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AbstractObjectiveTo consolidate evidence from systematic reviews and meta-analyses investigating the association between reproductive factors in women of reproductive age and their subsequent risk of cardiovascular disease.DesignUmbrella review.Data sourcesMedline, Embase, and Cochrane databases for systematic reviews and meta-analyses from inception until 31 August 2019.Review methodsTwo independent reviewers undertook screening, data extraction, and quality appraisal. The population was women of reproductive age. Exposures were fertility related factors and adverse pregnancy outcomes. Outcome was cardiovascular diseases in women, including ischaemic heart disease, heart failure, peripheral arterial disease, and stroke.Results32 reviews were included, evaluating multiple risk factors over an average follow-up period of 7-10 years. All except three reviews were of moderate quality. A narrative evidence synthesis with forest plots and tabular presentations was performed. Associations for composite cardiovascular disease were: twofold for pre-eclampsia, stillbirth, and preterm birth; 1.5-1.9-fold for gestational hypertension, placental abruption, gestational diabetes, and premature ovarian insufficiency; and less than 1.5-fold for early menarche, polycystic ovary syndrome, ever parity, and early menopause. A longer length of breastfeeding was associated with a reduced risk of cardiovascular disease. The associations for ischaemic heart disease were twofold or greater for pre-eclampsia, recurrent pre-eclampsia, gestational diabetes, and preterm birth; 1.5-1.9-fold for current use of combined oral contraceptives (oestrogen and progesterone), recurrent miscarriage, premature ovarian insufficiency, and early menopause; and less than 1.5-fold for miscarriage, polycystic ovary syndrome, and menopausal symptoms. For stroke outcomes, the associations were twofold or more for current use of any oral contraceptive (combined oral contraceptives or progesterone only pill), pre-eclampsia, and recurrent pre-eclampsia; 1.5-1.9-fold for current use of combined oral contraceptives, gestational diabetes, and preterm birth; and less than 1.5-fold for polycystic ovary syndrome. The association for heart failure was fourfold for pre-eclampsia. No association was found between cardiovascular disease outcomes and current use of progesterone only contraceptives, use of non-oral hormonal contraceptive agents, or fertility treatment.ConclusionsFrom menarche to menopause, reproductive factors were associated with cardiovascular disease in women. In this review, presenting absolute numbers on the scale of the problem was not feasible; however, if these associations are causal, they could account for a large proportion of unexplained risk of cardiovascular disease in women, and the risk might be modifiable. Identifying reproductive risk factors at an early stage in the life of women might facilitate the initiation of strategies to modify potential risks. Policy makers should consider incorporating reproductive risk factors as part of the assessment of cardiovascular risk in clinical guidelines.Systematic review registrationPROSPERO CRD42019120076.

ObjectiveAtrial fibrillation (AF) is the most common cardiac arrhythmia and an important risk factor for stroke. Treatment with anticoagulants substantially reduces risk of stroke. Current prevalence and treatment rates of AF in the UK as well as changes in recent years are not known. The aim of this analysis was to determine trends in age–sex specific prevalence and treatment of AF in the UK from 2000 to 2016.Methods17 sequential cross-sectional analyses were carried out between 2000 and 2016 using a large database of electronic primary care records of patients registered with UK general practitioners. These determined the prevalence of patients diagnosed with AF, the stroke risk of those with AF and the proportion of AF patients currently receiving anticoagulants. Stroke risk was assessed using CHA2DS2-VASc score.ResultsAge–sex standardised AF prevalence increased from 2.14% (95% CI 2.11% to 2.17%) in 2000 to 3.29% (95% CI 3.27% to 3.32%) in 2016. Between 2000 and 2016, the proportion of patients with AF prescribed anticoagulants increased from 35.4% (95% CI 34.7% to 36.1%) to 75.5% (95% CI 75.1% to 75.8%) in those with high stroke risk (p for change over time <0.001) and from 32.8% (95% CI 30.5% to 35.2%) to 47.1% (95% CI 45.4% to 48.7%) in those with moderate stroke risk (p<0.001). In patients with low risk of stroke, the proportion decreased from 19.9% (95% CI 17.8% to 22.2%) to 9.7% (95% CI 8.4% to 11.1%) (p<0.001). Anticoagulant prescribing performance varied between practices; in 2016, the proportion of eligible patients treated was 82.9% (95% CI 82.2% to 83.7%) and 62.0% (95% CI 61.0% to 63.0%) in the highest-performing and lowest-performing practice quintiles, respectively. There was poor agreement in individual practice performance over time from 2006 to 2016: linear-weighted κ=0.10 (95% CI 0.02 to 0.19).ConclusionsFrom 2000 to 2016, the prevalence of recorded AF has increased in all age groups and both sexes. Anticoagulant treatment of eligible patients with AF has more than doubled, with marked improvements since 2011, alongside a reduction in the use of anticoagulants in ineligible patients with AF.

Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a “glucose-sensor” or “glucose receptor” in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose “gate-keeper” in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs) may increase insulin secretion from the pancreas and promote glycogen synthesis in the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and a novel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.

The use of primary care electronic health records for research is abundant. The benefits gained from utilising such records lies in their size, longitudinal data collection and data quality. However, the use of such data to undertake high quality epidemiological studies, can lead to significant challenges particularly in dealing with misclassification, variation in coding and the significant effort required to pre-process the data in a meaningful format for statistical analysis. In this paper, we describe a methodology to aid with the extraction and processing of such databases, delivered by a novel software programme; the “Data extraction for epidemiological research” (DExtER). The basis of DExtER relies on principles of extract, transform and load processes. The tool initially provides the ability for the healthcare dataset to be extracted, then transformed in a format whereby data is normalised, converted and reformatted. DExtER has a user interface designed to obtain data extracts specific to each research question and observational study design. There are facilities to input the requirements for; eligible study period, definition of exposed and unexposed groups, outcome measures and important baseline covariates. To date the tool has been utilised and validated in a multitude of settings. There have been over 35 peer-reviewed publications using the tool, and DExtER has been implemented as a validated public health surveillance tool for obtaining accurate statistics on epidemiology of key morbidities. Future direction of this work will be the application of the framework to linked as well as international datasets and the development of standardised methods for conducting electronic pre-processing and extraction from datasets for research purposes.

Gestational diabetes mellitus (GDM) is associated with developing type 2 diabetes, but very few studies have examined its effect on developing cardiovascular disease. We conducted a retrospective cohort study utilizing a large primary care database in the United Kingdom. From 1 February 1990 to 15 May 2016, 9,118 women diagnosed with GDM were identified and randomly matched with 37,281 control women by age and timing of pregnancy (up to 3 months). Adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated for cardiovascular risk factors and cardiovascular disease. Women with GDM were more likely to develop type 2 diabetes (IRR = 21.96; 95% CI 18.31-26.34) and hypertension (IRR = 1.85; 95% CI 1.59-2.16) after adjusting for age, Townsend (deprivation) quintile, body mass index, and smoking. For ischemic heart disease (IHD), the IRR was 2.78 (95% CI 1.37-5.66), and for cerebrovascular disease 0.95 (95% CI 0.51-1.77; p-value = 0.87), after adjusting for the above covariates and lipid-lowering medication and hypertension at baseline. Follow-up screening for type 2 diabetes and cardiovascular risk factors was poor. Limitations include potential selective documentation of severe GDM for women in primary care, higher surveillance for outcomes in women diagnosed with GDM than control women, and a short median follow-up postpartum period, with a small number of outcomes for IHD and cerebrovascular disease. Women diagnosed with GDM were at very high risk of developing type 2 diabetes and had a significantly increased incidence of hypertension and IHD. Identifying this group of women in general practice and targeting cardiovascular risk factors could improve long-term outcomes.

