Exploring a Potential Interaction Between the Effect of Specific Maternal Smoking Patterns and Comorbid Antenatal Depression in Causing Postpartum Depression.

Purpose: To explore a potential interaction between the effect of specific maternal smoking patterns and the presence of antenatal depression, as independent exposures, in causing postpartum depression (PPD). Methods: This case-control study of participants with singleton term births (N = 51220) was based on data from the 2017-2018 Pregnancy Risk Assessment Monitoring System. Multivariable log-binomial regression models examined the main effects of smoking patterns and self-reported symptoms of antenatal depression on the risk of PPD on the adjusted risk ratio (aRR) scale and tested a two-way interaction adjusting for covariates selected in a directed acyclic graph (DAG). The interaction effects were measured on the additive scale using relative excess risk due to interaction (RERI), the attributable proportion of interaction (AP), and the synergy index (SI). Causal effects were defined in a counterfactual framework. The E-value quantified the potential impact of unobserved/unknown covariates, conditional on observed covariates. Results: Among 6841 women in the sample who self-reported PPD, 35.7% also reported symptoms of antenatal depression. Out of 3921 (7.7%) women who reported smoking during pregnancy, 32.6% smoked at high intensity (≥10 cigarettes/day) in all three trimesters and 36.6% had symptoms of antenatal depression. The main effect of PPD was the strongest for women who smoked at high intensity throughout pregnancy (aRR 1.65; 95% CI: 1.63, 1.68). A synergistic interaction was detected, and the effect of all maternal smoking patterns was augmented, particularly in late pregnancy for Increasers and Reducers. Conclusion: Strong associations and interaction effects between maternal smoking patterns and co-occurring antenatal depression support smoking prevention and cessation interventions during pregnancy to lower the likelihood of PPD.

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Development of a diagnostic support tool for predicting cervical arterial dissection in primary care.

OBJECTIVES: Cervical arterial dissection (CAD) is an important cause of stroke in young people which may be missed because early features may mimic migraine or a musculoskeletal presentation. The study aimed to develop a diagnostic support tool for early identification of CAD. DESIGN: Retrospective observational study. SETTING: Tertiary hospital. PARTICIPANTS: Radiologically confirmed CAD cases (n = 37), non-CAD stroke cases (n = 20), and healthy controls (n = 100). MAIN OUTCOME MEASURES: The presence of CAD is confirmed with imaging. Predictive variables included risk factors and clinical characteristics of CAD. Variables with a p-value <0.2 included in a multivariable model. Predictive utility of the model is assessed by calculating area underthe ROC curve (AUC). RESULTS: The model including four variables: age 40-55 years (vs < 40), trauma, recent onset headache, and > 2 neurological features, demonstrated excellent discrimination: AUC of 0.953 (95% CI: 0.916, 0.987). A predictive scoring system (total score/7) identified an optimal threshold of ≥ 3 points, with a sensitivity of 87% and specificity of 79%. CONCLUSIONS: The study identified a diagnostic support tool with four variables to predict increased risk of CAD. Validation in a clinical sample is needed to confirm variables and refine descriptors to enable clinicians to efficiently apply the tool.Optimum cutoff scores of ≥ 3/7 points will help identify those in whom CAD should be considered and further investigation instigated. The potential impact of the tool is to improve early recognition of CAD in those with acute headache or neck pain, thereby facilitating more timely medical intervention, preventing inappropriate treatment, and improving patient outcomes.Wordcount: 3195.

Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

BACKGROUND: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetics of BP could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. METHODS: In this observational genetic study, we leveraged cross-sectional data from up to 296 475 genotyped individuals drawn from the UK Biobank cohort for whom BP and urinary electrolytes (sodium and potassium), biomarkers of sodium and potassium intake, were measured. Biologically directed genetic scores for BP were constructed specifically among pathways related to sodium and potassium biology (pharmagenic enrichment scores), as well as unannotated genome-wide scores (conventional polygenic scores). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on BP. RESULTS: Genetic risk and urinary electrolytes both independently correlated with BP. However, urinary sodium was associated with a larger BP increase among individuals with higher genetic risk in sodium- and potassium-related pathways than in those with comparatively lower genetic risk. For example, each SD in urinary sodium was associated with a 1.47-mm Hg increase in systolic BP for those in the top 10% of the distribution of genetic risk in sodium and potassium transport pathways versus a 0.97-mm Hg systolic BP increase in the lowest 10% (P=1.95×10-3). This interaction with urinary sodium remained when considering estimated glomerular filtration rate and indexing sodium to urinary creatinine. There was no strong evidence of an interaction between urinary sodium and a standard genome-wide polygenic score of BP. CONCLUSIONS: The data suggest that genetic risk in sodium and potassium pathways could be used in a precision medicine model to direct interventions more specifically in the management of hypertension. Intervention studies are warranted.

High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile.

Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual's polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) (n = 407,800, 40-69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study (n = 2122, 55-85 years), Older Australian Twins Study (n = 539, 65-90 years) and Sydney Memory and Ageing Study (n = 925, 70-90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies (n = 2273, 70-93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22-30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10-42) and its components (p < 2.30 × 10-8). Meta-analyses of the replication cohorts showed nominal associations with MetS (p = 0.028) and 3 MetS components (p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.

Patient characteristics, short-term and long-term outcomes after incident heart failure admissions in a regional Australian setting.

AIMS: This study aims to (1) define the characteristics of patients with a first admission for heart failure (HF), stratified by type (reduced (HFrEF) vs preserved (HFpEF) ejection fraction) in a regional Australian setting; (2) compare the outcomes in terms of mortality and rehospitalisation and (3) assess adherence to the treatment guidelines. METHODS: We identified all index hospitalisations with HF to John Hunter Hospital and Tamworth Rural Referral Hospital in the Hunter New England Local Health District over a 12 months. We used the recent Australian HF guidelines to classify HFrEF and HFpEF and assess adherence to guideline-directed therapy. The primary outcome of the study was to compare short-term (1 year) and long-term all-cause mortality and the composite of all-cause hospitalisation or all-cause mortality of patients with HFrEF and HFpEF. RESULTS: There were 664 patients who had an index HF admission to John Hunter and Tamworth hospitals in 2014. The median age was 80 years, 47% were female and 22 (3%) were Aboriginal. In terms of HF type, 29% had HFrEF, 37% had HFpEF, while the remainder (34%) did not have an echocardiogram within 1 year of admission and could not be classified. The median follow-up was 3.3 years. HFrEF patients were predominantly male (64%) and in 48% the aetiology was ischaemic heart disease. The 1-year all-cause mortality was 23% in HFpEF subgroup and 29% in HFrEF subgroup (p=0.15). Five-year mortality was 61% in HFpEF and HFrEF patients. Of the HFrEF patients, only 61% were on renin-angiotensin-aldosterone blockers, 74% were on ß-blockers and 39% were on aldosterone antagonist. CONCLUSION: HF patients are elderly and about evenly split between HFrEF and HFpEF. In this regional cohort, both HF types are associated with similar 1-year and 5-year mortality following incident HF hospitalisation. Echocardiography and guideline-directed therapies were underused.

The effect of zinc supplementation on glucose homeostasis: a randomised double-blind placebo-controlled trial.

