Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study

Background:People whose singleton pregnancy is affected by hypertensive disorders of pregnancy (HDP) are at risk of future cardiovascular disease. It is unclear, however, whether this association can be extrapolated to twin pregnancies. We aimed to compare the association between HDP and future cardiovascular disease after twin and singleton pregnancies.Methods:We conducted a population-based retrospective cohort study that included nulliparous people in Ontario, Canada, 1992–2017. We compared the future risk of cardiovascular disease among pregnant people from the following 4 groups: those who delivered a singleton without HDP (referent) and with HDP, and those who delivered twins either with or without HDP.Results:The populations of the 4 groups were as follows: 1 431 651 pregnant people in the singleton birth without HDP group; 98 631 singleton birth with HDP; 21 046 twin birth without HDP; and 4283 twin birth with HDP. The median duration of follow-up was 13 (interquartile range 7–20) years. The incidence rate of cardiovascular disease was lowest among those with a singleton or twin birth without HDP (0.72 and 0.74 per 1000 person-years, respectively). Compared with people with a singleton birth without HDP, the risk of cardiovascular disease was highest among those with a singleton birth and HDP (1.47 per 1000 person-years; adjusted hazard ratio [HR] 1.81 [95% confidence interval (CI) 1.72–1.90]), followed by people with a twin pregnancy and HDP (1.07 per 1000 person-years; adjusted HR 1.36 [95% CI 1.04–1.77]). The risk of the primary outcome after a twin pregnancy with HDP was lower than that after a singleton pregnancy with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]), when compared directly.Interpretation:In a twin pregnancy, HDP are weaker risk factors for postpartum cardiovascular disease than in a singleton pregnancy.

Cardiovascular disease has been shown to be the leading cause of death among women.^1–3 Classic risk factors for cardiovascular disease include obesity, diabetes mellitus, hypertension and family history of cardiovascular disease. ³ More recently, an association has been established between a history of hypertensive disorders of pregnancy (HDP) — gestational hypertension and pre-eclampsia — and future risk of cardiovascular disease.^1,4–11 Consequently, some recommend using a history of HDP for cardiovascular disease risk stratification in women.^3,12The leading hypothesis for the pathogenesis of HDP is that it results from abnormal placentation due to impaired trophoblast invasion,^13–16 resulting in reduced placental perfusion.^17–19 This, in turn, leads to abnormal secretion of the angiogenic factors soluble FMS-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng),²⁰ which induce endothelial dysfunction and the clinical manifestations of HDP.^19,21–24 The mechanisms underlying the association between HDP and future cardiovascular disease are under debate.²⁵ One hypothesis is that HDP are merely a marker of underlying subclinical or clinical vascular risk factors that predispose a person to both HDP and future cardiovascular disease.A person who is pregnant with twins is at about 3–4 times higher risk of HDP than a person with a singleton pregnancy,^26–33 with rates of 14% and 5%, respectively.³⁴ The higher risk of HDP in twin pregnancies may be due to higher circulating sFlt1 and sEng owing to greater placental mass in twin pregnancies, ^35–37 and less related to the classic vascular risk factors for HDP in a singleton pregnancy. Therefore, a logical question is whether the established higher risk of future cardiovascular disease after singleton pregnancies with HDP also occurs in twin pregnancies with HDP. Limited data are available to answer this question.³⁸ In the current study, we aimed to test the hypothesis that the association between HDP and future cardiovascular disease is less pronounced in twin versus singleton pregnancies.     

Risk of end-stage renal disease associated with gout: a nationwide population study

Introduction

We explored the risk of end-stage renal disease (ESRD) among gout patients in a representative cohort in Taiwan.

Methods

The primary database used was the Taiwan National Health Insurance Research Database. Subjects older than 20 years without ESRD, coronary heart disease, or stroke were included in the study. The case definition of gout in the present study was gout diagnosis and medical treatment for gout. An ESRD case was defined by the presence of chronic renal failure necessitating long-term renal replacement therapy. Multivariate Cox proportional hazards models were used to evaluate the risk of ESRD among gout patients.

