BACKGROUND: Although smoking is known to be powerful risk factor for other vascular diseases, such as cardiac and peripheral vascular disease, only relatively recently has evidence for the role of smoking in the development of stroke been established. The reasons for this advance lie in the acknowledgement that stroke is a heterogeneous disease, in which its subtypes are associated with different risk factors. Furthermore, improvements in the stringency of epidemiological studies and the greater use of CT scanning have enabled the role of smoking in the development of stroke to be elucidated. SUMMARY OF REVIEW: This is a qualitative examination of high quality epidemiological studies in which the role of smoking and passive smoking, as a risk factor for cerebral infarction, intracerebral haemorrhage and subarachnoid haemorrhage, is examined. In addition, the pathological mechanisms by which smoking or passive smoking may contribute to the development of stroke are reviewed. CONCLUSION: Smoking is a crucial independent determinant of cerebral infarction and subarachnoid haemorrhage, however its role in intracerebral haemorrhage is unclear. Although studies are limited, there is evidence that exposure to passive smoking may also increase the risk of stroke. Smoking appears to be involved in the pathogenesis of stroke via direct injury to the vasculature and also by altering haemodynamic factors within the circulation. Importantly, smoking is modifiable risk factor for stroke. Therefore, the encouragement of smoking cessation may result in a substantial reduction in the incidence of this devastating disease.

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated ( approximately 45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure-function relationships for lymphocyte perforin.

BACKGROUND: This study aimed to establish whether changes in the socioeconomic context were associated with changes in population-level antenatal mental health indicators in Vietnam. METHODS: Social, economic and public policies introduced in Vietnam (1986-2010) were mapped. Secondary analyses of data from two cross-sectional community-based studies conducted in 2006 (n = 134) and 2010 (n = 419), involving women who were ≥ 28 weeks pregnant were completed. Data for these two studies had been collected in structured individual face-to-face interviews, and included indicators of antenatal mental health (mean Edinburgh Postnatal Depression Scale Vietnam-validation (EPDS-V) score), intimate partner relationships (Intimate Bonds Measure Vietnam-validation) and sociodemographic characteristics. Socioeconomic characteristics and mean EPDS-V scores in the two study years were compared and mediation analyses were used to establish whether indicators of social and economic development mediated differences in EPDS-V scores. RESULTS: Major policy initiatives for poverty reduction, hunger eradication and making domestic violence a crime were implemented between 2006 and 2010. Characteristics and circumstances of pregnant women in Ha Nam improved significantly. Mean EPDS-V score was lower in 2010, indicating better population-level antenatal mental health. Household wealth and intimate partner controlling behaviours mediated the difference in EPDS-V scores between 2006 and 2010. CONCLUSIONS: Changes in the socioeconomic and political context, particularly through policies to improve household wealth and reduce domestic violence, appear to influence women's lives and population-level antenatal mental health. Cross-sectoral policies that reduce social risk factors may be a powerful mechanism to improve antenatal mental health at a population level.

Introduction: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods: CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results: CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion: CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.

INTRODUCTION: Diabetic patients with peripheral arterial disease (PAD) are challenging to assess. Non-contrast magnetic resonance angiography (MRA) offers a safe alternative in patients with renal impairment. The study objective is to evaluate accuracy of lower limb quiescent-interval single-shot (QISS) MRA and pedal QISS-arterial spin-labelled (ASL) MRA for detection of significant stenosis in diabetic patients with PAD. METHODS: Combined QISS and QISS-ASL MRA was performed in 32 diabetic PAD patients (20 male, 12 female; mean 69 years; 8 with critical ischaemia). Two readers assessed haemodynamically significant (>50%) stenosis and diagnostic confidence on MRA, against digital subtraction angiography (DSA) as the reference standard, with subgroup analysis of patients with severe renal impairment (n = 7). Inter-reader agreement of stenosis and diagnostic confidence were evaluated. Test-retest reproducibility was evaluated in 10 subjects who underwent repeat MRA on a different day. RESULTS: At DSA, 262/645 segments (40.6%) had haemodynamically significant stenoses. MRA accuracy was 78.1% (478/612) and 75.6% (464/614), sensitivity 64.7% (161/249) and 77.5% (193/249), and specificity 87.3% (317/363) and 74.2% (271/365) for 2 readers. MRA accuracy was 80.9% and 80.7% for readers 1 and 2, respectively, in patients with severe renal impairment. QISS MRA but not pedal QISS-ASL MRA was considered of diagnostic image quality. Inter-reader agreement was moderate for stenosis (ĸ = 0.60) and diagnostic confidence (ĸ = 0.41). Test-retest reproducibility was high (ĸ = 0.87) and moderate (ĸ = 0.54) for individual readers. CONCLUSIONS: Quiescent-interval single-shot MRA has reasonable accuracy in a diabetic PAD population with high burden of disease, providing a non-contrast option in patients with renal impairment. QISS-ASL MRA requires further optimisation to be clinically feasible.