AIMS: The burden and health costs of Type 2 Diabetes Mellitus continue to increase globally and prevention strategies in at-risk people need to be explored. Previous work, in both animal models and humans, supports the role of zinc in improving glucose homeostasis. We, therefore, aimed to test the effectiveness of zinc supplementation on glycaemic control in pre-diabetic adults. METHODS: We conducted a randomized, double-blind, placebo-controlled trial across 10 General Practitioner (GP) practices in NSW, Australia. The trial is known as Zinc in Preventing the Progression of pre-Diabetes (ZIPPeD)Study. Pre-diabetic (haemoglobin A1c [HbA1c] 5.7-6.4%, 39-46 mmol/mol) men and women (N = 98) were all assigned to a free state government telephone health coaching service (New South Wales Get Healthy Information and Coaching Service) and then randomised to either daily 30 mg zinc gluconate or placebo. Blood tests were collected at baseline, 1, 6 and 12 months for the primary outcomes (HbA1c, fasting blood glucose (FBG)); secondary outcomes included Homeostasis Model Assessment 2 (HOMA 2) parameters, lipids, body weight, height, waist circumference, blood pressure and pulse. RESULTS: The baseline-adjusted mean group difference at 6 months, expressed as treatment-placebo, (95% CI) was -0.02 (-0.14, 0.11, p = 0.78) for HbA1c and 0.17 (-0.07, 0.42; p = 0.17) for FBG, neither of which were statistically significant. There were also no significant differences between groups in any of the secondary outcomes. Zinc was well tolerated, and compliance was high (88%). CONCLUSION: We believe our results are consistent with other Western clinical trial studies and do not support the use of supplemental zinc in populations with a Western diet. There may still be a role for supplemental zinc in the developing world where diets may be zinc deficient. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12618001120268. Registered on 6 July 2018.

Antiseptic Skin Preparation Agents to Prevent Surgical Site Infection in Colorectal Surgery: A 3-Armed Randomized Controlled Trial.

BACKGROUND: There is much debate surrounding the ideal antiseptic skin preparation agent to reduce postoperative surgical site infection. International guidelines suggest that chlorhexidine- and alcohol-containing compounds have superior efficacy. However, there are minimal clinical trials specifically looking at skin preparation agents for colorectal surgery. OBJECTIVE: The aim of this study was to compare the efficacy of chlorhexidine in alcohol versus povidone-iodine in alcohol versus povidone-iodine in aqueous solution for the prevention of surgical site infection in colorectal surgery. DESIGN: This is a prospective, 3-armed, randomized controlled trial. SETTING: This study was conducted at the 800-bed John Hunter Hospital and Newcastle Private Hospital, with all subspecialty services in New South Wales, Australia. PATIENTS: All eligible, consenting adults undergoing colorectal surgery between July 2015 and December 2018 were included. INTERVENTIONS: Patients were andomized to receive preincision skin preparation with one of the following: chlorhexidine in 70% alcohol, povidone-iodine in 70% alcohol, or povidone-iodine in aqueous solution. MAIN OUTCOME MEASURE: The primary measure was surgical site infection within 30 days. RESULTS: A total of 482 patients were randomized to chlorhexidine in alcohol, povidone-iodine in alcohol, or aqueous povidone-iodine. The overall surgical site infection rate was 22% (107/482). There was no difference in rates of surgical site infection: 20.6% (29/141), 22.8% (44/193), and 23.0% (34/148), respectively ( p = 0.5267). There was no difference in complication rates: 54.6% (77/141), 46.1% (89/193), and 49.3% (73/148), respectively ( p = 0.1762). The median length of stay was 6 days in all 3 groups. LIMITATIONS: This is a subset analysis of a larger clinical trial for all forms of incisional surgery (the NewSKIN Prep trial), and noninferiority cannot be assessed. Changes in government regulations resulted in a change from 0.5% chlorhexidine in 70% ethanol to 2% chlorhexidine in 70% ethanol during the trial. CONCLUSION: This large, prospective, randomized clinical trial appears to indicate that there is no difference in surgical site infection, complications, or length of stay among the 3 commonest forms of skin preparation in colorectal surgery. See Video Abstract at http://links.lww.com/DCR/B875 .New Zealand Clinical Trials registry: ACTRN12615000021572Agentes antisépticos para la preparación de la piel para prevenir la infección del sitio quirúrgico en la cirugía colorrectal: un ensayo clínico aleatorizado de tres grupos. ANTECEDENTES: Existe un gran debate en torno al agente de preparación de la piel antiséptico ideal para reducir la infección posoperatoria del sitio quirúrgico. Las pautas internacionales sugieren que los compuestos que contienen clorhexidina y alcohol tienen una eficacia. Sin embargo, existen ensayos clínicos mínimos que analizan específicamente los agentes de preparación de la piel para la cirugía colorrectal. OBJETIVO: Comparar la eficacia de la clorhexidina en alcohol versus povidona yodada en alcohol versus povidona yodada en solución acuosa para la prevención de la infección del sitio quirúrgico en cirugía colorrectal. DISEO: Este es un ensayo controlado aleatorio prospectivo de tres brazos. AJUSTE: Este estudio se realizó en el Hospital John Hunter de 800 camas y el Hospital Privado de Newcastle con todos los servicios de subespecialidad en Nueva Gales del Sur, Australia. PACIENTES: Se incluyeron todos los adultos elegibles que dieron su consentimiento para someterse a una cirugía colorrectal entre julio de 2015 y diciembre de 2018. INTERVENCIONES: Aleatorizados para recibir una preparación para la piel previa a la incisión con uno de: clorhexidina en alcohol al 70%, povidona yodada en alcohol al 70% o povidona yodada en solución acuosa. MEDIDA DE RESULTADO PRINCIPAL: La medida principal fue la infección del sitio quirúrgico dentro de los 30 días. RESULTADOS: Un total de 482 pacientes fueron aleatorizados para recibir clorhexidina en alcohol, povidona yodada en alcohol o povidona yodada acuosa. La tasa global de infección del sitio quirúrgico fue del 22% (107/482). No hubo diferencias en las tasas de infección del sitio quirúrgico; 20,6% (29/141), 22,8% (44/193) y 23,0% (34/148) respectivamente; p = 0,5267. No hubo diferencia en las tasas de complicaciones; 54,6% (77/141), 46,1% (89/193) y 49,3% (73/148) respectivamente; p = 0,1762. La duración media de la estancia hospitalaria fue de 6,0 días en los tres grupos. LIMITACIONES: Este es un análisis de subconjunto de un ensayo clínico más grande para todas las formas de cirugía incisional (el ensayo NewSKIN Prep) y no se puede evaluar la no inferioridad. Los cambios en las regulaciones gubernamentales dieron como resultado un cambio de clorhexidina al 0,5% en etanol al 70% a clorhexidina al 2% en etanol al 70% durante la prueba. CONCLUSINES: Este gran ensayo clínico prospectivo y aleatorizado parece indicar que no hay diferencia en la infección del sitio quirúrgico, las complicaciones o la duración de la estancia entre las 3 formas más comunes de preparación de la piel en la cirugía colorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B875 . (Traducción-Dr. Gonzalo Hagerman )Este ensayo se registró de forma prospectiva en el registro de ensayos clínicos de Australia Nueva Zelanda el 15/01/2015: ACTRN12615000021572.

