational associations in the Avon Longitudinal Study of Parents and Children (N = 9441) using multivariable regression accounting for educational attainment, ethnicity, maternal age, parity, offspring sex, and adiposity. We conducted two-sample Mendelian randomization (MR) using data from the Mendelian Randomization in Pregnancy (MR-PREG) collaboration (77 683-707 797 pregnancies) and multivariable MR (MVMR) accounting for genetically-proxied adiposity. RESULTS:Older age at menarche was associated with lower risks of hypertensive disorders of pregnancy, gestational hypertension, and preeclampsia, but accounting for adiposity attenuated these effects across approaches. For example, per 1-year older age at menarche, the odds ratio (OR) for hypertensive disorders of pregnancy was 0.88 (95% confidence interval (CI) : 0.84, 0.93) in inverse variance weighted MR and 0.95 (95% CI: 0.90, 1.01) in MVMR, while the observational association attenuated from OR = 0.91 (95% CI: 0.87, 0.94) to OR = 0.97 (95% CI: 0.93, 1.01). No clear evidence was found for the effects of age at menarche on small-for-gestational-age, low birthweight, post-term birth, or perinatal depression from either approach. For other outcomes evidence was limited by imprecision (very preterm birth, gestational diabetes) or inconsistent effects in sensitivity analyses (offspring birthweight, large-for-gestational-age, high birthweight, preterm birth). CONCLUSION:We find little robust evidence for causal effects of age at menarche on pregnancy outcomes. Effects of younger menarche on increased risks of hypertensive disorders of pregnancy may be driven by adiposity.

OBJECTIVE:Our objective was to investigate causal associations of adiposity in different locations and metabolically favorable and unfavorable adiposity (MetFA and MetUFA, respectively) with grip strength. METHODS:Observational cross-sectional and Mendelian randomization (MR) (sex combined and stratified) analysis within UK Biobank (N ≤ 340,258) was used to assess the relationships of  visceral, abdominal subcutaneous, and gluteofemoral adipose tissue, anterior and posterior thigh muscle fat infiltration (ATMFI and PTMFI, respectively), body fat (BF) percentage, MetFA, and MetUFA with grip strength. RESULTS:In inverse variance weighted MR analysis, SD increases in BF, MetFA, and ATMFI were associated with lower grip strength by the following: -0.10 SD (95% CI: -0.16 to -0.04), -0.31 SD (95% CI: -0.45 to -0.18), and -0.05 SD (95% CI: -0.09 to -0.01), respectively. PTMFI associations aligned with ATMFI. Observational analyses were consistent for BF and ATMFI/PTMFI, but weighted median/mode MR corroborated findings for MetFA and ATMFI/PTMFI only. Higher visceral adipose tissue was associated with lower grip strength in observational analyses only. Associations for higher abdominal subcutaneous adipose tissue were inconsistent: Observational analyses suggested weaker grip; MR analyses suggested stronger grip, particularly in female individuals. There was no strong evidence in MR for associations with MetUFA or gluteofemoral adipose tissue. CONCLUSIONS:Targeting fat infiltration in muscle may improve muscle function. MetFA appears to negatively impact muscle strength, requiring further investigation into underlying mechanisms.

Introduction There is a lack of evidence on whether vaping harm perceptions can predict vaping and smoking behaviors among young adults in the United Kingdom. We aimed to assess whether the perceived harm of vaping relative to smoking is associated with subsequent changes in vaping and smoking behaviors in this population.Methods Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective cohort study. Longitudinal associations were assessed between the perceived harm of vaping relative to smoking at baseline (approximately 24 years old; Nov'15-Aug'17) and the following smoking/vaping outcomes at follow-up (approximately 30 years old; May-Oct'22): (1) stopping smoking, (2) initiation of ever smoking and/or vaping, and (3) uptake of past 30-day smoking and/or vaping. Multinomial logistic regressions were used, adjusting for sociodemographic factors.Results Among young adults who smoked but did not vape at baseline (n = 687), the perception that vaping is less harmful than smoking (vs. equally/more harmful, or don't know) was associated with stopping smoking and now vaping at follow-up (adjusted Relative Risk Ratio (aRRR)=1.69, 95%CI = 1.02 to 2.81, p = .04). Initiation of ever smoking/vaping, or uptake of past 30-day smoking/vaping, were not common during the study period and there was little evidence that these outcomes were associated with relative vaping harm perceptions at baseline.Conclusions Among young adults who smoke, perceiving vaping as less harmful than smoking was associated with switching from smoking to vaping six years later. Few young adults who did not smoke or vape initiated these behaviors during the study period.Implications This is the first study in England to find that young adults who smoked and who accurately perceived vaping as less harmful than smoking were more likely to switch to vaping 6 years later. This is consistent with prior studies among adults and highlights the need for interventions to improve the pervasive misperceptions about vaping that are currently observed among young adults who smoke.

