Tayside Screening For Cardiac Events (TASCFORCE) study: a prospective cardiovascular risk screening study.

PURPOSE: Risk factor-based models struggle to accurately predict the development of cardiovascular disease (CVD) at the level of the individual. Ways of identifying people with low predicted risk who will develop CVD would allow stratified advice and support informed treatment decisions about the initiation or adjustment of preventive medication, and this is the aim of this prospective cohort study. PARTICIPANTS: The Tayside Screening for Cardiac Events (TASCFORCE) study recruited men and women aged≥40 years, free from known CVD, with a predicted 10-year risk of coronary heart disease<20%. If B-type natriuretic peptide (BNP) was greater than their gender median, participants were offered a whole-body contrast-enhanced MRI (WBCE-MRI) scan (cardiac imaging, whole-body angiography to determine left ventricular parameters, delayed gadolinium enhancement, atheroma burden). Blood, including DNA, was stored for future biomarker assays. Participants are being followed up using electronic record-linkage cardiovascular outcomes. FINDINGS TO DATE: 4423 (1740, 39.3% men) were recruited. Mean age was 52.3 years with a median BNP of 7.50 ng/L and 15.30 ng/L for men and women, respectively. 602 had a predicted 10-year risk of 10%-19.9%, with the remainder<10%. Age, female sex, ex-smoking status, lower heart rate, higher high-density lipoprotein and lower total cholesterol were independently associated with higher log10 BNP levels. Mean left ventricular mass was 129.2 g and 87.0 g in men and women, respectively. FUTURE PLANS: The TASCFORCE study is investigating the ability of a screening programme, using BNP and WBCE-MRI, at the time of enrolment, to evaluate prediction of CVD in a population at low/intermediate risk. Blood stored for future biomarker analyses will allow testing/development of novel biomarkers. We believe this could be a new UK Framingham study allowing study for many years to come. CLINICAL TRIAL REGISTRATION: ISRCTN38976321.

Chronic kidney disease and risk of atrial fibrillation and heart failure in general population-based cohorts: the BiomarCaRE project.

AIMS: Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. The aim of this study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. We also included an assessment of baseline biomarkers of inflammation, myocardial injury, and left ventricular dysfunction with risk of AF and HF, respectively, to shed light on the potential underlying pathophysiology. METHODS AND RESULTS: This study was conducted within the BiomarCaRE project using harmonized data from 12 European population-based cohorts (n = 48 518 participants). Renal function was assessed by glomerular filtration rate estimated using the combined Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation with standardized serum creatinine (Cr) and non-standardized serum cystatin C (CysC). Incidence of AF and HF respectively, during a median follow-up of 8 years was recorded. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and the competing risk of mortality after adjustment for covariates. The mean age at baseline was 51.4 (standard deviation 12.1) years, 49% were men. Overall, 4.3% of subjects had CKD at baseline. The rate for AF was 3.8 per 1000 person-years during follow-up. The HR for AF in patients with CKD compared with patients without CKD was 1.28 (95% confidence interval 1.07-1.54) after adjustment for covariates. The rate for incident HF was 4.1 per 1000 person-years and the HR of CKD for HF was 1.71 (95% confidence interval 1.45-2.01. In subjects with CKD, N-terminal-pro-brain natriuretic peptide (NT-proBNP) showed an association with AF, whereas NT-proBNP and C-reactive protein were associated with HF. CONCLUSIONS: Chronic kidney disease is an independent risk factor for subsequent AF and is even more closely associated with HF. In these relatively young participants with CKD, NT-proBNP was strongly associated with subsequent risk of AF. For HF, in addition, elevated levels of hs-C-reactive protein at baseline were related to incident events.

An 18 year data-linkage study on the association between air pollution and acute limb ischaemia.