Serum L-arginine and endogenous methylarginine concentrations predict irritable bowel syndrome in adults: A nested case-control study.

BACKGROUND & AIMS: Nitric oxide, a major inhibitory nonadrenergic, noncholinergic neurotransmitter that relaxes smooth muscle, may be implicated in the pathophysiology of visceral hypersensitivity in irritable bowel syndrome (IBS). Impaired bioavailability of the nitric oxide precursor molecule L-arginine and higher concentrations of methylarginines (endogenous inhibitors of nitric oxide synthesis) are known to impair nitric oxide synthesis in numerous gastrointestinal cell types. We therefore examined serum concentrations of L-arginine and the methylarginines in a nested case-control study, to assess whether these factors are associated with adult IBS. METHODS: Data on clinical characteristics, methylarginines, and L-arginine (measured using LC-MS/MS) were collected from a random population-based cohort of Australian adults (median age = 64 years; IQR = 60-70). Cases of IBS, defined according to Rome III criteria (N = 156), and controls (N = 332) were identified from within the cohort at the 5-year follow-up. RESULTS: In adjusted logistic regression analyses, L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, L-arginine/asymmetric dimethylarginine ratio, and Kessler-10 psychological distress scores were significantly associated with IBS (p < 0.05). [Correction added on 18 September 2021, after first online publication: In the preceding sentence, the value (p > 0.05) has been changed to (p < 0.05)]. Similar results were found for IBS subtypes. Higher serum L-arginine concentration had the strongest association with IBS diagnosis, with an odds ratio of 9.03 for those with serum L-arginine at the 75th (84 µmol/L) versus 25th (46 µmol/L) percentile (95% CI: 5.99-13.62). L-arginine had the best discriminative ability with a bias-adjusted area under the receiver operator characteristic curve of 0.859. CONCLUSIONS: Higher serum concentrations of L-arginine and endogenous methylarginines are strongly associated with IBS in adults.