Results

The analysis included data of 656,108 patients who were followed up for a mean of 8.0 years. Among them, 19,963 (3.0%) patients had gout. At the end of 2008, 2,377 individuals (gout, n = 276; non-gout, n = 2,101) had ESRD, and 861 individuals (gout, n = 77, 27.9%; non-gout, n = 521, 24.8%) died due to ESRD. The rates of incidence of ESRD were 1.73 and 0.41 cases per 1,000 patient-years in the gout and non-gout groups. After adjustment for age, sex, and history of diabetes mellitus and/or hypertension, gout was associated with a hazard ratio (HR) of 1.57 for ESRD (95% confidence interval [CI], 1.38-1.79; P < 0.001). In patients with ESRD, the adjusted HR for death in patients with gout was 0.95 (0.74-1.23, P = 0.71), which was similar to the HR obtained in patients without gout.

Conclusions

Gout is associated with an increased hazard for development of ESRD.     

Association of angiotensinogen M235T gene polymorphism with end-stage renal disease risk: a meta-analysis

Association between angiotensinogen (AGT) M235T gene polymorphism and end-stage renal disease (ESRD) risk is still controversial. This meta-analysis was performed to evaluate the association of AGT M235T gene polymorphism with ESRD susceptibility. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases of PubMed, Embase and Cochrane Library. Sixteen literatures were identified for the analysis of association of AGT M235T gene polymorphism with ESRD risk. T allele and TT genotype were associated with ESRD susceptibility in Caucasians (T: OR = 1.13, 95 % CI: 1.02–1.25, P = 0.02; TT: OR = 1.22, 95 % CI: 1.03–1.45, P = 0.02). However, MM genotype might not play a protective role against ESRD risk in Caucasians. Furthermore, there was no a markedly positive association between AGT M235T gene polymorphism and ESRD susceptibility in overall populations, Asians and Africans. In conclusion, T allele or TT homozygote is associated with the onset of ESRD in Caucasians. However, more studies should be performed in the future.     

SIMS REIN: a multi-source information system for end-stage renal disease

In France, the prevalence of End-Stage Renal Disease (ESRD) is not precisely known. The sources of information are scattered and not coordinated. Consequently, care is ill adapted to meet the demand. The Multi-Source Information System is the basis of the Renal Epidemiology and Information Network (REIN). It is dedicated to improve and organise our medical and epidemiological knowledge of ESRD and to aid public health decision-making in this area. The proposed approach is based on the datawarehouses. This model allows a unified vision of scattered data into distinct databases, for a better management, be it particular (patient follow-up) or global (regional follow-up), with a finality of aid in decision-making. Several categories of problems were considered: the global conception of the information system, the organisation of the datawarehouse, which offers different viewpoints of the data, the integration of heterogeneous data coming from different sources, data exchange and definition of a specific ontology.     

CUBN as a novel locus for end-stage renal disease: insights from renal transplantation

Chronic kidney disease (CKD) is a complex disorder. As genome-wide association studies identified cubilin gene CUBN as a locus for albuminuria, and urinary protein loss is a risk factor for progressive CKD, we tested the hypothesis that common genetic variants in CUBN are associated with end-stage renal disease (ESRD) and proteinuria. First, a total of 1142 patients with ESRD, admitted for renal transplantation, and 1186 donors were genotyped for SNPs rs7918972 and rs1801239 (case-control study). The rs7918972 minor allele frequency (MAF) was higher in ESRD patients comparing to kidney donors, implicating an increased risk for ESRD (OR 1.39, p?=?0.0004) in native kidneys. Second, after transplantation recipients were followed for 5.8 [3.8-9.2] years (longitudinal study) documenting ESRD in transplanted kidneys--graft failure (GF). During post-transplant follow-up 92 (9.6%) cases of death-censored GF occurred. Donor rs7918972 MAF, representing genotype of the transplanted kidney, was 16.3% in GF vs 10.7% in cases with functioning graft. Consistently, a multivariate Cox regression analysis showed that donor rs7918972 is a predictor of GF, although statistical significance was not reached (HR 1.53, p?=?0.055). There was no association of recipient rs7918972 with GF. Rs1801239 was not associated with ESRD or GF. In line with an association with the outcome, donor rs7918972 was associated with elevated proteinuria levels cross-sectionally at 1 year after transplantation. Thus, we identified CUBN rs7918972 as a novel risk variant for renal function loss in two independent settings: ESRD in native kidneys and GF in transplanted kidneys.     

Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood,adolescence, and young adulthood: A national population-based cohort study

BackgroundThe prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited.Methods and findingsWe conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare.ConclusionsOffspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring.

Chen Huang and co-workers study associations between maternal hypertensive disorders and cardiovascular disease in offspring.     

Risk of interpersonal violence during and after pregnancy among people with schizophrenia: a population-based cohort study

Background:Schizophrenia is associated with increased risk of experiencing interpersonal violence. Little is known about risk specifically around the time of pregnancy.Methods:This population-based cohort study included all individuals (aged 15–49 yr) listed as female on their health cards who had a singleton birth in Ontario, Canada, between 2004 and 2018. We compared those with and without schizophrenia on their risk of an emergency department (ED) visit for interpersonal violence in pregnancy or within 1 year postpartum. We adjusted relative risks (RRs) for demographics, prepregnancy history of substance use disorder and history of interpersonal violence. In a subcohort analysis, we used linked clinical registry data to evaluate interpersonal violence screening and self-reported interpersonal violence during pregnancy.Results:We included 1 802 645 pregnant people, 4470 of whom had a diagnosis of schizophrenia. Overall, 137 (3.1%) of those with schizophrenia had a perinatal ED visit for interpersonal violence, compared with 7598 (0.4%) of those without schizophrenia, for an RR of 6.88 (95% confidence interval [CI] 5.66–8.37) and an adjusted RR of 3.44 (95% CI 2.86–4.15). Results were similar when calculated separately for the pregnancy (adjusted RR 3.47, 95% CI 2.68–4.51) period and the first year postpartum (adjusted RR 3.45, 95% CI 2.75–4.33). Pregnant people with schizophrenia were equally likely to be screened for interpersonal violence (74.3% v. 73.8%; adjusted RR 0.99, 95% CI 0.95–1.04), but more likely to self-report it (10.2% v. 2.4%; adjusted RR 3.38, 95% CI 2.61–4.38), compared with those without schizophrenia. Among patients who did not self-report interpersonal violence, schizophrenia was associated with an increased risk for a perinatal ED visit for interpersonal violence (4.0% v. 0.4%; adjusted RR 6.28, 95% CI 3.94–10.00).Interpretation:Pregnancy and postpartum are periods of higher risk for interpersonal violence among people with schizophrenia compared with those without schizophrenia. Pregnancy is a key period for implementing violence prevention strategies in this population.

Interpersonal violence is defined as the intentional use of force or power against others, including physical, sexual and psychological abuse perpetrated by strangers, acquaintances, family members or intimate partners.^1–5 Around the time of pregnancy, interpersonal violence affects not only the person experiencing it, but also the developing fetus or infant.⁶ Maternal consequences include acute injuries, chronic pain and psychiatric disorders.^7,8 Interpersonal violence is also associated with absent or delayed prenatal care, preterm birth, poor fetal growth, difficulties in maternal–child attachment, and maternal, fetal and neonatal death.^9–14Women with schizophrenia are at high risk of experiencing interpersonal violence during their lifetime from known and unknown perpetrators.^15–17 The lifetime prevalence of physical or sexual assault in this population is 20.7%, about 9 times the risk of those without serious mental illness.¹⁸ Many women with schizophrenia become pregnant, but little is known about their risk of experiencing interpersonal violence around this time.^19,20 In 2 small clinical studies, rates of self-reported interpersonal violence in pregnancy were upward of 20%.^21,22 However, these studies had no comparator groups without schizophrenia, included only self-reported risk and did not evaluate postpartum risk.We sought to compare the risk of an emergency department (ED) visit for interpersonal violence during pregnancy and until 1 year postpartum among people with and without schizophrenia in Ontario. We also sought to compare rates of interpersonal violence screening and disclosure in response to screening in these 2 groups, as well as risk for an ED visit for interpersonal violence in pregnancy or within the first year postpartum among those who did not self-report interpersonal violence. The latter question is important given that people with schizophrenia report being concerned that disclosure of any social issues during the perinatal period could possibly lead to undesirable consequences, such as child apprehension.^23,24     

Prevalence and related factors of common mental disorders during pregnancy in Japan: a cross-sectional study

Background

Common mental disorders (CMD) during pregnancy can have a clearly harmful influence on both mothers and children. Some studies have reported related factors for mental disorders, such as region-specific background. This study examined the prevalence of CMD and its related factors in mid-pregnancy in Japan.

