Detection of rare mutations, copy number alterations, and methylation in the same template DNA molecules.

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.

Lower versus Higher Glycemic Criteria for Diagnosis of Gestational Diabetes.

BACKGROUND: Treatment of gestational diabetes improves maternal and infant health, although diagnostic criteria remain unclear. METHODS: We randomly assigned women at 24 to 32 weeks' gestation in a 1:1 ratio to be evaluated for gestational diabetes with the use of lower or higher glycemic criteria for diagnosis. The lower glycemic criterion was a fasting plasma glucose level of at least 92 mg per deciliter (≥5.1 mmol per liter), a 1-hour level of at least 180 mg per deciliter (≥10.0 mmol per liter), or a 2-hour level of at least 153 mg per deciliter (≥8.5 mmol per liter). The higher glycemic criterion was a fasting plasma glucose level of at least 99 mg per deciliter (≥5.5 mmol per liter) or a 2-hour level of at least 162 mg per deciliter (≥9.0 mmol per liter). The primary outcome was the birth of an infant who was large for gestational age (defined as a birth weight above the 90th percentile according to Fenton-World Health Organization standards). Secondary outcomes were maternal and infant health. RESULTS: A total of 4061 women underwent randomization. Gestational diabetes was diagnosed in 310 of 2022 women (15.3%) in the lower-glycemic-criteria group and in 124 of 2039 women (6.1%) in the higher-glycemic-criteria group. Among 2019 infants born to women in the lower-glycemic-criteria group, 178 (8.8%) were large for gestational age, and among 2031 infants born to women in the higher-glycemic-criteria group, 181 (8.9%) were large for gestational age (adjusted relative risk, 0.98; 95% confidence interval, 0.80 to 1.19; P = 0.82). Induction of labor, use of health services, use of pharmacologic agents, and neonatal hypoglycemia were more common in the lower-glycemic-criteria group than in the higher-glycemic-criteria group. The results for the other secondary outcomes were similar in the two trial groups, and there were no substantial between-group differences in adverse events. Among the women in both groups who had glucose test results that fell between the lower and higher glycemic criteria, those who were treated for gestational diabetes (195 women), as compared with those who were not (178 women), had maternal and infant health benefits, including fewer large-for-gestational-age infants. CONCLUSIONS: The use of lower glycemic criteria for the diagnosis of gestational diabetes did not result in a lower risk of a large-for-gestational-age infant than the use of higher glycemic criteria. (Funded by the Health Research Council of New Zealand and others; GEMS Australian New Zealand Clinical Trials Registry number, ACTRN12615000290594.).

Impact of a private sector residential early parenting program on clinically significant postnatal depressive symptoms experienced by women: Audit of routinely collected data.

INTRODUCTION: Early parenting services in Australia offer brief structured residential programs to address moderate to severe non-psychotic mental health problems among women and unsettled infant/toddler behaviours. The aims were to (1) estimate the immediate and medium-term impact of a five-night psychoeducational residential early parenting program on postpartum depressive symptoms and (2) identify the factors associated with improvement or worsening of postpartum depressive symptoms after completing the program and six weeks post-discharge. METHODS: Audit of routinely collected medical record data from pre-admission, pre-discharge and post-discharge assessments of a consecutive cohort of women admitted, with their infants/toddlers in a 15-month period to Masada Private Hospital Early Parenting Centre. Data included structured questions assessing: demographic characteristics, access to family and social support, past and current mental health problems, reproductive and obstetric health, chronic health conditions, breastfeeding problems, coincidental major life events, health risk behaviours and infant/toddler feeding, sleeping and crying behaviours. Standardised instruments included the Partner Interaction after Birth Scale (PIBS), the MacLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), Modified Fatigue Assessment Scale (FAS) and selected items from the Karitane Parenting Confidence Scale. The primary outcomes were Edinburgh Postnatal Depression Scale scores at pre-discharge and follow up assessments. Data were analysed using multinomial logistic regression models in which individual and psychosocial characteristics at pre-admission were included as predictors of the likelihood of the changes of the outcomes from pre-admission to pre-discharge and follow up. RESULTS: Complete data from 1220 of 1290 (95%) eligible women were available to assess pre-admission to pre-discharge and from 559 (45.8%) to assess pre-discharge to six-week follow-up changes. The mean pre-admission EPDS score was 11.7 (95% CI: 11.5; 12.0), pre-discharge it was 7.1 (95% CI: 6.9; 7.4) and at six-week follow up it was 5.7 (95% CI: 5.3; 6.1). We found that almost all women experienced a clinically meaningful and rapid improvement in depressive symptoms of at least this magnitude (reduction in mean EPDS scores of 4.6 points from pre-admission to pre-discharge (five nights) and a further reduction of 1.2 points pre-discharge to follow up) (six weeks) and we identified an interpretable set of risk factors for symptoms that did not improve or worsened. The adverse outcomes were associated with having symptoms of borderline personality disorder, a partner experienced as lacking kindness and care, coincidental adverse events and having a child younger than six months. CONCLUSION: Residential early parenting programs, which take a psycho-educational approach to strengthening caregiving skills, maximising agency, and reducing helplessness, have a rapid beneficial effect on women's postpartum depressive symptoms. These programs provide a valuable and effective component of comprehensive mental health services. Long-term dialectical behaviour therapy is indicated for women with borderline personality disorder traits for whom early parenting programs alone are insufficient to improve depressive symptoms.