Background: There is limited information regarding the effects of air pollutants, such as nitrogen oxides (NOx), nitric oxide (NO2), nitrous oxide (NO) and particulate matter with a diameter smaller than 10 µm (PM10), on acute limb ischaemia (ALI), a peripheral arterial disease (PAD) often with a poor clinical outcome. Patients and methods: We conducted an 18-year retrospective cohort study using routinely collected healthcare records from Ninewells Hospital, Dundee, and Perth Royal Infirmary, in Tayside, Scotland, UK from 2000 to 2017. ALI hospitalisation events and deaths were linked to daily NOx, NO2, NO and PM10 levels extracted from publicly available data over this same time period. Distributed lag models were used to estimate risk ratios for ALI hospitalisation and for ALI mortality, adjusting for temperature, humidity, day of the week, month and public holiday. Results: 5,608 hospital admissions in 2,697 patients were identified over the study period (mean age 71.2 years, ±11.1). NOx and NO were associated with an increase of ALI hospital admissions on days of exposure to pollutant (p=.018), while PM10 was associated with a cumulative (lag 0-9 days) increase (p=.027) of ALI hospital admissions in our study. There was no increase of ALI mortality associated with pollution levels. Conclusions: ALI hospital admissions were positively associated with ambient NOx and NO on day of high measured pollution levels and a cumulative effect was seen with PM10.

Congenital defects and early childhood outcomes following in-utero exposure to antihypertensive medication.

BACKGROUND: Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in-utero exposure to antihypertensive treatment is conflicting with many studies suffering from significant methodological issues. METHOD: We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010-2014 in Scotland to assess outcomes following in-utero exposure to antihypertensive medication. RESULTS: We identified a cohort of 265 488 eligible mother-child pairs born over the study period; of which, 2433 were exposed in utero to antihypertensive medication, 4391 exposed to treated late-onset hypertension and 6066 exposed to untreated hypertension during pregnancy. In-utero antihypertensive exposure was associated with an increased risk of circulatory defects (aOR 2.29; 99% CI 1.14-4.59) compared with normal controls and the untreated hypertensive group. We report no increased odds of any developmental outcomes at 2.5 years of age following exposure to antihypertensive medication during pregnancy, untreated hypertension or late-onset hypertension. CONCLUSION: Although circulatory defects may be associated with antihypertensive medication exposure during pregnancy, the mechanisms underlying this process are unclear.

Educational and health outcomes of children and adolescents receiving antidepressant medication: Scotland-wide retrospective record linkage cohort study of 766 237 schoolchildren.

BACKGROUND: Childhood depression is relatively common, under-researched and can impact social and cognitive function and self-esteem. METHODS: Record linkage of routinely collected Scotland-wide administrative databases covering prescriptions [prescribing information system (PIS)], hospitalizations (Scottish Morbidity Records 01 and 04), maternity records (Scottish Morbidity Records 02), deaths (National Records of Scotland), annual pupil census, school absences/exclusions, special educational needs (Scottish Exchange of Educational Data; ScotXed), examinations (Scottish Qualifications Authority) and (un)employment (ScotXed) provided data on 766 237 children attending Scottish schools between 2009 and 2013 inclusively. We compared educational and health outcomes of children receiving antidepressant medication with their peers, adjusting for confounders (socio-demographic, maternity and comorbidity) and explored effect modifiers and mediators. RESULTS: Compared with peers, children receiving antidepressants were more likely to be absent [adjusted incidence rate ratio (IRR) 1.90, 95% confidence interval (CI) 1.85-1.95] or excluded (adjusted IRR 1.48, 95% CI 1.29-1.69) from school, have special educational needs [adjusted odds ratio (OR) 1.77, 95% CI 1.65-1.90], have the lowest level of academic attainment (adjusted OR 3.00, 95% CI 2.51-3.58) and be unemployed after leaving school (adjusted OR 1.88, 95% CI 1.71-2.08). They had increased hospitalization [adjusted hazard ratio (HR) 2.07, 95% CI 1.98-2.18] and mortality (adjusted HR 2.73, 95% CI 1.73-4.29) over 5 years' follow-up. Higher absenteeism partially explained poorer attainment and unemployment. Treatment with antidepressants was less common among boys than girls (0.5% vs 1.0%) but the associations with special educational need and unemployment were stronger in boys. CONCLUSIONS: Children receiving antidepressants fare worse than their peers across a wide range of education and health outcomes. Interventions to reduce absenteeism or mitigate its effects should be investigated.

