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.

Lactate dehydrogenase contribution to symptom persistence in long COVID: A pooled analysis.

There's critical need for risk predictors in long COVID. This meta-analysis evaluates the evidence for an association between plasma lactate dehydrogenase (LDH) and long COVID and explores the contribution of LDH to symptoms persistent across the distinct post-acute sequelae of COVID-19 (PASC) domains. PubMed, EMBASE, Web of Science, and Google Scholar were searched for articles published up to 20 March 2023 for studies that reported data on LDH levels in COVID-19 survivors with and without PASC. Random-effect meta-analysis was employed to estimate the standardized mean difference (SMD) with corresponding 95% confidence interval of each outcome. There were a total of 8289 study participants (3338 PASC vs. 4951 controls) from 46 studies. Our meta-analysis compared to the controls showed a significant association between LDH elevation and Resp-PASC [SMD = 1.07, 95%CI = 0.72, 1.41, p = 0.01] but not Cardio-PASC [SMD = 1.79, 95%CI = -0.02, 3.61, p = 0.05], Neuro-PASC [SMD = 0.19, 95%CI = -0.24, 0.61, p = 0.40], and Gastrointestinal-PASC [SMD = 0.45, 95%CI = -1.08, 1.98, p = 0.56]. This meta-analysis suggests elevated LDH can be used for predicting Resp-PASC, but not Cardio-PASC, Neuro-PASC or gastrointestinal-PASC. Thus, elevated plasma LDH following COVID infection may be considered as a disease biomarker.

Effectiveness of NSW health get healthy telephone coaching in adults screened from general practices.

BACKGROUND: The effectiveness of the NSW Health "Get Healthy Information and Coaching Service®"(Get Healthy) to facilitate weight loss on a population scale has been documented, but this was based on self-reported measures. Our study aims to test the effectiveness of the Get Healthy Service on objectively measured weight, BMI, waist circumference, and changes in other health behaviours, including nutrition, physical activity and alcohol intake. METHODS: Men and women aged 40-70 years (n = 154) with pre-diabetes (5.7% < HbA1c < 6.5%) were referred from GP Practices to the Get Healthy Service, NSW Health. A subset (n = 98) participated in the "Zinc In Preventing the Progression of pre-Diabetes" (ZIPPeD) trial (ACTRN12618001120268). RESULTS: The self-reported outcomes showed a statistically significant improvement from baseline to 12 months in weight (mean 2.7 kg loss, p < 0.001), BMI (mean 1 unit reduction, p < 0.001), and waist circumference (mean 4.3 cm reduction, p < 0.001). However, in the objectively measured outcomes from ZIPPeD, the differences were more modest, with point estimates of 0.8 kg mean weight loss (p = 0.1), 0.4 unit reduction in BMI (p = 0.03), and 1.8 cm reduction in waist circumference (p = 0.04). Bland-Altman plots indicated that discrepancies were due to a small number of participants who dramatically underestimated their weight or BMI. There were minimal changes in nutrition, physical activity, and alcohol. CONCLUSIONS: The potential benefits of Get Healthy should be interpreted with caution as we have shown significant differences between self-reported and objectively measured values. More valid and objective evidence is needed to determine the program's effectiveness and cost-effectiveness.

Overweight or obesity increases the risk of cardiovascular disease among older Australian adults, even in the absence of cardiometabolic risk factors: a Bayesian survival analysis from the Hunter Community Study.