Methods

Pregnant women between 12 and 24 weeks gestation and aged ≥20 years were consecutively recruited at a maternity hospital in Japan between May 2014 and September 2014. CMD were diagnosed using the Mini-International Neuropsychiatric Interview (MINI), self-rated depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale, and interpersonal traumatic experience was measured using the Life Events Checklist.

Results

Among 297 eligible pregnant women, 177 participated in the study. Two participants (1.1 %) met the criteria for major depressive disorder. The most frequent diagnosis was agoraphobia (n?=?7; 3.9 %). Eleven participants (6.2 %) met the criteria for one or more diagnoses, with 2 participants having two mental disorders and 3 having three mental disorders. Six participants developed CMD after gestation. Logistic regression analysis revealed history of psychiatric disorder, past interpersonal traumatic experience, and feeling pressure to have a child were associated with CMD.

Conclusion

These findings indicate a lower prevalence of CMD in mid-pregnancy in Japan than reported in most other countries. Besides the related factors reported previously, feeling pressure to have a child might increase risk for CMD among pregnant women in Japan. Asian cultural background might be related to the lower CMD prevalence and risk factors identified in this study.

     

Reducing all-cause mortality among patients with psychiatric disorders: a population-based study

Background:

Among patients with psychiatric disorders, there are 10 times as many preventable deaths from physical disorders as there are from suicide. We investigated whether compulsory community treatment, such as community treatment orders, could reduce all-cause mortality among patients with psychiatric disorders.

Methods:

We conducted a population-based survival analysis of an inception cohort using record linking. The study period extended from November 1997 to December 2008. The cohort included patients from all community-based and inpatient psychiatric services in Western Australia (state population 1.8 million). We used a 2-stage design of matching and Cox regression to adjust for demographic characteristics, previous use of health services, diagnosis and length of psychiatric history. We collected data on successive cohorts for each year for which community treatment orders were used to measure changes in numbers of patients, their characteristics and outcomes. Our primary outcome was 2-year all-cause mortality. Our secondary outcomes were 1-and 3-year all-cause mortality.

Results:

The study population included 2958 patients with community treatment orders (cases) and 2958 matched controls (i.e., patients with psychiatric disorders who had not received a community treatment order). The average age for cases and controls was 36.7 years, and 63.7% (3771) of participants were men. Schizophrenia and other nonaffective psychoses were the most common diagnoses (73.4%) among participants. A total of 492 patients (8.3%) died during the study. Cox regression showed that, compared with controls, patients with community treatment orders had significantly lower all-cause mortality at 1, 2 and 3 years, with an adjusted hazard ratio of 0.62 (95% confidence interval 0.45–0.86) at 2 years. The greatest effect was on death from physical illnesses such as cancer, cardiovascular disease or diseases of the central nervous system. This association disappeared when we adjusted for increased outpatient and community contacts with psychiatric services.

Interpretation:

Community treatment orders might reduce mortality among patients with psychiatric disorders. This may be partly explained by increased contact with health services in the community. However, the effects of uncontrolled confounders cannot be excluded.Mortality among patients with psychiatric disorders is higher than in the general population.¹ Chronic physical disorders such as cardiovascular disease and cancer are the main causes of death in this population, with risks 10 times that of suicide; however, such causes receive far less attention than suicides.^1,2 Patients with schizophrenia die 15–20 years earlier than people in the general population, a difference that has increased over time.^1,3 Reasons for this difference include socioeconomic disadvantage, adverse effects of medication and reduced access to health care.^4,5There are limited data on possible interventions aimed at preventing such deaths, most of which stress regular monitoring of physical status, peer support and collaboration with primary care.^6,7 One study from Victoria, Australia, found that patients on conditional release from hospital had lower mortality than expected when use of community care, age, sex, inpatient experience and diagnosis were taken into account.⁸ However, 10% of these patients had dementia or other diseases of the nervous system, and patients with these diagnoses made up 29% of the deaths in the study. Dementia is not a typical indication for compulsory community treatment. In addition, Victoria has one of the highest levels of use of community treatment orders, about 60 per 100 000 population; thus, those results may not be generalizable to other locales.⁸ Although the authors controlled for time at risk, death could occur from 1 day to 11 years after the index date;⁹ most evaluations of community treatment orders are limited to 1 or 2 years after the order is issued.^9,10 Finally, the results were not adjusted for patients’ marital status, education, country of birth, indigenous status or use of health services before the introduction of community treatment orders. Adjusting for these variables could reduce the bias inherent in drawing cases and controls from the same jurisdiction given the difficulties in controlling for all possible reasons for issuing these orders once they have been introduced.We sought to assess the impact of community treatment orders on 1-, 2-, and 3-year survival in Western Australia. Community treatment orders provide a legal framework within which patients with a serious mental disorder are required to accept psychiatric treatment while living outside hospital. These orders are used across both Canada and Australia, are of similar duration in both countries, and are clinician-initiated rather than court-ordered (in contrast to the United States).^10,11 Unlike in Canada, patients in Australia can be given community treatment orders without having been previously admitted to hospital. In practice, patients in both countries spend similar amounts of time in hospital before being given a community treatment order.¹²We focused on deaths from physical illness, rather than suicides, as these are the most common causes of preventable death among people with severe mental illness.^1,2 We thought that patients with community treatment orders would have lower mortality because of improved engagement with health services, thus allowing greater monitoring and management of physical health. Greater engagement would be shown via increased outpatient contacts following the receipt of a community treatment order, which would influence any association between compulsory community treatment and mortality.     

Glutamine kinetics and protein turnover in end-stage renal disease

Alanine and glutamine constitute the two most important nitrogen carriers released from the muscle. We studied the intracellular amino acid transport kinetics and protein turnover in nine end-stage renal disease (ESRD) patients and eight controls by use of stable isotopes of phenylalanine, alanine, and glutamine. The amino acid transport kinetics and protein turnover were calculated with a three-pool model from the amino acid concentrations and enrichment in the artery, vein, and muscle compartments. Muscle protein breakdown was more than synthesis (nmol.min(-1).100 ml leg(-1)) during hemodialysis (HD) (169.8 +/- 20.0 vs. 125.9 +/- 21.8, P < 0.05) and in controls (126.9 +/- 6.9 vs. 98.4 +/- 7.5, P < 0.05), but synthesis and catabolism were comparable pre-HD (100.7 +/- 15.7 vs. 103.4 +/- 14.8). Whole body protein catabolism decreased by 15% during HD. The intracellular appearance of alanine (399.0 +/- 47.1 vs. 243.0 +/- 34.689) and glutamine (369.7 +/- 40.6 vs. 235.6 +/- 27.5) from muscle protein breakdown increased during dialysis (nmol.min(-1).100 ml leg(-1), P < 0.01). However, the de novo synthesis of alanine (3,468.9 +/- 572.2 vs. 3,140.5 +/- 467.7) and glutamine (1,751.4 +/- 82.6 vs. 1,782.2 +/- 86.4) did not change significantly intradialysis (nmol.min(-1).100 ml leg(-1)). Branched-chain amino acid catabolism (191.8 +/- 63.4 vs. -59.1 +/- 42.9) and nonprotein glutamate disposal (347.0 +/- 46.3 vs. 222.3 +/- 43.6) increased intradialysis compared with pre-HD (nmol.min(-1).100 ml leg(-1), P < 0.01). The mRNA levels of glutamine synthase (1.45 +/- 0.14 vs. 0.33 +/- 0.08, P < 0.001) and branched-chain keto acid dehydrogenase-E2 (3.86 +/- 0.48 vs. 2.14 +/- 0.27, P < 0.05) in the muscle increased during HD. Thus intracellular concentrations of alanine and glutamine are maintained during HD by augmented release of the amino acids from muscle protein catabolism. Although muscle protein breakdown increased intradialysis, the whole body protein catabolism decreased, suggesting central utilization of amino acids released from skeletal muscle.     