Symptoms of depression and risk of emergency department visits among people aged 70 years and over.

BACKGROUND: Older people experiencing depression and anxiety have higher rates of health service utilisation than others, but little is known about whether these influence their seeking of emergency care. The aim was to examine the associations between symptoms of depression and the use of emergency health care, in an Australian context, among a population of people aged 70 years and over initially free of cardiovascular disease, dementia or major physical disability. METHODS: We undertook secondary analyses of data from a large cohort of community-dwelling Australians aged [Formula: see text]70 years. Multivariable logistic regression was used to compare the association of symptoms of depression (measured using the Center for Epidemiological Studies Depression Scale 10 question version, CESD at baseline) with subsequent episodes of emergency care, adjusting for physical and social factors of clinical interest. Marginal adjusted odds ratios were calculated from the logistic regression. RESULTS: Data were available for 10,837 Australian participants aged at least 70 years. In a follow-up assessment three years after the baseline assessment, 17.6% of people self-reported an episode of emergency care (attended an ED of called an emergency ambulance) in the last 12 months. Use of emergency healthcare was similar for men and women (17.8% vs. 17.4% p = 0.61). A score above the cut-off on the CESD at baseline was associated with greater use of emergency health care (OR = 1.35, 95% CI 1.11,1.64). When modelled separately, there was a greater association between a score above the cut-off on the CESD and emergency healthcare for women compared with men. CONCLUSIONS: This study is unique in demonstrating how depressive symptoms among healthy older persons are associated with subsequent increased use of emergency healthcare. Improved understanding and monitoring of mental health in primary care is essential to undertake effective healthcare planning including prevention of needing emergency care.

Effects of a residential psychoeducational parenting program on maternal anxiety and fatigue symptoms.

AIMS: To evaluate the effects of a 5-day residential psychoeducational program on maternal anxiety and fatigue symptoms among women admitted with their unsettled infants and determine the psychological, social and demographic characteristics which are associated with the effect sizes. METHODS: This is a secondary analysis of routinely collected data from mothers with children aged up to 24 months who were admitted to and completed the residential early parenting psychoeducational program at Masada Private Hospital Early Parenting Centre in Melbourne. Maternal anxiety symptoms were assessed using the Edinburgh Postnatal Depression Scale Three-item Anxiety subscale and maternal fatigue symptoms were the Modified Fatigue Assessment Scale at preadmission, predischarge and follow-up 6-weeks post discharge. RESULTS: Overall, 1220 admissions were included in analyses. Cohen's d for reductions in the anxiety symptoms during the program was 0.64 (95% CI 0.59 to 0.70) and from pre-discharge to post-discharge was 0.14 (95% CI 0.09 to 01.9), and for fatigue was 1.21 (95% CI 1.11 to 1.32). Higher borderline personality disorder symptoms and experiencing more stressful life events were associated with lower mean reductions in anxiety and fatigue symptoms. Women with a history of mental health problems had lower anxiety symptom reductions. Women who were older or had younger babies had lower fatigue score reductions. CONCLUSION: This study confirms the effectiveness of a 5-day residential early parenting psychoeducational program provided by a private sector facility in reducing postnatal anxiety and fatigue rapidly, with effects maintained to at least 6-weeks post-discharge.

The association between multimorbidity and osteoporosis investigation and treatment in high-risk fracture patients in Australia: A prospective cohort study.