OBJECTIVE: To estimate the risk of cardiovascular disease (CVD) in older adults with overweight or obesity without metabolic risk factors using a Bayesian survival analysis. DESIGN: Prospective cohort study with median follow-up of 9.7 years. SETTING: Newcastle, New South Wales, Australia. PARTICIPANTS: A total of 2313 community-dwelling older men and women. INTERVENTION/EXPOSURE: Participants without known CVD and with a body mass index (BMI) ≥ 18.5 kg m2 were stratified by BMI and metabolic risk to create six BMI-metabolic health categories. Metabolic risk was defined according to the International Diabetes Federation criteria for metabolic syndrome. 'Metabolically healthy' was defined as absence of metabolic risk factors. Bayesian survival analysis, incorporating prior information from a previously published meta-analysis was used to assess the effect of BMI-metabolic health categories on time from recruitment to CVD. MAIN OUTCOME: Incident physician-diagnosed CVD, defined as fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, angina, or coronary revascularisation procedure, was determined by linkage to hospital admissions records and Medicare Australia data. Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS: From 2313 adults with complete metabolic health data over a median follow-up of 9.7 years, 283 incident CVD events, 58 CVD related deaths and 277 deaths from any cause occurred. In an adjusted Bayesian survival model of complete cases with informative prior and metabolically healthy normal weight as the reference group, the risk of CVD was increased in metabolically healthy overweight (HR = 1.52, 95% credible interval 0.96-2.36), and in metabolically healthy obesity (HR = 1.86, 95% credible interval 1.14-3.08). Imputation of missing metabolic health and confounding data did not change the results. CONCLUSION: There was increased risk of CVD in older adults with overweight or obesity, even in the absence of any metabolic abnormality. This argues against the notion of 'metabolically healthy' overweight or obesity.

A systematic review and meta-analysis of long-term sequelae of COVID-19 2-year after SARS-CoV-2 infection: A call to action for neurological, physical, and psychological sciences.

Long-term sequelae conditions of COVID-19 at least 2-year following SARS-CoV-2 infection are unclear and little is known about their prevalence, longitudinal trajectory, and potential risk factors. Therefore, we conducted a comprehensive meta-analysis of survivors' health-related consequences and sequelae at 2-year following SARS-CoV-2 infection. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched up to February 10, 2023. A systematic review and meta-analysis were performed to calculate the pooled effect size, expressed as event rate (ER) with corresponding 95% confidence interval (CI) of each outcome. Twelve studies involving 1 289 044 participants from 11 countries were included. A total of 41.7% of COVID-19 survivors experienced at least one unresolved symptom and 14.1% were unable to return to work at 2-year after SARS-CoV-2 infection. The most frequent symptoms and investigated findings at 2-year after SARS-CoV-2 infection were fatigue (27.4%; 95% CI 17%-40.9%), sleep difficulties (25.1%; 95% CI 22.4%-27.9%), impaired diffusion capacity for carbon monoxide (24.6%; 95% CI 10.8%-46.9%), hair loss (10.2%; 95% CI 7.3%-14.2%), and dyspnea (10.1%; 95% CI 4.3%-21.9%). Individuals with severe infection suffered more from anxiety (OR = 1.69, 95% CI 1.17-2.44) and had more impairments in forced vital capacity (OR = 9.70, 95% CI 1.94-48.41), total lung capacity (OR = 3.51, 95% CI 1.77-6.99), and residual volume (OR = 3.35, 95% CI 1.85-6.07) after recovery. Existing evidence suggest that participants with a higher risk of long-term sequelae were older, mostly female, had pre-existing medical comorbidities, with more severe status, underwent corticosteroid therapy, and higher inflammation at acute infection. Our findings suggest that 2-year after recovery from SARS-CoV-2 infection, 41.7% of survivors still suffer from either neurological, physical, and psychological sequela. These findings indicate that there is an urgent need to preclude persistent or emerging long-term sequelae and provide intervention strategies to reduce the risk of long COVID.