Association between serum cholesterol and eating behaviours during early childhood: a cross-sectional study

Background:

Modifiable behaviours during early childhood may provide opportunities to prevent disease processes before adverse outcomes occur. Our objective was to determine whether young children’s eating behaviours were associated with increased risk of cardiovascular disease in later life.

Methods:

In this cross-sectional study involving children aged 3–5 years recruited from 7 primary care practices in Toronto, Ontario, we assessed the relation between eating behaviours as assessed by the NutriSTEP (Nutritional Screening Tool for Every Preschooler) questionnaire (completed by parents) and serum levels of non–high-density lipoprotein (HDL) cholesterol, a surrogate marker of cardiovascular risk. We also assessed the relation between dietary intake and serum non-HDL cholesterol, and between eating behaviours and other laboratory indices of cardiovascular risk (low-density lipoprotein [LDL] cholesterol, apolipoprotein B, HDL cholesterol and apoliprotein A1).

Results:

A total of 1856 children were recruited from primary care practices in Toronto. Of these children, we included 1076 in our study for whom complete data and blood samples were available for analysis. The eating behaviours subscore of the NutriSTEP tool was significantly associated with serum non-HDL cholesterol (p = 0.03); for each unit increase in the eating behaviours subscore suggesting greater nutritional risk, we saw an increase of 0.02 mmol/L (95% confidence interval [CI] 0.002 to 0.05) in serum non-HDL cholesterol. The eating behaviours subscore was also associated with LDL cholesterol and apolipoprotein B, but not with HDL cholesterol or apolipoprotein A1. The dietary intake subscore was not associated with non-HDL cholesterol.

Interpretation:

Eating behaviours in preschool-aged children are important potentially modifiable determinants of cardiovascular risk and should be a focus for future studies of screening and behavioural interventions.Modifiable behaviours during early childhood may provide opportunities to prevent later chronic diseases, in addition to the behavioural patterns that contribute to them, before adverse outcomes occur. There is evidence that behavioural interventions during early childhood (e.g., ages 3–5 yr) can promote healthy eating.¹ For example, repeated exposure to vegetables increases vegetable preference and intake,² entertaining presentations of fruits (e.g., in the shape of a boat) increase their consumption,³ discussing internal satiety cues with young children reduces snacking,⁴ serving carrots before the main course (as opposed to with the main course) increases carrot consumption,⁵ and positive modelling of the consumption of healthy foods increases their intake by young children.^6,7 Responsive eating behavioural styles in which children are given access to healthy foods and allowed to determine the timing and pace of eating in response to internal cues with limited distractions, such as those from television, have been recommended by the Institute of Medicine.⁸Early childhood is a critical period for assessing the origins of cardiometabolic disease and implementing preventive interventions.⁸ However, identifying behavioural risk factors for cardiovascular disease during early childhood is challenging, because signs of disease can take decades to appear. One emerging surrogate marker for later cardiovascular risk is the serum concentration of non–high-density lipoprotein (HDL) cholesterol (or total cholesterol minus HDL cholesterol).^9–12 The Young Finn Longitudinal Study found an association between non-HDL cholesterol levels during childhood (ages 3–18 yr) and an adult measure of atherosclerosis (carotid artery intima–media thickness), although this relation was not significant for the subgroup of younger female children (ages 3–9 yr).^10,11 The Bogalusa Heart Study, which included a subgroup of children aged 2–15 years, found an association between low-density lipoprotein (LDL) cholesterol concentration (which is highly correlated with non-HDL cholesterol) and asymptomatic atherosclerosis at autopsy.¹² The American Academy of Pediatrics recommends non-HDL cholesterol concentration as the key measure for screening for cardiovascular risk in children.⁹ Serum non-HDL cholesterol concentration is the dyslipidemia screening test recommended by the American Academy of Pediatrics for children aged 9–11 years.⁹ Cardiovascular risk stratification tools such as the Reynold Risk Score (www.reynoldsriskscore.org) and the Framingham Heart Study coronary artery disease 10-year risk calculator (www.framinghamheartstudy.org/risk) for adults do not enable directed interventions when cardiovascular disease processes begin — during childhood.The primary objective of our study was to determine whether eating behaviours at 3–5 years of age, as assessed by the NutriSTEP (Nutritional Screening for Every Preschooler) questionnaire,^13,14 are associated with non-HDL cholesterol levels, a surrogate marker of cardiovascular risk. Our secondary objectives were to determine whether other measures of nutritional risk, such as dietary intake, were associated with non-HDL cholesterol levels and whether eating behaviours are associated with other cardiovascular risk factors, such as LDL cholesterol, apolipoprotein B, HDL cholesterol and apoliprotein A1.     