The interactions between genetics and early childhood nutrition influence adult cardiometabolic risk factors.

It is well established that genetics, environment, and interplay between them play a crucial role in adult disease. We aimed to evaluate the role of genetics, early life nutrition, and the interaction between them, on optimal adult health. As part of a large international consortium (n ~ 154,000), we identified 60 SNPs associated with both birthweight and adult disease. Utilising the Raine Study, we developed a birthweight polygenic score (BW-PGS) based on the 60 SNPs and examined relationships between BW-PGS and adulthood cardiovascular risk factors, specifically evaluating interactions with early life nutrition. Healthy nutrition was beneficial for all individuals; longer duration of any breastfeeding was particularly associated with lower BMI and lower Systolic Blood Pressure in those with higher BW-PGS. Optimal breastfeeding offers the greatest benefit to reduce adult obesity and hypertension in those genetically predisposed to high birthweight. This provides an example of how precision medicine in early life can improve adult health.

Secondary Prevention of Stroke: Study Protocol for a Telehealth-Delivered Physical Activity and Diet Pilot Randomized Trial (ENAbLE-Pilot).

BACKGROUND: Increasing physical activity (PA) and improving diet quality are opportunities to improve secondary stroke prevention, but access to appropriate services is limited. Interventions co-designed with stroke survivors and delivered by telehealth are a potential solution. AIM: The aim of this study is to test the feasibility, safety, and potential efficacy of a 6-month, telehealth-delivered PA and/or dietary (DIET) intervention. METHODS: Pilot randomized trial. 80 adults with previous stroke who are living at home with Internet access and able to exercise will be randomized in a 2 × 2 factorial (4-arm) pilot randomized, open-label, blinded outcome assessment trial to receive PA, DIET, PA + DIET, or control interventions via telehealth. The PA intervention aims to support participants to meet the minimum recommended levels of PA (150 min/week moderate exercise), and the DIET intervention aims to support participants to follow the AusMed (Mediterranean-style) diet. The control group receives usual care plus education about PA and healthy eating. The co-primary outcomes are feasibility (proportion and characteristics of eligible participants enrolled and proportion of scheduled intervention sessions attended) and safety (adverse events) at 6 months. The secondary outcomes include recurrent stroke risk factors (blood pressure, physical activity levels, and diet quality), fatigue, mood, and quality of life. Outcomes are measured at 3, 6, and 12 months. CONCLUSION: This trial will produce evidence for the feasibility, safety, and potential effect of telehealth-delivered PA and DIET interventions for people with stroke. Results will inform development of an appropriately powered trial to test effectiveness to reduce major risk factors for recurrent stroke. TRIAL REGISTRATION: ACTRN12620000189921.

Genetic association and causal inference converge on hyperglycaemia as a modifiable factor to improve lung function.