In Utero Antihypertensive Medication Exposure and Neonatal Outcomes: A Data Linkage Cohort Study.

Hypertensive disorders during pregnancy are an important risk to mother and fetus, frequently necessitating antihypertensive treatment. Data describing the safety of in utero exposure to antihypertensive treatment is conflicting, with many studies suffering from significant methodological issues, such as inappropriate study design, small sample sizes, and no untreated control group. We conducted a retrospective cohort study using linked routinely collected healthcare records for 268 711 children born 2010-2014 in Scotland to assess outcomes following in utero exposure to antihypertensive medication. We identified a cohort of 265 488 eligible children born over the study period; of which, 2350 were exposed to in utero antihypertensive medication, 4391 exposed to treated late-onset hypertension, and 7971 exposed to untreated hypertension during pregnancy. Untreated hypertension was associated with increased risk of preterm birth (adjusted risk ratio [aRR], 1.15 [99% CI, 1.01-1.30]), low birth weight (aRR, 2.01 [99% CI, 1.72-2.36]) and being small for gestational age (aRR, 1.50 [99% CI, 1.35-1.66]), while in utero antihypertensive exposure was also associated with preterm birth (aRR, 3.12 [99% CI, 2.68-3.64]), low birth weight (aRR, 2.23 [99% CI, 1.79-2.78]), and being small for gestational age (aRR, 2.13 [99% CI, 1.81-2.52]). Late-onset hypertension was also associated with preterm birth (aRR, 2.21 [99% CI, 1.86-2.62]), low birth weight (aRR, 2.06 [99% CI, 1.74-2.43]), and being small for gestational age (aRR, 1.90 [99% CI, 1.68-2.16]). Our results suggest that hypertension is a key risk factor for low birth weight and preterm birth. Although preterm birth may be associated with antihypertensive medication exposure during pregnancy, these associations may reflect increasing hypertension severity necessitating treatment.

Educational and Health Outcomes of Children Treated for Type 1 Diabetes: Scotland-Wide Record Linkage Study of 766,047 Children.

OBJECTIVE: This study was conducted to determine the association between childhood type 1 diabetes and educational and health outcomes. RESEARCH DESIGN AND METHODS: Record linkage of nine Scotland-wide databases (diabetes register, dispensed prescriptions, maternity records, hospital admissions, death certificates, annual pupil census, school absences/exclusions, school examinations, and unemployment) produced a cohort of 766,047 singleton children born in Scotland who attended Scottish schools between 2009 and 2013. We compared the health and education outcomes of schoolchildren receiving insulin with their peers, adjusting for potential confounders. RESULTS: The 3,330 children (0.47%) treated for type 1 diabetes were more likely to be admitted to the hospital (adjusted hazard ratio [HR] 3.97, 95% CI 3.79-4.16), die (adjusted HR 3.84, 95% CI 1.98-7.43), be absent from school (adjusted incidence rate ratio [IRR] 1.34, 95% CI 1.30-1.39), and have learning difficulties (adjusted odds ratio [OR] 1.19, 95% CI 1.03-1.38). Among children with type 1 diabetes, higher mean HbA1c (particularly HbA1c in the highest quintile) was associated with greater absenteeism (adjusted IRR 1.75, 95% CI 1.56-1.96), increased school exclusion (adjusted IRR 2.82, 95% CI 1.14-6.98), poorer attainment (adjusted OR 3.52, 95% CI 1.72-7.18), and higher risk of unemployment (adjusted OR 2.01, 95% CI 1.05-3.85). CONCLUSIONS: Children with type 1 diabetes fare worse than their peers in respect of education and health outcomes, especially if they have higher mean HbA1c. Interventions are required to minimize school absence and ensure that it does not affect educational attainment.

Educational and health outcomes of children treated for asthma: Scotland-wide record linkage study of 683 716 children.