New-onset type 1 diabetes in children and adolescents as postacute sequelae of SARS-CoV-2 infection: A systematic review and meta-analysis of cohort studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents may increase risk for a variety of post-acute sequelae including new-onset type 1 diabetes mellitus (T1DM). Therefore, this meta-analysis aims to estimate the risk of developing new-onset type 1 diabetes in children and adolescents as post-acute sequelae of SARS-CoV-2 infection. PubMed/MEDLINE, CENTRAL, and EMBASE were systematically searched up to March 20, 2023. A systematic review and subsequent meta-analyses were performed to calculate the pooled effect size, expressed as risk ratio (RR) with corresponding 95% confidence interval (CI) of each outcome based on a one-stage approach and the random-effects estimate of the pooled effect sizes of each outcome were generated with the use of the DerSimonian-Laird method. Eight reports from seven studies involving 11 220 530 participants (2 140 897 patients with a history of diagnosed SARS-CoV-2 infection and 9 079 633 participants in the respective control groups) were included. The included studies reported data from four U.S. medical claims databases covering more than 503 million patients (IQVIA, HealthVerity, TriNetX, and Cerner Real-World Data), and three national health registries for all children and adolescents in Norway, Scotland, and Denmark. It was shown that the risk of new-onset T1DM following SARS-CoV-2 infection in children and adolescents was 42% (95% CI 13%-77%, p = 0.002) higher compared with non-COVID-19 control groups. The risk of developing new-onset T1DM following SARS-CoV-2 infection was significantly higher (67%, 95% CI 32 %-112%, p = 0.0001) in children and adolescents between 0 and 11 years, but not in those between 12 and 17 years (RR = 1.10, 95% CI 0.54-2.23, p = 0.79). We also found that the higher risk for developing new-onset T1DM following SARS-CoV-2 infection only exists in studies from the United States (RR = 1.70, 95% CI 1.37-2.11, p = 0.00001) but not Europe (RR = 1.02, 95% CI 0.67-1.55, p = 0.93). Furthermore, we found that SARS-CoV-2 infection was associated with an elevation in the risk of diabetic ketoacidosis (DKA) in children and adolescents compared with non-COVID-19 control groups (RR = 2.56, 95% CI 1.07-6.11, p = 0.03). Our findings mainly obtained from US medical claims databases, suggest that SARS-CoV-2 infection is associated with higher risk of developing new-onset T1DM and diabetic ketoacidosis in children and adolescents. These findings highlight the need for targeted measures to raise public health practitioners and physician awareness to provide intervention strategies to reduce the risk of developing T1DM in children and adolescents who have had COVID-19.

Treatment efficacy for adult persistent immune thrombocytopenia: a systematic review and network meta-analysis.

Persistent immune thrombocytopenia (ITP) patients require second-line treatments, for which information on clinical outcomes are lacking. A systematic review and network meta-analysis (NMA) were conducted. Only randomised controlled trials (RCT) of second-line drugs in adult persistent ITP patients with platelet response, platelet count, any bleeding or serious adverse events (SAE) outcome were eligible. Twelve RCTs (n = 1313) were included in NMA. For platelet response outcome, eltrombopag and romiplostin were the best relative to placebo; the former had a non-significant advantage [risk ratio (RR) = 1·10 (95% confidence interval: 0·46, 2·67)]. Both treatments were superior to rituximab and recombinant human thrombopoietin (rhTPO)+rituximab, with corresponding RRs of 4·56 (1·89, 10·96) and 4·18 (1·21, 14·49) for eltrombopag; 4·13 (1·56, 10·94) and 3·79 (1·02, 14·09) for romiplostim. For platelet count, romiplostim ranked highest, followed by eltrombopag, rhTPO+rituximab, and rituximab. For bleeding, rituximab had lowest risk, followed by eltrombopag and romiplostim. For SAEs, rhTPO+rituximab had highest risk, followed by rituximab, eltrombopag and romiplostim. From clustered ranking, romiplostim had the best balance between short-term efficacy and SAEs, followed by eltrombopag. In conclusion, romiplostim and eltrombopag may yield high efficacy and safety. Rituximab may not be beneficial due to lower efficacy and higher complications compared with the thrombopoietin receptor agonists. RCTs with long-term clinical outcomes are required.

The Apolipoprotein Allele and Sensorineural Hearing Loss in Older Community-Dwelling Adults in Australia.