BACKGROUND: Multimorbidity is common among fracture patients. However, its association with osteoporosis investigation and treatment to prevent future fractures is unclear. This limited knowledge impedes optimal patient care. This study investigated the association between multimorbidity and osteoporosis investigation and treatment in persons at high risk following an osteoporotic fracture. METHODS AND FINDINGS: The Sax Institute's 45 and Up Study is a prospective population-based cohort of 267,153 people in New South Wales, Australia, recruited between 2005 and 2009. This analysis followed up participants until 2017 for a median of 6 years (IQR: 4 to 8). Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection (APDC)), emergency presentations (Emergency Department Data Collection (EDDC)), Pharmaceutical Benefits Scheme (PBS), and Medicare Benefits Schedule (MBS). Data were linked by the Centre for Health Record Linkage and stored in a secured computing environment. Fractures were identified from APDC and EDDC, Charlson Comorbidity Index (CCI) from APDC, Dual-energy X-ray absorptiometry (DXA) investigation from MBS, and osteoporosis treatment from PBS. Out of 25,280 persons with index fracture, 10,540 were classified as high-risk based on 10-year Garvan Fracture Risk (age, sex, weight, prior fracture and falls) threshold ≥20%. The association of CCI with likelihood of investigation and treatment initiation was determined by logistic regression adjusted for education, socioeconomic and lifestyle factors). The high-risk females and males averaged 77 ± 10 and 86 ± 5 years, respectively; >40% had a CCI ≥2. Only 17% of females and 7% of males received a DXA referral, and 22% of females and 14% males received osteoporosis medication following fracture. A higher CCI was associated with a lower probability of being investigated [adjusted OR, females: 0.73 (95% CI, 0.61 to 0.87) and 0.43 (95% CI, 0.30 to 0.62); males: 0.47 (95% CI, 0.33 to 0.68) and 0.52 (0.31 to 0.85) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively] and of receiving osteoporosis medication [adjusted OR, females: 0.85 (95% CI, 0.74 to 0.98) and 0.78 (95% CI, 0.61 to 0.99); males: 0.75 (95% CI, 0.59 to 0.94) and 0.37 (95% CI, 0.23 to 0.53) for CCI: 2 to 3, and ≥4 versus 0 to 1, respectively]. The cohort is relatively healthy; therefore, the impact of multimorbidity on osteoporosis management may have been underestimated. CONCLUSIONS: Multimorbidity contributed significantly to osteoporosis treatment gap. This suggests that fracture risk is either underestimated or underprioritized in the context of multimorbidity and highlights the need for extra vigilance and improved fracture care in this setting.

Longitudinal changes in bone mineral density during perimenopausal transition: the Vietnam Osteoporosis Study.

Based on the prospective cohort of the Vietnam Osteoporosis Study, we show that bone loss occurred before menopause, and that the loss accelerated in the first 5 years post-menopause. PURPOSE: To define the change in bone mineral density (BMD) among women during the menopausal transition. METHODS: The study involved 1062 women aged 40-59 who were participants of the population-based prospective Vietnam Osteoporosis Study. BMD at the femoral neck (FN), lumbar spine (LS), and whole body scan was measured by DXA. Each woman has had two BMD measurements separated by approximately 2 years, and the rate of BMD change was calculated for each woman. Multivariable linear regression models were used to quantify the association between body composition parameters and the rate of BMD change. RESULTS: At FN, there were 3 phases of BMD change: a slight decline before the age of 45-49 (average loss of 0.51%/year); a substantial decline between the ages of 49 and 54 (average loss of 1.39%/year); and then slowed down between the ages of 54 and 59 (average loss of 0.31%/year). The same trend was also observed at LS: a slight decline (- 0.56%/year) among women aged 45-49; then a significant decline between the ages of 50 and 54 (- 1.33%/year); but then slowed down at - 0.31%/year after the age of 55. Changes in BMD were not significantly associated with changes in lean mass or fat mass. CONCLUSIONS: Although bone loss occurred before menopause, the loss accelerated in the early perimenopausal transition (45-50 years of age). This finding suggests that screening for osteoporosis in women should be considered at the age of 45.

Factors associated with fragility fractures in type 2 diabetes: An analysis of the randomised controlled Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS: Fracture risk is elevated in some type 2 diabetes patients. Bone fragility may be associated with more clinically severe type 2 diabetes, although prospective studies are lacking. It is unknown which diabetes-related characteristics are independently associated with fracture risk. In this post-hoc analysis of fracture data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (ISRCTN#64783481), we hypothesised that diabetic microvascular complications are associated with bone fragility. MATERIALS AND METHODS: The FIELD trial randomly assigned 9795 type 2 diabetes participants (aged 50-75 years) to receive oral co-micronised fenofibrate 200 mg (n = 4895) or placebo (n = 4900) daily for a median of 5 years. We used Cox proportional hazards models to identify baseline sex-specific diabetes-related parameters independently associated with incident fractures. RESULTS: Over 49,470 person-years, 137/6138 men experienced 141 fractures and 143/3657 women experienced 145 fractures; incidence rates for the first fracture of 4∙4 (95% CI 3∙8-5∙2) and 7∙7 per 1000 person-years (95% CI 6∙5-9∙1), respectively. Fenofibrate had no effect on fracture outcomes. In men, baseline macrovascular disease (HR 1∙52, 95% CI 1∙05-2∙21, p = 0∙03), insulin use (HR 1∙62, HR 1∙03-2∙55, p = 0∙03), and HDL-cholesterol (HR 2∙20, 95% CI 1∙11-4∙36, p = 0∙02) were independently associated with fracture. In women, independent risk factors included baseline peripheral neuropathy (HR 2∙04, 95% CI 1∙16-3∙59, p = 0∙01) and insulin use (HR 1∙55, 95% CI 1∙02-2∙33, p = 0∙04). CONCLUSIONS: Insulin use and sex-specific complications (in men, macrovascular disease; in women, neuropathy) are independently associated with fragility fractures in adults with type 2 diabetes.