BACKGROUND: The global prevalence of childhood asthma is increasing. The condition impacts physical and psychosocial morbidity; therefore, wide-ranging effects on health and education outcomes are plausible. METHODS: Linkage of eight Scotland-wide databases, covering dispensed prescriptions, hospital admissions, maternity records, death certificates, annual pupil census, examinations, school absences/exclusions and unemployment, provided data on 683 716 children attending Scottish schools between 2009 and 2013. We compared schoolchildren on medication for asthma with peers, adjusting for sociodemographic, maternity and comorbidity confounders, and explored effect modifiers and mediators. RESULTS: The 45 900 (6.0%) children treated for asthma had an increased risk of hospitalisation, particularly within the first year of treatment (incidence rate ratio 1.98, 95% CI 1.93-2.04), and increased mortality (HR 1.77, 95% CI 1.30-2.40). They were more likely to have special educational need for mental (OR 1.76, 95% CI 1.49-2.08) and physical (OR 2.76, 95% CI 2.57-2.95) health reasons, and performed worse in school exams (OR 1.11, 95% CI 1.06-1.16). Higher absenteeism (incidence rate ratio 1.25, 95% CI 1.24-1.26) partially explained their poorer attainment. CONCLUSIONS: Children with treated asthma have poorer education and health outcomes than their peers. Educational interventions that mitigate the adverse effects of absenteeism should be considered.

Educational and health outcomes of children and adolescents receiving antiepileptic medication: Scotland-wide record linkage study of 766 244 schoolchildren.

BACKGROUND: Childhood epilepsy can adversely affect education and employment in addition to health. Previous studies are small or highly selective producing conflicting results. This retrospective cohort study aims to compare educational and health outcomes of children receiving antiepileptic medication versus peers. METHODS: Record linkage of Scotland-wide databases covering dispensed prescriptions, acute and psychiatric hospitalisations, maternity records, deaths, annual pupil census, school absences/exclusions, special educational needs, school examinations, and (un)employment provided data on 766,244 children attending Scottish schools between 2009 and 2013. Outcomes were adjusted for sociodemographic and maternity confounders and comorbid conditions. RESULTS: Compared with peers, children on antiepileptic medication were more likely to experience school absence (Incidence Rate Ratio [IRR] 1.43, 95% CI: 1.38, 1.48), special educational needs (Odds ratio [OR] 9.60, 95% CI: 9.02, 10.23), achieve the lowest level of attainment (OR 3.43, 95% CI: 2.74, 4.29) be unemployed (OR 1.82, 95% CI: 1.60, 2.07), be admitted to hospital (Hazard Ratio [HR] 3.56, 95% CI: 3.42, 3.70), and die (HR 22.02, 95% CI: 17.00, 28.53). Absenteeism partly explained poorer attainment and higher unemployment. Girls and younger children on antiepileptic medication had higher risk of poor outcomes. CONCLUSIONS: Children on antiepileptic medication fare worse than peers across educational and health outcomes. In order to reduce school absenteeism and mitigate its effects, children with epilepsy should receive integrated care from a multidisciplinary team that spans education and healthcare.

Herbal Medicinal Product Use During Pregnancy and the Postnatal Period: A Systematic Review.

OBJECTIVE: To report the incidence and nature of herbal medicinal products' adverse events and herb-drug interactions used by some pregnant and postnatal women. DATA SOURCES: The Allied and Complementary Medicine Database, the Cumulative Index to Nursing and Allied Health Literature, EMBASE, the Cochrane Library, MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched from inception until August 2018. METHODS OF STUDY SELECTION: Any studies reporting adverse events, herb-drug interactions or absence thereof associated with herbal medicinal products used during pregnancy or the postnatal period were included. Conference abstracts, pilot studies, and nonhuman studies were excluded. All included studies were critically appraised by two independent reviewers. TABULATION, INTEGRATION AND RESULTS: Database searches retrieved 3,487 citations. After duplicate removal and review of titles, abstracts, and full-text, 115 articles were critically appraised. After excluding irrelevant and low-quality articles, 74 articles were included for data extraction and synthesis. Adverse drug reactions, congenital malformations, fetal growth retardation or herb-drug interactions were the primary study objective reported by 19 of the 74 included studies, 16 cohort studies, one cross-sectional survey, and two randomized controlled trials. A total of 47 herbal medicinal products and 1,067,071 women were included in this review. Use of almond oil was associated with preterm birth (odds ratio 2.09, 95% CI 1.07-4.08), oral raspberry leaf was associated with cesarean delivery (adjusted odds ratio [AOR] 3.47, 95% CI 1.45-8.28); heavy licorice use was associated with early preterm birth by 3.07-fold (95% CI 1.17-8.05). African herbal medicine mwanaphepo was associated with maternal morbidity (AOR 1.28; 95% CI 1.09-1.50), and neonatal death or morbidity. Fourteen studies reported absence of adverse events. Four studies reported herb-drug interactions, but none studied adverse events arising from them. CONCLUSION: The use of herbal medicinal products during pregnancy and the postnatal period should be discouraged until robust evidence of safety is available. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42017081058.