OBJECTIVES: Previous research has investigated whether the apolipoprotein E (APOE) ε4 allele, which is associated with an increased risk of cognitive decline, is also associated with hearing loss in older people. Results of the very limited research to date are conflicting, and sample sizes for all but one study were small. The present study aimed to investigate whether there is an association between the APOE ε4 allele and hearing loss in a large, population-based sample of community-dwelling older adults. DESIGN: Cross-sectional audiometric data on hearing levels and APOE genotypes for 2006 participants (aged 55 to 85 years) of the Hunter Community Study were analyzed using multiple linear regression to examine the association between APOE ε4 carrier status and the 4-frequency pure-tone average (0.5 to 4 kHz) in the better hearing ear, and also across individual frequencies in the better ear. RESULTS: Observed and expected APOE allele frequency distributions did not differ significantly overall from established general population allele frequency distributions. Unadjusted modeling using better ear pure-tone average showed a statistically significant association between APOE ε4 allele status (0, 1, 2 copies) and reduced hearing loss, but when the model was adjusted for age, this was no longer statistically significant. Across individual hearing frequencies, unadjusted regression modeling showed APOE ε4 status was significantly associated with a reduction in mean hearing thresholds at 1 and 2 kHz, but again this effect was no longer statistically significant after adjusting for age. CONCLUSIONS: The results of this study did not provide any evidence of a statistically significant association between APOE ε4 allele status and hearing loss for older adults. Further investigation of the effect of homozygous carrier status on hearing thresholds is required.

Better diet quality scores are associated with a lower risk of hypertension and non-fatal CVD in middle-aged Australian women over 15 years of follow-up.

OBJECTIVE: To explore if better diet quality scores as a measure of adherence to the Australian Dietary Guidelines (ADG) and the Mediterranean diet (MedDiet) are associated with a lower incidence of hypertension and non-fatal CVD. DESIGN: Prospective analysis of the 1946-1951 cohort of the Australian Longitudinal Study on Women's Health (ALSWH). The Australian Recommended Foods Score (ARFS) was calculated as an indicator of adherence to the ADG; the Mediterranean Diet Score (MDS) measured adherence to the MedDiet. Outcomes included hypertension and non-fatal CVD. Generalised estimating equations estimated OR and 95 % CI across quartiles of diet quality scores. SETTING: Australia, 2001-2016. PARTICIPANTS: 1946-1951 cohort of the ALSWH (n 5324), without CVD, hypertension and diabetes at baseline (2001), with complete FFQ data. RESULTS: There were 1342 new cases of hypertension and 629 new cases of non-fatal CVD over 15 years of follow-up. Multivariate analysis indicated that women reporting better adherence to the ARFS (≥38/74) had 15 % (95 % CI 1, 28 %; P = 0·05) lower odds of hypertension and 46 % (95 % CI 6, 66 %; P = 0·1) lower odds of non-fatal CVD. Women reporting better adherence to the MDS (≥8/17) had 27 % (95 % CI 15, 47 %; P = 0·0006) lower odds of hypertension and 30 % (95 % CI 2, 50 %; P = 0·03) lower odds of non-fatal CVD. CONCLUSIONS: Better adherence to diet quality scores is associated with lower risk of hypertension and non-fatal CVD. These results support the need for updated evidenced based on the ADG as well as public health nutrition policies in Australia.

Factors to consider during the implementation of nutrition and physical activity trials for people with psychotic illness into an Australian community setting.

BACKGROUND: Research in lifestyle interventions focusing on nutrition and physical activity in people living with psychotic illness, highlights anthropometric and metabolic benefits of these interventions. However, little is known about potential factors to consider during implementation into real-world contexts. Community-managed organisations (CMOs) that provide services for people with mental illness, offer an ideal implementation context for lifestyle interventions. Successful translation of lifestyle interventions into CMOs may be achieved though considering the factors associated with program access and delivery in these settings. This study primarily aimed to identify the factors that affect program access in a local CMO from the perspective of consumers and staff. The secondary aim was to describe the elements that impact on program delivery from the perspective of staff. METHODS: Thirteen semi-structured interviews were conducted with 6 consumers and 7 staff in a CMO in regional Australia. Topics explored in interviews were based on implementation concepts identified in the "Integrated Promoting Action on Research Implementation in Health Systems" (i-PARIHS) knowledge translation framework. Thematic data analysis was conducted using Nvivo software. RESULTS: Emergent themes on issues that influenced program access were (1) consumer financial status, domestic responsibilities, and health; (2) the design and delivery of programs; (3) structure and practices of the organisation; (4) attitude, skills and effort of staff involved in program delivery; and (5) social connections and stigma experienced by consumers during program access. Moreover, staff perceptions on elements that impacted program delivery highlighted themes on consumer attendance and interest in prospective programs, availability and restrictions to the use of funding, as well as the organisational structure and practices. CONCLUSIONS: The factors affecting program access and delivery can generally be managed or planned for during the design of lifestyle interventions and subsequent translation into the CMO context. However, resolution of issues related to consumer financial status and health requires the collaboration of various government sectors for system-wide solutions.