Glycemic control in gestational diabetes and impact on biomarkers in women and infants.

BACKGROUND: Gestational diabetes mellitus (GDM) is linked to the dysregulation of inflammatory markers in women with GDM compared to women without. It is unclear whether the intensity of glycemic control influences these biomarkers. We aimed to assess whether different glycemic targets for women with GDM and compliance influence maternal and infant biomarkers. METHODS: Maternity hospitals caring for women with GDM were randomized in the TARGET Trial to tight or less tight glycemic targets. Maternal blood was collected at study entry, 36 weeks' gestation, and 6 months postpartum, and cord plasma after birth. We assessed compliance to targets and concentrations of maternal serum and infant biomarkers. RESULTS: Eighty-two women and infants were included in the study. Concentrations of maternal and infant biomarkers did not differ between women assigned to tighter and less tight glycemic targets; however, concentrations were altered in maternal serum leptin and CRP and infant cord C-peptide, leptin, and IGF in women who complied with tighter targets. CONCLUSIONS: Use of tighter glycemic targets in women with GDM does not change the concentrations of maternal and infant biomarkers compared to less tight targets. However, when compliance is achieved to tighter targets, maternal and infant biomarkers are altered. IMPACT: The use of tighter glycemic targets in gestational diabetes does not result in changes to maternal or cord plasma biomarkers. However, for women who complied with tighter targets, maternal serum leptin and CRP and infant cord C-peptide, leptin and IGF were altered compared with women who complied with the use of the less tight targets. This article adds to the current evidence base regarding the impact of gestational diabetes on maternal and infant biomarkers. This article highlights the need for further research to assess enablers to meet the tighter target recommendations and to assess the impact on relevant biomarkers.

Do glycaemic treatment targets affect the perinatal mental health status of women with gestational diabetes? - Data from the TARGET Trial.

BACKGROUND: Gestational diabetes mellitus is associated with perinatal mental disorders. Effective management may reduce this risk, but there is little evidence on effects of different glycaemic treatment targets. We assessed whether tight glycaemic treatment targets compared with less-tight targets reduce the risk of poor mental health outcomes in women with gestational diabetes. METHODS: This was a secondary analysis of data from women who consented to complete perinatal mental health questionnaires as participants in the TARGET Trial, a stepped-wedge cluster randomized trial in 10 hospitals in New Zealand. All hospitals initially used less tight glycaemic targets for management of gestational diabetes and were sequentially randomized, in clusters of two at 4-monthly intervals, to using tighter glycaemic targets. Data were collected from 414 participants on anxiety (6-item Spielberger State Anxiety scale), depression (Edinburgh Postnatal Depression Scale), and health-related quality of life (36-Item Short-Form General Health Survey) at the time of diagnosis (baseline), 36 weeks of gestation, and 6 months postpartum. The primary outcome was composite poor mental health (any of anxiety, vulnerability to depression, or poor mental health-related quality of life). Generalized linear mixed models were used to determine the main treatment effect with 95% confidence intervals using an intention-to-treat approach. RESULTS: We found no differences between randomised glycaemic target groups in the primary outcome at 36 weeks' (relative risk (RR): 1.07; 95% confidence interval 0.58, 1.95) and 6 months postpartum (RR: 1.03; 0.58, 1.81). There were similarly no differences in the components of the primary outcome at 36 weeks' [anxiety (RR: 0.85; 0.44, 1.62), vulnerability to depression (RR: 1.10; 0.43, 2.83), or poor mental health-related quality of life (RR: 1.05; 0.50, 2.20)] or at 6 months postpartum [anxiety (RR:1.21; 0.59, 2.48), vulnerability to depression (RR:1.41; 0.53, 3.79), poor mental health-related quality of life (RR: 1.11; 0.59, 2.08)]. CONCLUSION: We found no evidence that adoption of tighter glycaemic treatment targets in women with gestational diabetes alters their mental health status at 36 weeks' gestation and at 6 months postpartum. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583 (ANZCTR-Registration). Date of registration: 25 March 2015.

Equity in Economic Evaluations of Early Childhood Development Interventions in Low-and Middle-Income Countries: Scoping Review.