BACKGROUND. Liver fibrosis is an important clinical endpoint of the progression of autoimmune liver disease (AILD); its monitoring would benefit from noninvasive imaging tools. OBJECTIVE. The purpose of this study was to assess the relationship between MR elastography (MRE) liver stiffness measurements and histologic liver fibrosis, as well as to evaluate the performance of MRE and biochemical-based clinical markers for stratifying histologic liver fibrosis severity, in children and young adults with AILD. METHODS. This retrospective study used an existing institutional registry of children and young adults diagnosed with AILD (primary sclerosing cholangitis [PSC], autoimmune sclerosing cholangitis [ASC], or autoimmune hepatitis [AIH]). The registry was searched to identify patients who underwent both a research abdominal 1.5-T MRI examination that included liver MRE (performed for registry enrollment) and a clinically indicated liver biopsy within 6 months of that examination. MRE used a 2D gradient-recalled echo sequence. One analyst measured mean liver shear stiffness (in kilopascals) for each examination. Laboratory markers of liver fibrosis (aspartate aminotransferase- to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] score) were recorded. For investigational purposes, one pathologist, blinded to clinical and MRI data, determined histologic Metavir liver fibrosis stage. The Spearman rank order correlation coefficient was calculated between MRE liver stiffness and Metavir liver fibrosis stage. ROC analysis was used to evaluate diagnostic performance for identifying advanced fibrosis (i.e., differentiating Metavir F0-F1 from F2-F4 fibrosis), and sensitivity and specificity were calculated using the Youden index. RESULTS. The study included 46 patients (median age, 16.6 years [IQR, 13.7-17.8 years]; 20 female patients, 26 male patients); 12 had PSC, 10 had ASC, and 24 had AIH. Median MRE liver stiffness was 2.9 kPa (IQR, 2.2-4.0 kPa). MRE liver stiffness and Metavir fibrosis stage showed strong positive correlation (rho = 0.68). For identifying advanced liver fibrosis, MRE liver stiffness had an AUC of 0.81, with sensitivity of 65.4% and specificity of 90.0%; APRI had an AUC of 0.72, with sensitivity of 64.0% and specificity of 80.0%; and FIB-4 score had an AUC of 0.71, with sensitivity of 60.0% and specificity of 85.0%. CONCLUSION. MRE liver stiffness measurements were associated with histologic liver fibrosis severity. CLINICAL IMPACT. The findings support a role for MRE in noninvasive monitoring of liver stiffness, a surrogate for fibrosis, in children and young adults with AILD.

The detrimental health effects of smoking are well-known, but the impact of regular nicotine use without exposure to the other constituents of tobacco is less clear. Given the increasing daily use of alternative nicotine delivery systems, such as e-cigarettes, it is increasingly important to understand and separate the effects of nicotine use from the impact of tobacco smoke exposure. Using a multivariable Mendelian randomisation framework, we explored the direct effects of nicotine compared with the non-nicotine constituents of tobacco smoke on health outcomes (lung cancer, chronic obstructive pulmonary disease [COPD], forced expiratory volume in one second [FEV-1], forced vital capacity [FVC], coronary heart disease [CHD], and heart rate [HR]). We used Genome-Wide Association Study (GWAS) summary statistics from Buchwald and colleagues, the GWAS and Sequencing Consortium of Alcohol and Nicotine, the International Lung Cancer Consortium, and UK Biobank. Increased nicotine metabolism increased the risk of COPD, lung cancer, and lung function in the univariable analysis. However, when accounting for smoking heaviness in the multivariable analysis, we found that increased nicotine metabolite ratio (indicative of decreased nicotine exposure per cigarette smoked) decreases heart rate (b = -0.30, 95% CI -0.50 to -0.10) and lung function (b = -33.33, 95% CI -41.76 to -24.90). There was no clear evidence of an effect on the remaining outcomes. The results suggest that these smoking-related outcomes are not due to nicotine exposure but are caused by the other components of tobacco smoke; however, there are multiple potential sources of bias, and the results should be triangulated using evidence from a range of methodologies.