An appraisal of methodology reporting in lifestyle interventions among people with psychosis: A systematic review.

ISSUE ADDRESSED: Lifestyle interventions use nutrition and physical activity behaviour modification techniques to decrease obesity and cardio-metabolic risk in people with psychosis. Evidence on the specific behaviour modification strategies applied to decrease obesity is weakened by inadequate methodology reporting of lifestyle interventions. A systematic review that we conducted earlier highlighted a possible deficiency in reporting; hence we aim to critically appraise lifestyle intervention studies that target weight outcomes for people with psychosis against the methods component of the CONSORT statement for randomised trials of nonpharmacologic treatments. METHODS COMPONENT: We considered randomised controlled studies which delivered lifestyle interventions to community-dwelling adults with psychotic disorders, and included those with the following outcomes of interest: weight, body mass index, waist circumference and waist-to-hip ratio. The Cochrane Library, MEDLINE/PREMEDLINE, EMBASE, CINAHL, Scopus and PsycINFO were searched for English publications between 1985 and 2018. Methodology and reporting of studies were evaluated using the CONSORT statement for randomised trials of nonpharmacologic treatments. RESULTS: Thirty-two studies met the inclusion criteria. Critical appraisals revealed that reporting of lifestyle intervention studies was generally incomplete. Fewer than 50% provided the recommended information on trial design, participant characteristics, detail of interventions, outcomes, sample size, randomisation, blinding and statistical methods. CONCLUSIONS: Application of guidelines, like the CONSORT statement, in future publications of lifestyle interventions for people with psychosis will improve accuracy of reporting. SO WHAT?: Enhanced reporting in lifestyle intervention studies for people with psychosis will promote guideline creation and translation of research, which is likely to positively impact physical health outcomes.

How and Whom to Monitor for Seizures in an ICU: A Systematic Review and Meta-Analysis.

OBJECTIVES: To pool prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, and epileptiform activity detected by different electroencephalography types in critically ills and to compare detection rates among them. DATA SOURCES: MEDLINE (via PubMed) and SCOPUS (via Scopus) STUDY SELECTION:: Any type of study was eligible if studies were done in adult critically ill, applied any type of electroencephalography, and reported seizure rates. Case reports and case series were excluded. DATA EXTRACTION: Data were extracted independently by two investigators. Separated pooling of prevalence of nonconvulsive seizure/nonconvulsive status epilepticus/epileptiform activity and odds ratio of detecting outcomes among different types of electroencephalography was performed using random-effect models. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and also adhered to the Meta-analyses Of Observational Studies in Epidemiology guidelines. Quality of evidence was assessed with the Newcastle-Ottawa Quality Assessment Scale for observational studies and Cochrane methods for randomized controlled trial studies. DATA SYNTHESIS: A total of 78 (16,707 patients) and eight studies (4,894 patients) were eligible for pooling prevalence and odds ratios. For patients with mixed cause of admission, the pooled prevalence of nonconvulsive seizure, nonconvulsive status epilepticus, either nonconvulsive seizure or nonconvulsive status epilepticus detected by routine electroencephalography was 3.1%, 6.2%, and 6.3%, respectively. The corresponding prevalence detected by continuous electroencephalography monitoring was 17.9%, 9.1%, and 15.6%, respectively. In addition, the corresponding prevalence was high in post convulsive status epilepticus (33.5%, 20.2%, and 32.9%), CNS infection (23.9%, 18.1%, and 23.9%), and post cardiac arrest (20.0%, 17.3%, and 22.6%). The pooled conditional log odds ratios of nonconvulsive seizure/nonconvulsive status epilepticus detected by continuous electroencephalography versus routine electroencephalography from studies with paired data 2.57 (95% CI, 1.11-5.96) and pooled odds ratios from studies with independent data was 1.57 (95% CI, 1.00-2.47). CONCLUSIONS: Prevalence of seizures detected by continuous electroencephalography was significantly higher than with routine electroencephalography. Prevalence was particularly high in post convulsive status epilepticus, CNS infection, and post cardiac arrest.