Objective(1) To estimate the pooled prevalence of multimorbidity in all age groups, globally. (2) To examine how measurement of multimorbidity impacted the estimated prevalence.MethodsIn this systematic review and meta-analysis, we conducted searches in nine bibliographic databases (PsycINFO, Embase, Global Health, Medline, Scopus, Web of Science, Cochrane Library, CINAHL and ProQuest Dissertations and Theses Global) for prevalence studies published between database inception and 21 January 2020. Studies reporting the prevalence of multimorbidity (in all age groups and in community, primary care, care home and hospital settings) were included. Studies with an index condition or those that did not include people with no long-term conditions in the denominator were excluded. Retrieved studies were independently reviewed by two reviewers, and relevant data were extracted using predesigned pro forma. We used meta-analysis to pool the estimated prevalence of multimorbidity across studies, and used random-effects meta-regression and subgroup analysis to examine the association of heterogeneous prevalence estimates with study and measure characteristics.Results13 807 titles were screened, of which 193 met inclusion criteria for meta-analysis. The pooled prevalence of multimorbidity was 42.4% (95% CI 38.9% to 46.0%) with high heterogeneity (I2 >99%). In adjusted meta-regression models, participant mean age and the number of conditions included in a measure accounted for 47.8% of heterogeneity in effect sizes. The estimated prevalence of multimorbidity was significantly higher in studies with older adults and those that included larger numbers of conditions. There was no significant difference in estimated prevalence between low-income or middle-income countries (36.8%) and high-income countries (44.3%), or between self-report (40.0%) and administrative/clinical databases (52.7%).ConclusionsThe pooled prevalence of multimorbidity was significantly higher in older populations and when studies included a larger number of baseline conditions. The findings suggest that, to improve study comparability and quality of reporting, future studies should use a common core conditions set for multimorbidity measurement and report multimorbidity prevalence stratified by sociodemographics. PROSPERO registration number CRD42020172409.

Introduction There are concerns that hydrochlorothiazide may increase the risk of incident nonmelanoma (cutaneous squamous cell carcinoma [cSCC], basal cell carcinoma [BCC]) and melanoma skin cancer, with regulatory agencies and societies calling for additional studies. Methods We conducted a propensity score-matched population-based cohort study using the United Kingdom Clinical Practice Research Datalink. A total of 20,513 new users of hydrochlorothiazide were propensity score matched, in a 1:1 ratio, to new users of other thiazide diuretics between January 1, 1988 and March 31, 2018, with follow-up until March 31, 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cSCC, BCC, and melanoma, comparing use of hydrochlorothiazide with use of other thiazide diuretics overall, by cumulative duration of use, and cumulative dose. Results After an 8.6-year median follow-up, hydrochlorothiazide was associated with an increased risk of cSCC (HR 1.50, 95% CI 1.06–2.11). HRs increased with cumulative duration of use, with evidence of an association after 5–10 years (HR 2.10, 95% CI 1.20–3.67) and highest after > 10 years (HR 3.70, 95% CI 1.77–7.73). Similarly, HRs increased with cumulative dose, with higher estimates for ≥ 100,000 mg (HR 4.96, 95% CI 2.51–9.81). In contrast, hydrochlorothiazide was not associated with an increased risk of BCC (HR 1.01, 95% CI 0.91–1.13) or melanoma (HR 0.82, 95% CI 0.63–1.08), with no evidence of duration– or dose–response relationships. Conclusions Use of hydrochlorothiazide was associated with an increased risk of cSCC and with evidence of a duration– and dose–response relationship. In contrast, no association was observed for BCC or melanoma.