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

Chronic respiratory disorders like asthma affect around 600 million people worldwide. Although these illnesses are widespread, they can have several different underlying causes, making them difficult to treat. Drugs that work well on one type of respiratory disorder may be completely ineffective on another. Understanding the biological and environmental factors that cause these illnesses will allow them to be treated more effectively by tailoring therapies to each patient. Reduced lung function is a factor in respiratory disorders and it can have many genetic causes. Studying the genes of patients with reduced lung function can reveal the genes involved, some of which may already be targets of existing drugs for other illnesses. So, could a patient's genetics be used to repurpose existing drugs to treat their respiratory disorders? Reay et al. combined three methods to link genetics and biological processes to the causes of reduced lung function. The results reveal several factors that could lead to new treatments. In one example, reduced lung function showed a link to genes associated with high blood sugar. As such, treatments used in diabetes might help improve lung function in some patients. Reay et al. also developed a scoring system that could predict the efficacy of a treatment based on a patient's genetics. The study suggests that COVID-19 infection could be affected by blood sugar levels too. Chronic respiratory disorders are a critical issue worldwide and have proven difficult to treat, but these results suggest a way to identify new therapies and target them to the right patients. The findings also support a connection between lung function and blood sugar levels. This implies that perhaps existing diabetes treatments ­ including diet and lifestyle changes aimed at reducing or limiting blood sugar ­ could be repurposed to treat respiratory disorders in some patients. The next step will be to perform clinical trials to test whether these therapies are in fact effective.

Reducing Hospital Transfers from Aged Care Facilities: A Large-Scale Stepped Wedge Evaluation.

BACKGROUND/OBJECTIVES: Older people living in residential aged care facilities (RACFs) experience acute deterioration requiring assessment and decision making. We evaluated the impact of a large-scale regional Aged Care Emergency (ACE) program in reducing hospital admissions and emergency department (ED) transfers. DESIGN: A stepped wedge nonrandomized cluster trial with 11 steps, implemented from May 2013 to August 2016. SETTING: A large regional and rural area of northern and western New South Wales, Australia. PARTICIPANTS: Nine hospital EDs and 81 RACFs participated in the evaluation. INTERVENTION: The ACE program is an integrated nurse-led intervention underpinned by a community of practice designed to improve the capability of RACFs managing acutely unwell residents. It includes telephone support, evidence-based algorithms, defining goals of care for ED transfer, case management in the ED, and an education program. MEASUREMENTS: ED transfers and subsequent hospital admissions were collected from administrative data including 13 months baseline and 9 months follow-up. RESULTS: A total of 18,837 eligible ED visits were analyzed. After accounting for clustering by RACFs and adjusting for time of the year as well as RACF characteristics, a statistically significant reduction in hospital admissions (adjusted incident rate ratio = .79; 95% confidence interval [CI] = .68-.92); P = .0025) was seen (i.e., residents were 21% less likely to be admitted to the hospital). This was also observed in ED visit rates (adjusted incidence rate ratio = .80; 95% CI = .69-.92; P = .0023) (i.e., residents were 20% less likely to be transferred to the ED). Seven-day ED re-presentation fell from 5.7% to 4.9%, and 30-day hospital readmissions fell from 12% to 10%. CONCLUSION: The stepped wedge design allowed rigorous evaluation of a real-world large-scale intervention. These results confirm that the ACE program can be scaled up to a large geographic area and can reduce ED visits and hospitalization of older people with complex healthcare needs living in RACFs.

Effectiveness of interventions to improve rates of intravenous thrombolysis using behaviour change wheel functions: a systematic review and meta-analysis.

BACKGROUND: Despite being one of the few evidence-based treatments for acute ischemic stroke, intravenous thrombolysis has low implementation rates-mainly due to a narrow therapeutic window and the health system changes required to deliver it within the recommended time. This systematic review and meta-analyses explores the differential effectiveness of intervention strategies aimed at improving the rates of intravenous thrombolysis based on the number and type of behaviour change wheel functions employed. METHOD: The following databases were searched: MEDLINE, EMBASE, PsycINFO, CINAHL and SCOPUS. Multiple authors independently completed study selection and extraction of data. The review included studies that investigated the effects of intervention strategies aimed at improving the rates of intravenous thrombolysis and/or onset-to-needle, onset-to-door and door-to-needle time for thrombolysis in patients with acute ischemic stroke. Interventions were coded according to the behaviour change wheel nomenclature. Study quality was assessed using the QualSyst scoring system for quantitative research methodologies. Random effects meta-analyses were used to examine effectiveness of interventions based on the behaviour change wheel model in improving rates of thrombolysis, while meta-regression was used to examine the association between the number of behaviour change wheel intervention strategies and intervention effectiveness. RESULTS: Results from 77 studies were included. Five behaviour change wheel interventions, 'Education', 'Persuasion', 'Training', 'Environmental restructuring' and 'Enablement', were found to be employed among the included studies. Effects were similar across all intervention approaches regardless of type or number of behaviour change wheel-based strategies employed. High heterogeneity (I2 > 75%) was observed for all the pooled analyses. Publication bias was also identified. CONCLUSION: There was no evidence for preferring one type of behaviour change intervention strategy, nor for including multiple strategies in improving thrombolysis rates. However, the study results should be interpreted with caution, as they display high heterogeneity and publication bias.