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

In-utero exposure to antihypertensive medication and neonatal and child health outcomes: a systematic review.

BACKGROUND: Although medication is generally avoided wherever possible during pregnancy, pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of maternal and fetal morbidity and mortality. The long-term effects to the child of in-utero exposure to antihypertensive agents remains largely unknown. OBJECTIVE: The aim of this study was to systematically review published studies on adverse outcomes to the child associated with in-utero exposure to antihypertensive medications. METHODS: OVID, Scopus, EBSCO Collections, the Cochrane Library, and Web of Science databases were searched for relevant publications published between January 1950 and October 2016 and a total of 688 potentially eligible studies were identified. RESULTS: Following review, 47 primary studies were eligible for inclusion. The Critical Appraisal Skills Programme checklist was used to assess study quality. Five studies were of excellent quality; the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth, and congenital defects following in-utero exposure to all antihypertensive agents were identified. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine. CONCLUSION: The current systematic review demonstrates a paucity of relevant published high-quality studies. A small number of studies suggest possible increased risk of adverse child health outcomes; however, most published studies have methodological weaknesses and/or lacked statistical power thus preventing any firm conclusions being drawn.

Educational and Health Outcomes of Children Treated for Attention-Deficit/Hyperactivity Disorder.

Importance: Attention-deficit/hyperactivity disorder (ADHD) affects 39 million people worldwide; in isolation, it doubles annual health care costs and, when associated with comorbid mental health problems, it quadruples the costs. Objective: To compare the education and health outcomes of schoolchildren treated for ADHD with their peers. Design, Setting, and Participants: In this population-based cohort study, individual-level record linkage was performed of 8 Scotland-wide administrative databases covering dispensed prescriptions, admissions to acute and psychiatric hospitals, maternity records, annual pupil census, examinations, school absences and exclusions, and unemployment. The study cohort comprised 766 244 children attending Scottish primary, secondary, and special schools at any point between September 21, 2009, and September 18, 2013. Data analysis was performed from June 1, 2015, to December 6, 2016. Exposures: Medication approved solely for ADHD treatment. Main Outcomes and Measures: Special educational needs, academic attainment, unauthorized absence, exclusion, age at leaving school, unemployment after leaving, and hospitalization. Outcomes were adjusted for potential sociodemographic, maternity, and comorbidity confounders. Results: Of the 766 244 schoolchildren, 7413 (1.0%) were treated for ADHD; 6287 (84.8%) were male. These children had higher rates of unauthorized absence (adjusted incidence rate ratio [IRR], 1.16; 95% CI, 1.14-1.19) and exclusion (adjusted IRR, 5.79; 95% CI, 5.45-6.16), more commonly had a record of special educational need (adjusted odds ratio [OR], 8.62; 95% CI, 8.26-9.00), achieved lower academic attainment (adjusted OR, 3.35; 95% CI, 3.00-3.75), were more likely to leave school before age 16 years (1546 [64.3%] vs 61 235 [28.4%]), and were more likely to be unemployed (adjusted OR, 1.39; 95% CI, 1.25-1.53). Children with ADHD were more likely to require hospitalization overall (adjusted hazard ratio [HR], 1.25; 95% CI, 1.19-1.31) and for injury (adjusted HR, 1.52; 95% CI, 1.40-1.65). Conclusions and Relevance: Even while receiving medication, children with ADHD fare worse than their peers across a wide range of outcomes relating not only to education but also to health.