OBJECTIVES: This study aimed to examine how equity is integrated into economic evaluations of early childhood development interventions in low-and middle-income countries (LMICs), and to narratively synthesize the study characteristics and findings. METHODS: We conducted a scoping review by searching three electronic databases with terms including equity, early childhood development intervention, economic evaluation, and LMICs. Interventions that aimed to improve child cognitive, physical, language, motor, or social and emotional development through health, nutrition, security and safety, responsive caregiving, and early learning interventions between conception and age 8 years were considered. Studies published in English peer-reviewed journals in the year 2000 and later were included. RESULTS: The review included 24 cost-effectiveness studies out of 1460 identified articles based on eligibility criteria. The included studies addressed health, nutrition, social protection, and water, sanitation and hygiene interventions for child development. The common type of intervention was immunization. Mostly, equity was measured using household wealth or geographic areas, and the study findings were presented through subgroup analyses. The study settings were LMICs, but most studies were conducted by research teams from high-income countries. Overall, 63% of included studies reported that early childhood development interventions improved equity with greater intervention benefits observed in disadvantaged groups. CONCLUSIONS: Consideration of equity in evaluations of early childhood interventions provides a more complete picture of cost-effectiveness, and can improve equity. Greater focus on promoting equity consideration, multi-sectoral interventions, and researchers in LMICs would support evidence-based interventions and policies to achieve equity in child development.

The review found that existing studies mostly measured equity by wealth groups or geographic areas, and presented their findings through subgroup analyses. The most common type of intervention was childhood immunization. The study settings were LMICs, but most studies were conducted by research teams from high-income countries. More than half of studies reported that early childhood development interventions improved equity with greater intervention benefits observed in disadvantaged groups.The small number of relevant studies in the review highlights that more emphasis on equity integration into economic evaluation, coordinated work across multiple sectors, and strong involvement of researchers based in LMICs, are necessary to improve child development.

Prenatal Intravenous Magnesium at 30-34 Weeks' Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomized Clinical Trial.

Importance: Intravenous magnesium sulfate administered to pregnant individuals before birth at less than 30 weeks' gestation reduces the risk of death and cerebral palsy in their children. The effects at later gestational ages are unclear. Objective: To determine whether administration of magnesium sulfate at 30 to 34 weeks' gestation reduces death or cerebral palsy at 2 years. Design, Setting, and Participants: This randomized clinical trial enrolled pregnant individuals expected to deliver at 30 to 34 weeks' gestation and was conducted at 24 Australian and New Zealand hospitals between January 2012 and April 2018. Intervention: Intravenous magnesium sulfate (4 g) was compared with placebo. Main Outcomes and Measures: The primary outcome was death (stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years' corrected age) or cerebral palsy (loss of motor function and abnormalities of muscle tone and power assessed by a pediatrician) at 2 years' corrected age. There were 36 secondary outcomes that assessed the health of the pregnant individual, infant, and child. Results: Of the 1433 pregnant individuals enrolled (mean age, 30.6 [SD, 6.6] years; 46 [3.2%] self-identified as Aboriginal or Torres Strait Islander, 237 [16.5%] as Asian, 82 [5.7%] as Maori, 61 [4.3%] as Pacific, and 966 [67.4%] as White) and their 1679 infants, 1365 (81%) offspring (691 in the magnesium group and 674 in the placebo group) were included in the primary outcome analysis. Death or cerebral palsy at 2 years' corrected age was not significantly different between the magnesium and placebo groups (3.3% [23 of 691 children] vs 2.7% [18 of 674 children], respectively; risk difference, 0.61% [95% CI, -1.27% to 2.50%]; adjusted relative risk [RR], 1.19 [95% CI, 0.65 to 2.18]). Components of the primary outcome did not differ between groups. Neonates in the magnesium group were less likely to have respiratory distress syndrome vs the placebo group (34% [294 of 858] vs 41% [334 of 821], respectively; adjusted RR, 0.85 [95% CI, 0.76 to 0.95]) and chronic lung disease (5.6% [48 of 858] vs 8.2% [67 of 821]; adjusted RR, 0.69 [95% CI, 0.48 to 0.99]) during the birth hospitalization. No serious adverse events occurred; however, adverse events were more likely in pregnant individuals who received magnesium vs placebo (77% [531 of 690] vs 20% [136 of 667], respectively; adjusted RR, 3.76 [95% CI, 3.22 to 4.39]). Fewer pregnant individuals in the magnesium group had a cesarean delivery vs the placebo group (56% [406 of 729] vs 61% [427 of 704], respectively; adjusted RR, 0.91 [95% CI, 0.84 to 0.99]), although more in the magnesium group had a major postpartum hemorrhage (3.4% [25 of 729] vs 1.7% [12 of 704] in the placebo group; adjusted RR, 1.98 [95% CI, 1.01 to 3.91]). Conclusions and Relevance: Administration of intravenous magnesium sulfate prior to preterm birth at 30 to 34 weeks' gestation did not improve child survival free of cerebral palsy at 2 years, although the study had limited power to detect small between-group differences. Trial Registration: anzctr.org.au Identifier: ACTRN12611000491965.

Tighter or less tight glycaemic targets for women with gestational diabetes mellitus for reducing maternal and perinatal morbidity: A stepped-wedge, cluster-randomised trial.