Thrombolysis implementation intervention and clinical outcome: a secondary analysis of a cluster randomized trial.

BACKGROUND: Multiple studies have attempted to increase the rate of intravenous thrombolysis for ischemic stroke using interventions to promote adherence to guidelines. Still, many of them did not measure individual-level impact. This study aimed to make a posthoc comparison of the clinical outcomes of patients in the "Thrombolysis ImPlementation in Stroke (TIPS)" study, which aimed to improve rates of intravenous thrombolysis in Australia. METHODS: A posthoc analysis was conducted using individual-level patient data. Excellent (Three-month post treatment modified Rankin Score 0-2) and poor clinical outcome (Three-month post treatment modified Rankin Score 5-6) and post treatment parenchymal haematoma were the three main outcomes, and a mixed logistic regression model was used to assess the difference between the intervention and control groups. RESULTS: There was a non-significant higher odds of having an excellent clinical outcome of 57% (odds ratio: 1.57; 95% CI: 0.73-3.39) and 33% (odds ratio: 1.33; 95% CI: 0.73-2.44) during the active-and post-intervention period respectively, for the intervention compared to the control group. A non-significant lower odds of having a poor clinical outcome was also found in the intervention, relative to control group of 4% (odds ratio: 0.96; 95% CI: 0.56-2.07) and higher odds of having poor outcome of 44% (odds ratio: 1.44 95% CI: 0.61-3.41) during both active and post-intervention period respectively. Similarly, a non-significant lower odds of parenchymal haematoma was also found for the intervention group during the both active- (odds ratio: 0.53; 95% CI: 0.21-1.32) and post-intervention period (odds ratio: 0.96; 95% CI: 0.36-2.52). CONCLUSION: The TIPS multi-component implementation approach was not effective in reducing the odds of post-treatment severe disability at 90 days, or post-thrombolysis hemorrhage. TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.anzctr.org.au/ Unique Identifier: ACTRN12613000939796 .

Global DNA methylation and cognitive and behavioral outcomes at 4 years of age: A cross-sectional study.

BACKGROUND: Accumulating evidence suggests that breastfeeding exclusivity and duration are positively associated with child cognition. This study investigated whether DNA methylation, an epigenetic mechanism modified by nutrient intake, may contribute to the link between breastfeeding and child cognition. The aim was to quantify the relationship between global DNA methylation and cognition and behavior at 4 years of age. METHODS: Child behavior and cognition were measured at age 4 years using the Wechsler Preschool and Primary Scale of Intelligence, third version (WPPSI-III), and Child Behavior Checklist (CBC). Global DNA methylation (%5-methylcytosines (%5mC)) was measured in buccal cells at age 4 years, using an enzyme-linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. RESULTS: Data were collected from 73 children recruited from the Women and Their Children's Health (WATCH) study. No statistically significant associations were found between global DNA methylation levels and child cognition or behavior (p > .05), though the estimates of effect were consistently negative. Global DNA methylation levels in males were significantly higher than in females (median %5mC: 1.82 vs. 1.03, males and females, respectively, (p < .05)). CONCLUSION: No association was found between global DNA methylation and child cognition and behavior; however given the small sample, this study should be pooled with other cohorts in future meta-analyses.

Door-to-needle time for thrombolysis: a secondary analysis of the TIPS cluster randomised controlled trial.