Participants in the 100,000 Genomes Project (100kGP) could consent to receive additional finding (AF) results, individual variants relating to genes associated with susceptibility to cancer and familial hypercholesterolemia (FH). In the study reported here, qualitative interviews were used to explore the experiences of National Health Service (NHS) professionals from across England who were tasked with returning over 80,000 "no AF" results and 700 positive AF results to 100kGP participants. Interviews were conducted with 45 professionals from a range of backgrounds, including Genetic Counsellors, Clinical Geneticists, FH Clinical Nurse Specialists and Clinical Scientists. Interviews were analysed using a codebook thematic analysis approach. Returning AF results has been a significant endeavour, with challenges for pathways, administrative processes and clinical and laboratory time when the capacity of NHS services is already stretched. Professionals discussed going "above and beyond" to prioritise patient care through pathway design, additional clinics, overtime, longer appointments and provision of follow-up appointments. Professionals also described facing practical and emotional challenges when returning AFs. Benefits for patients from receiving AFs in the 100kGP were highlighted and professionals were generally positive about offering clinically actionable AFs within routine NHS clinical care. Professionals were, however, cautious around the implementation of AFs into routine care and felt more research and discussion was needed to determine which AFs to offer, approaches to consent and communication of results, costs and the potential strain on NHS capacity and resources. Further consultation is required with careful review of pathways and resources before offering AFs in clinical practice.

Background:Children with autoimmune liver disease (AILD) may develop fibrosis-related complications necessitating a liver transplant. We hypothesize that tissue-based analysis of liver fibrosis by second harmonic generation (SHG) microscopy with artificial intelligence analysis can yield prognostic biomarkers in AILD.Methods:Patients from single-center studies with unstained slides from clinically obtained liver biopsies at AILD diagnosis were identified. Baseline demographics and liver biochemistries at diagnosis and 1 year were collected. Clinical endpoints studied included the presence of varices, variceal bleeding, ascites, HE, and liver transplant. In collaboration with HistoIndex, unstained slides underwent SHG/artificial intelligence analysis to map fibrosis according to 10 quantitative fibrosis parameters based on tissue location, including total, periportal, perisinusoidal, and pericentral area and length of strings.Results:Sixty-three patients with AIH (51%), primary sclerosing cholangitis (30%), or autoimmune sclerosing cholangitis (19%) at a median of 14 years old (range: 3-24) were included. An unsupervised analysis of quantitative fibrosis parameters representing total and portal fibrosis identified a patient cluster with more primary sclerosing cholangitis/autoimmune sclerosing cholangitis. This group had more fibrosis at diagnosis by METAVIR classification of histopathological review of biopsies (2.5 vs. 2; p = 0.006). This quantitative fibrosis pattern also predicted abnormal 12-month ALT with an OR of 3.6 (1.3-10, p = 0.014), liver complications with an HR of 3.2 (1.3-7.9, p = 0.01), and liver transplantation with an HR of 20.1 (3-135.7, p = 0.002).Conclusions:The application of SHG/artificial intelligence algorithms in pediatric-onset AILD provides improved insight into liver histopathology through fibrosis mapping. SHG allows objective identification of patients with biliary tract involvement, which may be associated with a higher risk for refractory disease.

OBJECTIVES:To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). SUBJECTS AND METHODS:Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. RESULTS:A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. CONCLUSION:This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