BACKGROUND: Cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, is the leading cause of death and disability globally. A large proportion of mortality occurs in people with prior CHD and effective and scalable strategies are needed to prevent associated deaths and hospitalisations. The aim of this study is to determine if a practice-level collaborative quality improvement program, focused on patients with CHD, reduces the rate of unplanned CVD hospitalisations and major adverse cardiovascular events, and increases the proportion of patients achieving risk factor targets at 24 months. METHODS: Cluster randomised controlled trial (cRCT) to evaluate the effectiveness of a primary care quality improvement program in 50 primary care practices (n~ 10,000 patients) with 24-month follow-up. Eligible practices will be randomised (1:1) to participate in either the intervention (collaborative quality improvement program) or control (standard care) regimens. Outcomes will be assessed based on randomised allocation, according to intention-to-treat. The primary outcome is the proportion of patients with unplanned CVD hospitalisations at 2 years. Secondary outcomes are proportion of patients with major adverse cardiovascular events, proportion of patients who received prescriptions for guideline-recommended medicines, proportion of patients achieving national risk factor targets and proportion with a chronic disease management plan or review. Differences in the proportion of patients who are hospitalised (as well as binary secondary outcomes) will be analysed using log-binomial regression or robust Poisson regression, if necessary. DISCUSSION: Despite extensive research with surrogate outcomes, to the authors' knowledge, this is the first randomised controlled trial to evaluate the effectiveness of a data-driven collaborative quality improvement intervention on hospitalisations, CVD events and cardiovascular risk amongst patients with CHD in the primary care setting. The use of data linkage for collection of outcomes will enable evaluation of this potentially efficient strategy for improving management of risk and outcomes for people with heart disease. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12619001790134 (dated 20th December 2019).

INTRODUCTION: Mounting evidence now indicates that preoperative opioid use is associated with an array of complications following total joint replacement (TJR). However, evidence of these risks remains fragmented. A comprehensive and well-integrated understanding of this body of evidence is necessary to appropriately inform treatment decisions, the allocation of limited healthcare resources, and the direction of future clinical research. The proposed systematic review and meta-analysis aims to identify and synthesise the available evidence of an association between opioid use prior to TJR and postoperative complications, categorised by complication type. METHODS AND ANALYSIS: We will search MEDLINE, EMBASE, CINAHL, PsycINFO, and Web of Science from inception to April 2020. Observational and experimental studies that compare preoperative opioid users who have undergone elective TJR to opioid naïve TJR patients will be included. The primary outcomes will be postoperative complications, which will be categorised as either mortality, morbidity, or joint-related complications. The secondary outcomes will be persistent postoperative opioid use, readmission, and length of stay. Individual study quality will be assessed using the relevant NIH-NHLBI study quality assessment tools. Findings will be reported in narrative and tabular form, and, where possible, odds ratios (dichotomous outcomes) or standardised mean differences (continuous outcomes) will be reported with 95% confidence intervals. Where appropriate, random effect meta-analyses will be conducted for each outcome, and heterogeneity will be quantified using the I2 statistic and Cochran's Q test. This study will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. ETHICS AND DISSEMINATION: Ethics approval will not be required as no primary or private data are being collected. Findings will be disseminated through peer-reviewed publication and presentation at academic conferences. PROSPERO REGISTRATION NUMBER: CRD42020153047.

Gestational diabetes mellitus (GDM) and large for gestational age (LGA) offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring. The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines.

BACKGROUND: Current guidelines for the management of obesity in women planning pregnancy suggest lifestyle modification before conception. However, there is little evidence that lifestyle modification alters pregnancy outcomes. Bariatric surgery results in significant weight loss. This appears to reduce the risk of adverse pregnancy outcomes for the mother but may increase the risk of adverse outcomes for the infant. In order to reduce the risks of obesity-related adverse pregnancy outcomes for both mother and offspring, alternative approaches to the management of obesity in women planning pregnancy are needed. METHODS/DESIGN: This study, a two-arm, parallel group, randomized control trial, will be conducted at the Metabolic Disorders Centre, University of Melbourne. This trial will recruit 164 women aged 18-38 years with a body mass index of 30-55 kg/m2 who plan to conceive in the next 6-12 months. Women will be randomized to one of two 12-week interventions (Group A and Group B). Group A will aim for modest weight loss (MWL; ≤ 3% body weight) using a hypocaloric diet. Group B will aim for substantial weight loss (SWL; 10-15% body weight) using a modified very low energy diet (VLED) program. All participants will be asked to comply with National Health and Medical Research Council (NHMRC) guidelines for exercise and will be provided with standard pre-pregnancy advice according to Royal Australian and New Zealand College of Obstetrics and Gynaecology guidelines. All participants will then be observed for the subsequent 12 months. If pregnancy occurs within the 12-month follow-up period, data on weight and metabolic status of the mother, and pregnancy outcomes of mother and offspring will be recorded. The primary outcome is maternal fasting plasma glucose at 26-28 weeks' gestation, given that this is known to correlate with pregnancy outcomes. Time to conception, live birth rate, gestational weight gain, and a composite of adverse pregnancy outcomes for mother and baby will comprise the secondary outcomes. DISCUSSION: There is increasing emphasis on obese women losing weight before conception. To date, no randomized controlled trial has demonstrated an effective means of weight loss that results in improved pregnancy outcomes for both mother and baby. This study intends to determine if substantial pre-conception weight loss, achieved using a VLED, improves pregnancy outcomes for mother and baby when compared with standard care. This research will potentially change clinical care of an obese woman planning pregnancy. TRIAL REGISTRATION: ANZCTR, 12,614,001,160,628 . Registered on 5 November 2014.