Associations between first and second primary cancers: a population-based study

Background:

Patients surviving certain types of cancer are at increased risk of a second primary cancer. We tested the hypothesis that excess risk of a second primary cancer is due mainly to excess risk of it being the same type of cancer as the first, rather than to excess risk of it being a different type.

Methods:

We conducted a nationwide study using data from three dabatases for the entire Danish population (n = 7 493 705) from 1980 through 2007. For each type of cancer, we performed a nested study matching each patient with incident cancer diagnosed in that period with up to five controls who did not have the examined cancer at the time of diagnosis. We used Cox regression models to calculate individual risk estimates and meta-analysis techniques to calculate aggregated risk estimates.

Results:

A total of 765 255 people had one or more diagnoses of primary cancer (total 843 118 diagnoses) during the study period. The aggregated hazard ratio (HR) for risk of any second primary cancer after any first cancer was 1.25 (95% confidence interval [CI] 1.24–1.26), with heterogeneity among cancer types. The aggregated HR for risk of a second primary cancer of the same type as the first was 2.16 (95% CI 1.98–2.34). The aggregated HR for risk of a second cancer of a different type from the first was 1.13 (95% CI 1.12–1.15). Results were similar when we excluded second primary cancers occurring within 1, 2, 5 or 10 years after the first cancer. Overall, we observed 74 significant associations among 27 types of first cancer and 27 possible types of second primary cancer.

Interpretation:

Excess risk of a second primary cancer was due mainly to a 2.2-fold risk of the second cancer being the same type as the first, whereas the risk of it being a different type was only 1.1-fold. However, heterogeneity among cancer types was substantial.Second primary cancers are seen in 15% of cancer survivors, resulting in increased morbidity and mortality.¹ Overall, patients surviving certain types of cancer are at increased risk of a second primary cancer.^2–4 It is unclear, however, whether this excess risk is due mainly to excess risk of the second primary cancer being the same type as the first cancer, or to excess risk of it being a different type from the first. Clinically, this is an important question, because a clear answer may help target continued surveillance of patients with cancer for the development of second primary cancers.Previously, the risk of second primary cancers was estimated through pair-wise examination of the risk of a specific second primary cancer following a specific first cancer^5–9 and in studies of the risk of a second cancer of the same type as the first.^10–13 We tested the hypothesis that excess risk of a second primary cancer is due mainly to excess risk of it being the same type of cancer as the first, rather than to excess risk of it being a different type. We studied the entire Danish population over a 28-year period using data from three national databases and calculated aggregated risk estimates across all cancer types and individual risk estimates for the different cancer types.     

Association of health behaviour with heart rate variability: a population-based study

Background

Multiple randomized controlled trials (RCTs) have examined the cardiovascular effects of omega-3 fatty acids and have provided unexplained conflicting results. A meta-analysis of these RCTs to estimate efficacy and safety and potential sources of heterogeneity may be helpful.

Methods

The Cochrane library, MEDLINE, and EMBASE were systematically searched to identify all interventional trials of omega-3 fatty acids compared to placebo or usual diet in high-risk cardiovascular patients. The primary outcome was all-cause mortality and secondary outcomes were coronary restenosis following percutaneous coronary intervention and safety. Meta-analyses were carried out using Bayesian random-effects models, and heterogeneity was examined using meta-regression.

Results

A total of 29 RCTs (n = 35,144) met our inclusion criteria, with 25 reporting mortality and 14 reporting restenosis. Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR] = 0.88, 95% Credible Interval [CrI] = 0.64, 1.03) or with restenosis prevention (RR = 0.89, 95% CrI = 0.72, 1.06), though the probability of some benefit remains high (0.93 and 0.90, respectively). However in meta-regressions, there was a >90% probability that larger studies and those with longer follow-up were associated with smaller benefits. No serious safety issues were identified.