BackgroundGenetic testing to identify germline high-risk pathogenic variants in breast cancer susceptibility genes is increasingly part of the breast cancer diagnostic pathway. Novel patient-centred pathways may offer opportunity to expand capacity and reduce turnaround time.MethodsWe recruited 1140 women with unselected breast cancer to undergo germline genetic testing through the BRCA-DIRECT pathway (which includes a digital platform, postal saliva sampling and a genetic counsellor telephone helpline). Ahead of consenting to the test, participants were randomised to receive information about genetic testing digitally (569/1140, 49.9%) or via a pre-test genetic counselling consultation (571/1140, 50.1%).Results1001 (87.8%) participants progressed to receive their pre-test information and consented to testing. The primary outcome, uptake of genetic testing, was higher amongst participants randomised to receive digital information compared with those randomised to a pre-test genetic counselling consultation (90.8% (95% CI: 88.5% to 93.1%) vs 84.7% (95% CI: 81.8% to 87.6%), p = 0.002, adjusted for participant age and site). Non-inferiority was observed in relation to patient knowledge, anxiety, and satisfaction.ConclusionsFindings demonstrate that standardised, digital information offers a non-inferior alternative to conventional genetic counselling, and an end-to-end patient-centred, digital pathway (supported by genetic counselling hotline) could feasibly be implemented into breast oncology settings.Clinical trial registrationThe study is registered with, and protocol available on, ClinicalTrials.gov (NCT04842799).

Participants in the 100,000 Genomes Project (100kGP) could consent to receive additional finding (AF) results, individual variants relating to genes associated with susceptibility to cancer and familial hypercholesterolemia (FH). In the study reported here, qualitative interviews were used to explore the experiences of National Health Service (NHS) professionals from across England who were tasked with returning over 80,000 “no AF” results and 700 positive AF results to 100kGP participants. Interviews were conducted with 45 professionals from a range of backgrounds, including Genetic Counsellors, Clinical Geneticists, FH Clinical Nurse Specialists and Clinical Scientists. Interviews were analysed using a codebook thematic analysis approach. Returning AF results has been a significant endeavour, with challenges for pathways, administrative processes and clinical and laboratory time when the capacity of NHS services is already stretched. Professionals discussed going “above and beyond” to prioritise patient care through pathway design, additional clinics, overtime, longer appointments and provision of follow-up appointments. Professionals also described facing practical and emotional challenges when returning AFs. Benefits for patients from receiving AFs in the 100kGP were highlighted and professionals were generally positive about offering clinically actionable AFs within routine NHS clinical care. Professionals were, however, cautious around the implementation of AFs into routine care and felt more research and discussion was needed to determine which AFs to offer, approaches to consent and communication of results, costs and the potential strain on NHS capacity and resources. Further consultation is required with careful review of pathways and resources before offering AFs in clinical practice.

The purpose of this study was to assess relationships between liver-corrected T1 (cT1) values (adjusted for T2* effect, MRI system manufacturer, and field strength) and histologic inflammation and fibrosis in 35 participants (15 women and girls, 20 boys and men; median age, 16.0 years) with autoimmune liver disease. At multivariable analysis, inflammation score (β = 15.5) and sex (β = 56.0 [female]) were independent predictors of cT1, and fibrosis score (β = 32.3) and age (β = 5.5) were independent predictors of cT1 IQR. Liver T1 may have relevance for assessing liver inflammatory activity and fibrosis stage.

AIMS:To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS:Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION:These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

ABSTRACT Objectives To examine association of conception by assisted reproductive technology (ART) with offspring cardio-metabolic health outcomes, and whether these differ by offspring age. Design Multi-cohort study. Setting Fourteen population-based cohort studies with offspring from the UK, Ireland, France, the Netherlands, Portugal, Greece, Italy, Norway, Singapore, and Australia for meta-analysis of various ages. Four cohorts (three European and one Singaporean) with repeated measures for pooled age-change (from 3 to 26 years) trajectory analysis. Participants Young people sampled from the general population with complete data on mode of conception, confounders, and ≥1 cardio-metabolic outcome measured after birth. Exposures Conception by ART versus natural conception (NC). Main outcome measures Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), triglycerides (TG), glucose, insulin, and glycated haemoglobin (HbA1c). Results Between 35,780 (605 ART) and 4,502 (67 ART) offspring were included in meta-analysis of various ages for each outcome. Mean age at outcome assessment ranged from 13 months to 27.4 years, with most cohorts ((11/14) having mean age <10 years. Compared with NC, ART-conceived offspring had similar SBP (mean difference (ART minus NC): -0.89 mmHg ; 95%CI: -1.91 to 0.14), DBP (−0.50 mmHg ; -1.65 to 0.66), and HR (0.02 beats/min ; -1.00 to 1.03). Cholesterol measures were higher in ART-conceived than NC offspring, for TC (mean % difference: 2.54 % ; 0.46 to 4.61), HDLc (4.17 % ; 1.79 to 6.56), and LDLc (4.95 % ; 0.99 to 8.92), whereas triglycerides were similar (−1.53 % ; -6.19 to 3.13). No clear differences were seen for glucose (0.25 % ; -1.38 to 1.88), insulin (−5.04 % ; -13.20 to 3.12), or HbA1c (−0.07 % ; -0.14 to 0.00). Trajectory models in up to 17,244 (244 ART) offspring showed that early life trajectory differences were consistent with the above pooled results and showed higher SBP emerging from mid-adolescence to adulthood with ART (e.g., predicted mean difference in SBP at age 26 years for ART versus NC was 5.06 mmHg ; 1.76 to 8.35). Conclusions Children conceived through ART had higher cholesterol and similar blood pressure and hyperglycaemic/insulin resistance measures compared with NC children. Whilst overall this is reassuring, our trajectory analysis in a sub-group of cohorts suggested that those conceived by ART may go on to develop higher blood pressure in early adulthood. Our study shows the importance of follow-up into adulthood and requires validation by independent studies with different study designs including within-sibship and mechanistic studies.