BACKGROUND: Transgender individuals receiving masculinising or feminising gender-affirming hormone therapy with testosterone or estradiol respectively, are at increased risk of adverse cardiovascular outcomes, including myocardial infarction and stroke. This may be related to the effects of testosterone or estradiol therapy on body composition, fat distribution, and insulin resistance but the effect of gender-affirming hormone therapy on these cardiovascular risk factors has not been extensively examined. AIM: To evaluate the impact of gender-affirming hormone therapy on body composition and insulin resistance in transgender individuals, to guide clinicians in minimising cardiovascular risk. METHODS: We performed a review of the literature based on PRISMA guidelines. MEDLINE, Embase and PsycINFO databases were searched for studies examining body composition, insulin resistance or body fat distribution in transgender individuals aged over 18 years on established gender-affirming hormone therapy. Studies were selected for full-text analysis if they investigated transgender individuals on any type of gender-affirming hormone therapy and reported effects on lean mass, fat mass or insulin resistance. RESULTS: The search strategy identified 221 studies. After exclusion of studies that did not meet inclusion criteria, 26 were included (2 cross-sectional, 21 prospective-uncontrolled and 3 prospective-controlled). Evidence in transgender men suggests that testosterone therapy increases lean mass, decreases fat mass and has no impact on insulin resistance. Evidence in transgender women suggests that feminising hormone therapy (estradiol, with or without anti-androgen agents) decreases lean mass, increases fat mass, and may worsen insulin resistance. Changes to body composition were consistent across almost all studies: Transgender men on testosterone gained lean mass and lost fat mass, and transgender women on oestrogen experienced the reverse. No study directly contradicted these trends, though several small studies of short duration reported no changes. Results for insulin resistance are less consistent and uncertain. There is a paucity of prospective controlled research, and existing prospective evidence is limited by small sample sizes, short follow up periods, and young cohorts of participants. CONCLUSION: Further research is required to further characterise the impact of gender-affirming hormone therapy on body composition and insulin resistance in the medium-long term. Until further evidence is available, clinicians should aim to minimise risk by monitoring cardiovascular risk markers regularly in their patients and encouraging healthy lifestyle modifications.

There is an increasing demand for trans and gender diverse (TGD) health services worldwide. Given the unique and diverse healthcare needs of the TGD community, best practice TGD health services should be community-led. We aimed to understand the healthcare needs of a broad group of TGD Australians, how health professionals could better support TGD people, and gain an understanding of TGD-related research priorities. An anonymous online survey received 928 eligible responses from TGD Australian adults. This paper focuses on three questions out of that survey that allowed for free-text responses. The data were qualitatively coded, and overarching themes were identified for each question. Better training for healthcare professionals and more accessible transgender healthcare were the most commonly reported healthcare needs of participants. Findings highlight a pressing need for better training for healthcare professionals in transgender healthcare. In order to meet the demand for TGD health services, more gender services are needed, and in time, mainstreaming health services in primary care will likely improve accessibility. Evaluation of training strategies and further research into optimal models of TGD care are needed; however, until further data is available, views of the TGD community should guide research priorities and the TGD health service delivery.

There is evidence to suggest that motor execution and motor imagery both involve planning and execution of the same motor plan, however, in the latter the output is inhibited. Currently, little is known about the underlying neural mechanisms of motor output inhibition during motor imagery. Uncovering the distinctive characteristics of motor imagery may help us better understand how we abstract complex thoughts and acquire new motor skills. The current study aimed to dissociate the cognitive processes involved in two distinct inhibitory mechanisms of motor inhibition and motor imagery restraint. Eleven healthy participants engaged in an imagined GO/NO-GO task during a 7 Tesla fMRI experiment. Participants planned a specific type of motor imagery, then, imagined the movements during the GO condition and restrained from making a response during the NO-GO condition. The results revealed that specific sub-regions of the supplementary motor cortex (SMC) and the primary motor cortex (M1) were recruited during the imagination of specific movements and information flowed from the SMC to the M1. Such condition-specific recruitment was not observed when motor imagery was restrained. Instead, general recruitment of the posterior parietal cortex (PPC) was observed, while the BOLD activity in the SMC and the M1 decreased below the baseline at the same time. Information flowed from the PPC to the SMC, and recurrently between the M1 and the SMC, and the M1 and the PPC. These results suggest that motor imagery involves task-specific motor output inhibition partly imposed by the SMC to the M1, while the PPC globally inhibits motor plans before they are passed on for execution during the restraint of responses.