BACKGROUND: Treatment for gestational diabetes mellitus (GDM) aims to reduce maternal hyperglycaemia. The TARGET Trial assessed whether tighter compared with less tight glycaemic control reduced maternal and perinatal morbidity. METHODS AND FINDINGS: In this stepped-wedge, cluster-randomised trial, identification number ACTRN12615000282583, 10 hospitals in New Zealand were randomised to 1 of 5 implementation dates. The trial was registered before the first participant was enrolled. All hospitals initially used less tight targets (fasting plasma glucose (FPG) <5.5 mmol/L (<99 mg/dL), 1-hour <8.0 mmol/L (<144 mg/dL), 2 hour postprandial <7.0 mmol/L (<126 mg/dL)) and every 4 months, 2 hospitals moved to use tighter targets (FPG ≤5.0 mmol/L (≤90 mg/dL), 1-hour ≤7.4 mmol/L (≤133 mg/dL), 2 hour postprandial ≤6.7 mmol/L) (≤121 mg/dL). Women with GDM, blinded to the targets in use, were eligible. The primary outcome was large for gestational age. Secondary outcomes assessed maternal and infant health. Analyses were by intention to treat. Between May 2015 and November 2017, data were collected from 1,100 women with GDM (1,108 infants); 598 women (602 infants) used the tighter targets and 502 women (506 infants) used the less tight targets. The rate of large for gestational age was similar between the treatment target groups (88/599, 14.7% versus 76/502, 15.1%; adjusted relative risk [adjRR] 0.96, 95% confidence interval [CI] 0.66 to 1.40, P = 0.839). The composite serious health outcome for the infant of perinatal death, birth trauma, or shoulder dystocia was apparently reduced in the tighter group when adjusted for gestational age at diagnosis of GDM, BMI, ethnicity, and history of GDM compared with the less tight group (8/599, 1.3% versus 13/505, 2.6%, adjRR 0.23, 95% CI 0.06 to 0.88, P = 0.032). No differences were seen for the other infant secondary outcomes apart from a shorter stay in intensive care (P = 0.041). Secondary outcomes for the woman showed an apparent increase for the composite serious health outcome that included major haemorrhage, coagulopathy, embolism, and obstetric complications in the tighter group (35/595, 5.9% versus 15/501, 3.0%, adjRR 2.29, 95% CI 1.14 to 4.59, P = 0.020). There were no differences between the target groups in the risk for pre-eclampsia, induction of labour, or cesarean birth, but more women using tighter targets required pharmacological treatment (404/595, 67.9% versus 293/501, 58.5%, adjRR 1.20, 95% CI 1.00 to 1.44, P = 0.047). The main study limitation is that the treatment targets used may vary to those in use in some countries. CONCLUSIONS: Tighter glycaemic targets in women with GDM compared to less tight targets did not reduce the risk of a large for gestational age infant, but did reduce serious infant morbidity, although serious maternal morbidity was increased. These findings can be used to aid decisions on the glycaemic targets women with GDM should use. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR). ACTRN12615000282583.

The role of fingernail selenium in the association between arsenic, lead and mercury and child development in rural Vietnam: a cross-sectional analysis.

As, Pb and Hg are common environmental contaminants in low- and middle-income countries. We investigated the association between child toxicant exposure and growth and development and determined if this association was mitigated by Se concentration. Toxicant concentrations in fingernail samples, anthropometry and Bayley's Scales of Infant Development, 3rd edition domains were assessed in 36-month-old children whose mothers had been part of a randomised controlled trial in rural Vietnam. Multivariable regression analyses were performed to estimate the effect of toxicant exposure on clinical outcomes with adjustments for potential confounders and interaction with fingernail Se concentration. We analysed 658 children who had data for at least one physical or developmental outcome, and at least one toxicant measurement, and each of the covariates. Fingernail As concentration was negatively associated with language (estimate per 10 % increase in As: -0·19, 95 % CI: (-0·32, -0·05)). Pb was negatively associated with cognition (estimate per 10 % increase in Pb: -0·08 (-0·15, -0·02)), language (estimate per 10 % increase in Pb: -0·18 (-0·28, -0·10)) and motor skills (estimate per 10 % increase in Pb: -0·12 (-0·24, 0·00)). Hg was negatively associated with cognition (estimate per 10 % increase in Hg: -0·48, (-0·72, -0·23)) and language (estimate per 10 % increase in Hg -0·51, (-0·88, -0·13)) when Se concentration was set at zero in the model. As Se concentration increased, the negative associations between Hg and both cognition and language scores were attenuated. There was no association between toxicant concentration and growth. As, Pb and Hg concentrations in fingernails of 3-year-old children were associated with lower child development scores. The negative association between Hg and neurological development was reduced in magnitude with increasing Se concentration. Se status should be considered when assessing heavy metal toxicants in children and their impact on neurodevelopmental outcomes.

Impact of economic factors, social health and stressful life events on physical health-related quality of life trajectories in older Australians.