Background Hereditary Spastic Paraplegia (HSP) is a rare genetic neurological disorder that causes progressive spasticity and weakness in the lower limbs. This study aims to describe the prevalence and incidence of HSP and examine common mental health outcomes (depression and anxiety) in HSP patients in England and Northern Ireland. Methods This retrospective cohort study used CPRD Aurum primary care data from 1 January 2000 to 31 December 2021. Annual cross-sectional and cohort studies were conducted for yearly prevalence and incidence of HSP. Common mental health outcomes were examined with a 1:4 matched cohort (age+/−1 year, sex, general practice). Descriptive analysis and logistic regression assessed the characteristics of the HSP cohort and baseline depression and anxiety. Cox regression assessed the hazard of new diagnosis of depression and anxiety. Results The overall cohort included 31,302,579 patients; the matched cohort included 1455 HSP patients and 5726 control non-HSP patients. Patients who were male (adjusted odds ratio [aOR] 1.45, 95% CI: 1.31–1.61), of White ethnicity (lower odds in all other ethnicity) and from most other geographical areas compared to London had higher odds of a HSP diagnosis, with the highest odds for North East (aOR 3.51, 95% CI: 2.73–4.50) and Northern Ireland (aOR 3.15, 95% CI: 1.62–6.16). HSP prevalence increased from 2.83 per 100,000 population (95% CI: 2.49–3.20) in 2000 to 6.27 per 100,000 population (95% CI: 5.83–6.73) in 2021. HSP incidence remained stable from 0.12 per 100,000 person-years (95% CI: 0.06–0.22) in 2000 to 0.29 per 100,000 person-years (95% CI: 0.20–0.40) in 2021. HSP patients had higher odds of baseline pre-existing depression (aOR: 1.74, 95% CI: 1.47–2.06) and anxiety (aOR: 1.31, 95% CI: 1.08–1.60); and higher hazard for new diagnosis of depression (adjusted hazard ratio [aHR]: 1.57, 95% CI: 1.26–1.96) and anxiety (aHR: 1.41, 95% CI: 1.12–1.76). Conclusion This first descriptive epidemiological study for HSP in England and Northern Ireland, demonstrated the utility of primary care routine health records for studying rare diseases. The higher rates of common mental health conditions in HSP patients illustrated the importance of access to mental health support.

Background There is a high prevalence of autoimmune conditions in women specially in the reproductive years; thus, the association with adverse pregnancy outcomes has been widely studied. However, few autoimmune conditions/adverse outcomes have been studied more than others, and this umbrella review aims to consolidate existing knowledge in this area with the aim to provide new knowledge and also identify gaps in this research area. Methods Medline, Embase, and Cochrane databases were searched from inception to December 2023. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data were synthesised narratively and quantitatively. Relative risks (RR)/odds ratio (OR) with 95% confidence intervals were reported. Results Thirty-two reviews were included consisting of 709 primary studies. The review reported the association between 12 autoimmune conditions and 16 adverse pregnancy outcomes. Higher risk of miscarriage is reported in women with Sjögren’s syndrome RR 8.85 (95% CI 3.10–25.26) and systemic lupus erythematosus (SLE) OR 4.90 (3.10–7.69). Pre-eclampsia was reported higher in women with type 1 diabetes mellitus (T1DM) OR 4.19 (3.08–5.71) and SLE OR 3.20 (2.54–4.20). Women reported higher risk of diabetes during pregnancy with inflammatory bowel disease (IBD) OR 2.96 (1.47–5.98). There was an increased risk of intrauterine growth restriction in women with systemic sclerosis OR 3.20 (2.21–4.53) and coeliac disease OR 1.71 (1.36–2.14). Preterm birth was associated with T1DM OR 4.36 (3.72–5.12) and SLE OR 2.79 (2.07–3.77). Low birth weight babies were reported in women with women with SLE or systemic sclerosis OR 5.95 (4.54–7.80) and OR 3.80 (2.16–6.56), respectively. There was a higher risk of stillbirth in women with T1DM OR 3.97 (3.44–4.58), IBD OR 1.57 (1.03–2.38), and coeliac disease OR 1.57 (1.17–2.10). T1DM in women was associated with 32% lower odds of small for gestational age baby OR 0.68 (0.56–0.83). Conclusions Pregnant women with autoimmune conditions are at a greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to postnatal care for women with autoimmune conditions.

Background Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs). Methods Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren’s syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications. Results Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42). Conclusions SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.