Background: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. Methods: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. Results: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. Conclusions: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner.

BACKGROUND:Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS:In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases. RESULTS:On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS:Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk.

ABSTRACTImportancePeople conceived using assisted reproductive technology (ART) make up an increasing proportion of the world’s population, and their numbers are expected to continue rising.ObjectiveInvestigate association of ART conception with growth and adiposity outcomes from infancy to early adulthood in offspring from a large multinational multi-cohort study.Design26 population-based cohort studies.SettingEurope, Asia-Pacific, and North AmericaParticipantsInfants, children, adolescents, and young adults born from 1984 to 2018, with mean ages at assessment of growth/adiposity outcomes ranging from 0.6 month to 27.4 years.ExposuresConception by ART (conventional in vitro fertilisation and intracytoplasmic sperm injection) versus natural conception (NC).Main Outcomes and MeasuresLength/height, weight, and body mass index (BMI). Each cohort was analysed separately with adjustment for maternal BMI, age, smoking, education, parity, ethnicity, and offspring sex and age. Cohort results were combined in random effects meta-analysis for thirteen age groups.ResultsUp to 158,066 offspring (4,329 conceived by ART) were included in each age-group meta-analysis; 47.6% to 60.6% were female. Compared with NC, ART-conceived offspring were slightly shorter, lighter, and thinner from infancy to early adolescence. The differences in growth/adiposity outcomes were largest at the youngest ages and attenuated with older child age, e.g., adjusted standardised mean differences (95% confidence intervals) in offspring weight at age ‘<3 months’, ‘17 to 23 months’, ‘6 to 9 years’, and ‘14 to 17 years’ were -0.27 standard deviation (SD) units (−0.39 to -0.16), -0.16SD (−0.22 to -0.09), -0.07SD (−0.10 to -0.04), and -0.02SD (−0.15 to 0.12), respectively. There was no evidence that results were driven by parental subfertility or of difference between conventional in vitro fertilisation and intracytoplasmic sperm injection however, smaller offspring size appeared to be limited to offspring conceived by fresh but not frozen embryo transfer, compared with NC. More marked but less precise differences were observed for body fat measurements. There was imprecise evidence that offspring conceived by ART may develop greater adiposity by early adulthood.Conclusions and RelevancePeople conceiving or conceived by ART can be reassured that differences in early growth and adiposity are small and no longer evident by late adolescence.KEY POINTSQuestionIs conception by assisted reproductive technology associated with growth and adiposity from infancy to early adulthood?FindingsIn this multi-cohort study of up to 158,066 European, Asian-Pacific, and Canadian infants, children, adolescents, and young adults, those conceived using assisted reproductive technology were on average shorter, lighter, and thinner from infancy up to early adolescence when compared with their naturally conceived peers though differences were small across all ages and reduced with older age.MeaningParents conceiving or hoping to conceive through assisted reproductive technology and their offspring should be reassured that differences in early life growth and adiposity are small and no longer apparent by late adolescence.

BackgroundGermline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing.MethodsWe designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing ofBRCA1/BRCA2/PALB2(BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway).ResultsUptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met.ConclusionPilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses.Trial registration numberISRCTN87845055.