PURPOSE: Physical health-related quality of life (HRQoL) is associated with adverse health outcomes, including hospitalizations and all-cause mortality. However, little is known about how physical HRQoL changes over time in older people and the predictors of this trajectory. This study (a) identified trajectories of physical HRQoL among older people and (b) explored whether economic factors, social health or stressful life events impact physical HRQoL trajectories. METHOD: A cohort of 12,506 relatively 'healthy' community-dwelling Australians aged ≥ 70 years (54.4% females), enrolled in the ASPREE Longitudinal Study of Older Persons (ALSOP) study and was followed for six years. Economic factors, social health and life events in the last 12 months were assessed through a questionnaire at baseline. Physical HRQoL was measured by using the 12-item short form at baseline and annual follow-ups. Growth mixture and structural equation modelling were used to identify physical HRQoL trajectories and their predictors. RESULTS: Four physical HRQoL trajectories were identified-stable low (7.1%), declining (9.0%), stable intermediate (17.9%) and stable high (66.0%). Living in more disadvantaged areas, having a lower household income, no paid work, no voluntary work, loneliness and stressful life events (i.e. spousal illness, friend/family illness, financial problem) were associated with a 10%-152% higher likelihood of being in the stable low or declining physical HRQoL trajectory than the stable high group. CONCLUSION: Specific stressful life events had a greater impact on adverse physical HRQoL trajectories in older people than other factors. Volunteering may prevent physical HRQoL decline and requires further investigation.

Burden of severe maternal peripartum mental disorders in low- and middle-income countries: a systematic review.

Peripartum severe mental disorders (PSMDs) encompass schizophrenia, affective psychosis, and psychotic and non-psychotic forms of bipolar disorders. PSMDs are well documented in high-income countries. However, much less is known about the prevalence of PSMDs in low- and middle-income countries (LMICs). The aim was to review the available literature systematically and estimate the prevalence of PSMDs among women in LMICs. We searched the Ovid MEDLINE, Embase, PsycINFO, CINAHL and Maternity and Infant Care databases systematically from the date of inception to Dec 31, 2020, for English-language publications with data on the prevalence of PSMDs among women in World Bank-defined LMICs. Selection of studies, extraction of data and assessment of study quality were each undertaken independently by at least two of the investigators. A total of five studies (completed in three countries spanning two continents) met the inclusion criteria. Five studies reported cumulative incidence of postpartum psychosis (ranging from 1.1 to 16.7 per 1000 births). We found no studies on the prevalence of severe mental disorder during pregnancy in these settings. Marked heterogeneity in methodology precluded meta-analysis. These findings indicate that PSMDs occur at a similar prevalence in low- and middle-income to high-income countries. However overall, there is a paucity of high-quality evidence from these settings. There is a need for rigorous studies with standardized methods to increase knowledge of the nature, prevalence, and determinants of PSMDs among women in resource-constrained LMICs to inform policies, service development, program planning and health professional training.

Factors influencing the attitudes of young Sri Lankan-Australians towards seeking mental healthcare: a national online survey.

BACKGROUND: Sri Lankans, as part of the South Asian diaspora, comprise one of the largest migrant groups in Australia. Although few data are available, South Asian migrants appear to experience higher rates of mental health problems, but seek help at lower rates than other migrant groups. Understanding factors that underpin mental health care seeking is necessary to inform mental health promotion strategies, including access to care. The aim was to investigate factors influencing attitudes to seeking care for mental health problems among young Sri Lankan-Australians born in Sri Lanka or in Australia. METHODS: An anonymous cross- sectional online survey which included the Multiethnic Identity Measure, Perceived Stigma Questionnaire, General Help-Seeking Questionnaire, Attitudes Towards Seeking Professional Psychological Help questionnaire and study specific questions to ascertain sociodemographic characteristics. The survey was advertised on social media and specifically included young adults aged between 18-30, who self-identified as being of Sri Lankan heritage and were living in Australia. Participation was not possible for those that did not have access to the internet. Data were analyzed using bivariable and multivariable statistics. RESULTS: Of the 396 people who attempted the survey, 323 provided fully completed data, 2 provided > 50% completed data which were included in the analyses. 71 were excluded because < 50% of the survey was completed. From all participants, 39.70% were born in Australia (SLaus), 54.46% born in Sri Lanka (SLsl) and 5.8% born in other countries. SLsl had more stigmatizing attitudes towards mental illness (p = 0.027) and seeking professional psychological help (p = 0.03). Women, those who had spent more years living in Australia and whose fathers were more highly educated had less stigmatized attitudes toward mental illness and help-seeking. CONCLUSION: Country of birth, family characteristics and gender influence stigma towards mental illness and help-seeking. Public health strategies to promote understanding of mental health problems and seeking mental healthcare are more likely to be effective if they address these factors directly.

Understanding the relationship between social support and mental health of humanitarian migrants resettled in Australia.