OBJECTIVE: The current study aimed to evaluate the effects of a multi-component in-hospital intervention on the door-to-needle time for intravenous thrombolysis in acute ischaemic stroke. DESIGN: This study was a post hoc analysis of door-to-needle time data from a cluster-randomised controlled trial testing an intervention to boost intravenous thrombolysis implementation. SETTING: The study was conducted among 20 hospitals from three Australian states. PARTICIPANT: Eligible hospitals had a Stroke Care Unit or staffing equivalent to a stroke physician and a nurse, and were in the early stages of implementing thrombolysis. INTERVENTION: The intervention was multifaceted and developed using the behaviour change wheel and informed by breakthrough collaborative methodology using components of the health behaviour change wheel. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome for this analysis was door-to-needle time for thrombolysis and secondary outcome was the proportion of patients received thrombolysis within 60 min of hospital arrival. RESULTS: The intervention versus control difference in the door-to-needle times was non-significant overall nor significant by hospital classification. To provide additional context for the findings, we also evaluated the results within intervention and control hospitals. During the active-intervention period, the intervention hospitals showed a significant decrease in the door-to-needle time of 9.25 min (95% CI: -16.93 to 1.57), but during the post-intervention period, the result was not significant. During the active intervention period, control hospitals also showed a significant decrease in the door-to-needle time of 5.26 min (95% CI: -8.37 to -2.14) and during the post-intervention period, this trend continued with a decrease of 12.13 min (95% CI: -17.44 to 6.81). CONCLUSION: Across these primary stroke care centres in Australia, a secular trend towards shorter door-to-needle times across both intervention and control hospitals was evident, however the TIPS (Thrombolysis ImPlementation in Stroke) intervention showed no overall effect on door-to-needle times in the randomised comparison. TRIAL REGISTRATION NUMBER: Trial Registration-URL: http://www.anzctr.org.au/ Unique Identifier: ACTRN 12613000939796.

Assessment of Restored Kidney Transplantation Including the Use of Wider Criteria for Accepting Renal Donors After Cancer Excision.

The transplantation of kidneys after cancer excision (restored kidney transplantation, RKT) warrants further evaluation as a source of kidneys for transplantation. We determined whether larger cancers can be safely transplanted, the risks of adverse events from RKT, and whether RKT confers a survival advantage for patients waiting for transplantation. METHODS: In a retrospective cohort study, 23 dialysis patients awaiting transplant underwent RKT at John Hunter Hospital, Australia between 2008 and 2015. Patients were >60 years old and accepted onto the National Organ Matching Service. This RKT Group was divided into donor renal cancers ≤30 mm and >30-≤50 mm. Adverse event profiles for RKT recipients were compared with 22 standard live donor recipients using logistic regression analyses. Recipient and transplant survivals for RKT were compared with 2050 controls from Australian New Zealand Dialysis Transplant Registry using Cox regression models. To increase statistical power for survival analyses, data from 25 RKT recipients from Princess Alexandra Hospital, Brisbane were added, thus creating 48 RKT recipients. RESULTS: There were no significant differences in mortality, transplant failure nor AEs between the 2 cancer Groups. RKT increased the risks of Adverse event profiles (odds ratio: 6.48 [2.92-15.44]; P < 0.001). RKT reduced mortality risk by 30% (hazard ratio [HR]: 0.70 [0.36-1.07]; P = 0.299) compared with those continuing on the transplant list who may or may not be transplanted. RKT significantly reduced mortality risk for those remaining on dialysis (HR: 2.86 [1.43-5.72]; P = 0.003). Transplant survival for RKT was reduced compared with control deceased donor (HR: 0.42 [0.21-0.83]; P = 0.013) and live donor transplants (HR: 0.33 [0.02-0.86]; P =0.023). CONCLUSIONS: The use of larger carefully selected cancer-resected kidneys for transplantation appears safe and effective. RKT confers a possible survival advantage compared with waiting for transplantation, an increased survival compared with those remaining on dialysis but reduced transplant survival.