Conclusions

Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis. However, caution must be exercised in interpreting these benefits as results were attenuated in higher quality studies, suggesting that bias may be at least partially responsible. Additional high quality studies are required to clarify the role of omega-3 fatty acid supplementation for the secondary prevention of cardiovascular disease.     

Sleep disorders and demand for medical services: evidence from a population-based longitudinal study

Background

The aim of this study was to investigate whether insomnia and obstructive sleep apnea (OSA) were predictors of hospitalizations or emergency department visits during two years following the Sao Paulo Epidemiologic Sleep Study (EPISONO) sample.

Methods and Findings

All participants (n = 1,101) who underwent a baseline evaluation between July and December 2007 were contacted in December 2009 and asked to fill out a questionnaire about body weight changes, number of hospitalizations and visits to the emergency department. Participants lost during the follow-up period represented 3.2% (n = 35) and 7 subjects had died. Hospitalizations were reported by 116 volunteers (10.5%) and emergency department visits were reported by 136 participants (12.4%). The average body mass index (BMI) did not vary significantly between the first and the second assessment [26.7(95%CI:26.3–27.1) vs. 26.9(26.5–27.4) kg/m2]. After adjusting for confounders, a multiple logistic regression model revealed that female gender [1.4(1.0–1.9)], age ≥40 years, insomnia diagnosed according to the DSM-IV criteria [1.6(1.0–2.6)], and apnea-hypopnea index ≥15 [1.5(1.0–2.2)] were predictors of hospitalizations and/or demand for emergency services.

Conclusion

Our study of a probabilistic sample of the Sao Paulo inhabitants shows that over a period of two years, insomnia and OSA were both associated with health impairment. Considering the high prevalence and public health burden of sleep disorders, the consequences of untreated disease for both the individual and society are undeniable and should be addressed.     

Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: A meta-analysis

Background

Recurrent pregnancy loss is an important clinical problem. Recently, high-level homocysteine in blood has been considered as a possible cause. Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proved to be the common hereditary factors of high-level homocysteine. The association between MTHFR polymorphisms and unexplained recurrent pregnancy loss (URPL) has been reported but with controversial results. The purpose of present study is to collect and analyze published available data, and evaluate the association between MTHFR polymorphisms and URPL.

Methods

A meta-analysis was performed to examine the association between MTHFR polymorphisms (C677T and A1298C) and URPL. Odds ratio (OR) and its 95% confidence interval (CI) were used in each study of genotype and allele contrast.

Result(s)

MTHFR C677T: The analysis included 3559 URPL cases and 5097 healthy controls. Overall random-effects odds ratios (ORs) were 1.68 (95% CI, 1.32–2.13; P < 0.0001) for TT versus total genotypes, 1.35 (95% CI, 1.04–1.76; P = 0.0224) for TT and CT genotype combined versus total genotypes and 1.34 (95%CI, 1.13–1.58; P < 0.0001) for T versus total alleles. Although significant heterogeneity was found in C677T, it became weaker in the East Asian subgroup and the mixed subgroup when separated by ethnic subgroups. The results showed significant association between MTHFR C677T and URPL in the East Asian subgroup (ORs 2.11 for TT versus total genotype (P = 0.0004) and 1.53 for T versus total alleles (P < 0.0001)) and in the mixed subgroup (ORs 3.47 for TT versus total genotypes (P < 0.0001) and 1.80 for T versus total alleles (P < 0.027)), but not in Caucasian subgroup.

MTHFR A1298C

The study involved 1163 URPL cases and 1061 healthy controls. Overall random-effects odds ratios (ORs) were 1.37 (95% CI, 0.71–2.67; P = 0.3456) for CC versus total genotypes, 1.16 (95%CI, 0.98–1.38; P = 0.0833) for CC + AC versus total genotypes and 1.04 (95%CI, 0.84–1.29; P = 0.7112) for C versus total alleles. No significant association between MTHFR A1298C polymorphism and URPL was found.

Conclusions

These results indicate a significant association between MTHFR C677T mutation and URPL in the East Asian subgroup and mixed subgroup, but no significance in MTHFR A1298C mutation.