BACKGROUND: Forced migration can lead to loss of social support and increased vulnerability to psychological distress of displaced individuals. The aims were to ascertain the associations of sociodemographic characteristics and social support received by resettled adult humanitarian migrants in Australia; determine the relationship between social support and mental health at different intervals following humanitarian migration; and examine the modification effects of gender, age and migration pathway on that relationship. METHODS: A secondary analysis was conducted of data generated in Waves One (three to six months after resettlement), Three (three years after resettlement) and Five (five years after resettlement) of the Building a New Life in Australia prospective cohort study. The association between sociodemographic characteristics and mental health were examined at each timepoint using a multivariate regression model. Exploratory factor analysis was used to develop a two-factor social support scale (emotional/instrumental and informational support) from a larger set of items collected in the BNLA. Psychological distress was measured by the Kessler-6 scale. Path analysis was used to analyse the relationships between social support and psychological distress among the three time points considering socio-demographic characteristics simultaneously. RESULTS: A total of 2264 participants were included in the analyses. Age, gender, birth region, migration pathway, education level and English proficiency were significantly associated with both social support types. Main source of income was only significantly associated with informational support. Remoteness area was only significantly associated with emotional/instrumental support. As emotional/instrumental support increased by one standard deviation (SD) at Wave One, psychological distress at Wave Three decreased by 0.34 score [95% CI (- 0.61; - 0.08)]. As informational support at Wave Three increased by one SD, psychological distress at Wave Five decreased by 0.35 score [95% CI (- 0.69; - 0.01)]. The relationships between social support and psychological distress varied between genders, age groups and migration pathways. CONCLUSION: Findings demonstrate the importance of emotional/instrumental support and informational support for the medium and long-term mental health of humanitarian migrants. This study also highlights the important of extending current social support provisions and tailoring programs to enhance support received by humanitarian migrant subgroups years after resettlement to improve mental health.

Lifetime impact of being underweight or overweight/obese during childhood in Vietnam.

BACKGROUND: There is limited evidence about lifetime burden of child malnutrition. This study aimed to estimate the lifetime impact of being underweight or overweight/obese during childhood in Vietnam. METHODS: We developed a life table model in combination with a Markov model for Vietnamese children aged 5-19 years and simulated until they reached 75 years of age or died using published data. The starting year was 2019 and the model estimated number of deaths, years of life lived and quality-adjusted life years (QALY) with an annual discount rate of 3%. We performed scenario, one-way, and probabilistic sensitivity analyses to assess the impact of uncertainties in input parameters. RESULTS: The model estimated 9.68 million deaths (6.44 million men and 3.24 million women), 622 million years of life lived (317 million men and 305 million women), and 601 million QALYs (308 million men and 293 million women). Scenario analyses showed that the reduction in either underweight or overweight/obesity alone, and reduction in both underweight and overweight/obesity resulted in fewer deaths, more years of life lived and more QALYs gained. In the scenario where everyone was a healthy weight, the model estimated 577,267 fewer deaths (6.0% less), 2 million more years of life lived (0.3% more), and 3 million QALYs gained (0.6% more) over base-case results which represents current situation in Vietnam. CONCLUSIONS: Our results suggest that addressing underweight and overweight/obesity will contribute to reducing deaths and increasing years of life lived and QALYs. Policies and interventions in alignment with Sustainable Development Goals to address underweight and overweight/obesity are necessary to achieve health for all.

Social isolation, social support and loneliness as independent concepts, and their relationship with health-related quality of life among older women.

Objectives: To assess whether social isolation, social support, and loneliness are independently associated with health-related quality of life (HRQoL).Method: Retrospective analysis including 10,517 women aged 70-75 years from the Australian Longitudinal Study on Women's Health (ALSWH). Social isolation, social support (Duke Social Support Index), and loneliness (single item) were investigated for their association with standardised HRQoL (physical [PCS] and mental [MCS] components of the SF-36® questionnaire). Analyses were adjusted for sociodemographic variables and number of medical conditions.Results: Only 3% reported being socially isolated, having low social support and being lonely, and 34% reported being not socially isolated, high social support and not being lonely. Each construct was independently associated with HRQoL, with loneliness having the strongest inverse association (PCS: isolation -0.98, low support -2.01, loneliness -2.03; MCS: isolation -1.97, low support -4.79, loneliness -10.20; p-value < 0.001 for each). Women who were not isolated or lonely and with high social support had the greatest HRQoL (compared to isolated, low social support and lonely; MCS: 17 to 18 points higher, PCS: 5 to 8 points higher). Other combinations of social isolation, social support and loneliness varied in their associations with HRQoL.Conclusion: Ageing populations face the challenge of supporting older people to maintain longer, healthy, meaningful and community-dwelling lives. Among older women, social isolation, low social support and loneliness are distinct, partially overlapping yet interconnected concepts that coexist and are each adversely associated with HRQoL. Findings should be replicated in other cohorts to ensure generalisability across other age groups and men.