Dietary nitrate consumption and risk of CHD in women from the Nurses' Health Study.

The consumption of nitrate-rich vegetables can acutely lower blood pressure and improve mediators shown to optimise vascular health. However, we do not yet understand the impact of long-term habitual dietary nitrate intake and its association with CVD. Therefore, the aim of this investigation was to examine the relationship between habitual dietary nitrate intakes and risk of CHD in women from the Nurses' Health Study. We prospectively followed 62 535 women who were free from diabetes, CVD and cancer at baseline in 1986. Information on diet was updated every 4 years with validated FFQ. The main outcome was CHD defined by the occurrence of non-fatal myocardial infarction or fatal CHD. Cox proportional hazard regression models were used to estimate the relative risks (RR) and 95 % CI. During 26 years of follow-up, 2257 cases of CHD were identified. When comparing the highest quintile of nitrate intake with the lowest quintile, in aged-adjusted analysis there was a protective association for CHD (RR=0·77, 95 % CI 0·68, 0·97; P=0·0002) which dissipated after further adjustment for smoking, physical activity, BMI and race (RR=0·91; 95 % CI 0·80, 1·04; P=0·27). This magnitude of association was further attenuated once we adjusted for the Alternative Healthy Eating Index excluding vegetable and fruit consumption (RR=1·04, 95 % CI 0·91, 1·20; P=0·34). Dietary nitrate intake was not related to the risk of CHD after adjustment for other lifestyle and non-vegetable dietary factors in a large group of US women.

Evaluating recruitment strategies for AUSPICE, a large Australian community-based randomised controlled trial.

OBJECTIVES: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). DESIGN, SETTING, PARTICIPANTS: Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. METHODS: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. MAIN OUTCOME: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. RESULTS: 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. CONCLUSIONS: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.

New horizons in arginine metabolism, ageing and chronic disease states.

The elucidation of the metabolic pathways of the amino acid arginine and their role in health and disease have been an intensive focus of basic and clinical research for over a century. The recent advent of robust analytical techniques for biomarker assessment in large population cohorts has allowed the investigation of the pathophysiological role of specific arginine metabolites in key chronic disease states in old age, particularly those characterised by a reduced synthesis of endothelial nitric oxide, with consequent vascular disease and atherosclerosis. Two arginine metabolites have been increasingly studied in regard to their potential role in risk stratification and in the identification of novel therapeutic targets: the methylated arginine asymmetric dimethylarginine (ADMA) and the arginine analogue homoarginine. Higher circulating concentrations of ADMA, a potent inhibitor of nitric oxide synthesis, have been shown to predict adverse cardiovascular outcomes. By contrast, there is emerging evidence that homoarginine might exert cardioprotective effects. This review highlights recent advances in the biological and clinical role of ADMA and homoarginine in cardiovascular disease and other emerging fields, particularly chronic obstructive pulmonary disease, dementia, and depression. It also discusses opportunities for future research directions with the ultimate goal of translating knowledge of arginine metabolism, and its role in health and disease, into the clinical care of older adults.

Mesh fixation technique in totally extraperitoneal inguinal hernia repair - A network meta-analysis.

Laparoscopic totally extra-peritoneal inguinal hernia repair is the standard option for inguinal hernia treatment. However, there are various types of mesh fixation and their relative uses are still controversial. This network meta-analysis was conducted to compare and rank the different fixations available for TEP. Medline and Scopus databases were search until February 1, 2017 and using randomized controlled trials comparing outcomes between different mesh fixation techniques were included. The results demonstrated that fifteen RCTs (n = 1783) were eligible for pooling. Five types of mesh fixation were used; metallic tack, no-fixation, absorbable tack, suture, and glue. Network meta-analysis that use metallic tack as the reference, indicated that suture and glue both carried a lower risk of recurrence with pooled risk ratios (RR) of 0.29 (95% CI 0.00, 18.81) and 0.29 (0.07, 1.30), respectively. For overall complications, absorbable tack had lower risk (0.63, 95% CI: 0.02, 16.13). However, none of these estimates reached statistical significance. So, this network meta-analysis suggests that glue and absorbable tack might be best in lowering recurrence risk and complications. However, a large scale RCT is still needed to confirm these results.

GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer.

Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.

Comparison of Superficial Surgical Site Infection Between Delayed Primary Versus Primary Wound Closure in Complicated Appendicitis: A Randomized Controlled Trial.

OBJECTIVE: To compare superficial surgical site infection (SSI) rates between delayed primary wound closure (DPC) and primary wound closure (PC) for complicated appendicitis. BACKGROUND: SSI is common in appendectomy for complicated appendicitis. DPC is preferentially used over PC, but its efficacy is still controversial. METHODS: A multicenter randomized controlled trial was conducted in 6 hospitals in Thailand, enrolling patients with gangrenous and ruptured appendicitis. Patients were randomized to PC (ie, immediately wound closure) or DPC (ie, wound closure at postoperative days 3-5). Superficial SSI was defined by the Center for Disease Control criteria. Secondary outcomes included postoperative pain, length of stay, recovery time, quality of life, and cost of treatment. RESULTS: In all, 303 and 304 patients were randomized to PC and DPC groups, and 5 and 4 patients were lost to follow-up, respectively, leaving 300 and 298 patients in the modified intention-to-treat analysis. The superficial SSI rate was lower in the PC than DPC groups [ie, 7.3% (95% confidence interval 4.4, 10.3) vs 10% (95% CI 6.6, 13.3)] with a risk difference (RD) of -2.7% (-7.1%, 1.9%), but this RD was not significant. Postoperative pain, length of stay, recovery times, and quality of life were nonsignificantly different with corresponding RDs of 0.3 (-2.5, 3.0), -0.1 (-0.5, 0.3), -0.2 (-0.8, 0.4), and 0.02 (-0.01, 0.04), respectively. However, costs for PC were 2083 (1410, 2756) Baht cheaper than DPC (∼$60 USD). CONCLUSIONS: Superficial SSI rates for the PC group were slightly lower than DPC group, but this did not reach statistical significance. Costs were significantly lower for the PC group.

Cardiovascular disease lifestyle risk factors in people with psychosis: a cross-sectional study.

BACKGROUND: People with psychosis die on average 25 years earlier than those in the general population, with cardiovascular disease (CVD) contributing to much of the excess mortality. This cross-sectional study aimed to identify the relationship between lifestyle risk factors for CVD - poor nutrition, smoking and low physical activity levels - and dyslipidaemia, hypertension and hyperglycaemia while controlling for potential confounders in 1825 people from the Survey of High Impact Psychosis (SHIP) in Australia. We also aimed to identify clustering patterns of lifestyle risk factors and associated demographic variables. METHODS: Three logistic regressions were used to predict the effect of nutrition, smoking and physical activity on dyslipidaemia, hypertension and hyperglycaemia while controlling for clozapine use, sex and age. Clustering patterns of nutrition, smoking and physical activity were examined using the two-step cluster method which is based on hierarchical cluster analysis. Demographic variables associated with different clusters were identified using measures of association. RESULTS: Smoking status had a positive association with dyslipidaemia (adjusted odds ratio = 0.50; 95% confidence interval = 0.32-0.78; p = 0.002). Other cardiovascular disease lifestyle risk factors did not have a significant relationship with dyslipidaemia, hypertension and hyperglycaemia. Clustering patterns of lifestyle risk factors showed that younger men, with low education levels, and relying on a government pension, were most likely to display the poorest lifestyle risk behaviours. The largest cluster (42%) of participants was characterised by a mixed demographic profile and were most likely to display poor nutrition and low physical activity levels but less likely to smoke. CONCLUSIONS: Only smoking status had a significant positive association with dyslipidaemia which could indicate that there are additional factors affecting the relationship between other cardiovascular lifestyle risk factors and dyslipidaemia, hypertension and hyperglycaemia in people with psychosis. Unknown confounders and traditional lifestyle risk factors may explain the high rates of CVD in this group. Clustering of lifestyle risk factors and their demographic profiles could help the design of intervention programs in people with psychosis.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.