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OBJECTIVE To identify the optimal AUSDRISK threshold score to screen for pre-diabetes and diabetes. METHODS A total of 406 adult patients not diagnosed with diabetes were screened in General Practices (GP) between May and October 2019. All patients received a point of care (POC) HbA1c test. HbA1c test results were categorised into diabetes (≥6.5% or ≥48 mmol/mol), pre-diabetes (5.7-6.4% or 39-47 mmol/mol), or normal (

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.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.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.Higher serum concentrations of L-arginine and endogenous methylarginines are strongly associated with IBS in adults.

OBJECTIVE: Irritable bowel syndrome (IBS) is a chronic disorder associated with an abnormal gastrointestinal microbiome. Microbiome-host interactions are known to influence organ function including in the central nervous system; thus, we sought to identify whether IBS may be a risk factor for the development of glaucoma.DESIGN: Two prospective cohort studies.SUBJECTS: The 1958 United Kingdom Birth Cohort (UKBC; 9091 individuals) and the Danish National Registry of Patients (DNRP; 62,541 individuals with IBS and 625,410 matched general population cohort members).METHODS: In the UKBC, participants were surveyed throughout life (including at ages 42 and 50). The DNRP contains records of hospital-based contacts and prescription data from the national prescription database.MAIN OUTCOME MEASURE: The main outcome measure was incidence of glaucoma. In the UKBC, incident glaucoma at age 50 (n = 48) was determined through comparison of survey responses at ages 42 and 50 years. In the DNRP, glaucoma was assessed by hospital diagnosis (n = 1510), glaucoma surgery (n = 582) and initiation of glaucoma medications (n = 1674).RESULTS: In the UKBC, the odds ratio (OR) of developing glaucoma between ages 42 and 50 in persons with a chronic IBS diagnosis was increased [OR: 5.84, 95% confidence interval (CI): 2.26-15.13]. People with an IBS diagnosis in the DNRP had a hazard ratio (HR) of 1.35 for developing physician-diagnosed glaucoma (95% CI: 1.16-1.56), an HR of 1.35 for undergoing glaucoma surgery (95% CI: 1.06-1.70) and an HR of 1.19 for initiating glaucoma medication (95% CI: 1.03-1.38).CONCLUSIONS: In two large European cohort studies, IBS is a risk factor for glaucoma.

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.

Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.

Background The efficacy of antibiotics in appendicitis remains controversial, and physicians are not confident in prescribing antibiotics as the first line treatment. This network meta-analysis was conducted to assess the efficacy and safety of individual antibiotics in uncomplicated appendicitis. Methods Randomized controlled trials (RCTs) were identified from MEDLINE and SCOPUS databases since inception to July 2017. Studies. Network meta-analysis was applied to estimate treatment effects and safety. Probability of being the best treatment was estimated using surface under the cumulative ranking curve (SUCRA). Results Among 9 RCTs meeting our inclusion criteria. A network meta-analysis indicated that those receiving antibiotics had about 12–32% lower chance of treatment success and lower risk of complication about 23–86%, especially Beta-lactamase than appendectomy. The overall appendicitis recurrence rate in the antibiotic group was about 18.2%. The SUCRA indicated that appendectomy was ranked first for treatment success and least complications, followed by Beta-lactamase. Conclusions Appendectomy is still the most effective treatment in uncomplicated appendicitis but it carries complications. Beta-lactamase, might be an alternative treatment if there are any contraindications for operation.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

This review examined the risk of cardiovascular disease in adults with metabolically healthy overweight/obesity. A systematic review and meta-analysis using data from Medline, EMBASE, SCOPUS and Cochrane Library searched from inception up to 31st October 2019. We included prospective cohort studies of adults who are metabolically healthy or unhealthy. Outcomes were fatal and nonfatal cardiovascular events, all-cause mortality. Pooled relative risk was calculated for each outcome in populations with metabolically healthy overweight and metabolically healthy obesity using metabolically healthy normal weight as reference. A random-effects model was used for meta-analysis, and risk of bias assessment tool for nonrandomized studies assessed risk of bias within each study. Twenty-three prospective cohort studies with 4,492,723 participants were included. Cardiovascular disease risk was increased in metabolically healthy groups with overweight (RR = 1.34, CI: 1.23-1.46, n = 20, I2 = 90.3%) and obesity (RR = 1.58, CI: 1.34-1.85, n = 21, I2 = 92.2) compared with a reference group with metabolically healthy normal weight. Cardiovascular disease risk was similar irrespective of the number of risk factors used to define metabolically healthy and the risk remained in the group with no metabolic risk factors. Cardiovascular disease risk is increased in populations with overweight and obesity classified as metabolically healthy even when there were no metabolic risk factors.

Background Laparoscopic appendectomy (LA) has been popular for decades because of shorter hospitalization and return to routine activity. However, complications (e.g., surgical site infection [SSI] and intra-abdominal abscess [IAA]) relative to open appendectomy (OA) are still debated. We therefore conducted an umbrella review to systematically appraise meta-analyses (MAs) comparing SSI and IAA between LA and OA. Methods Meta-analyses that included only randomized controlled trials were identified from MEDLINE and Scopus databases from inception until July 2018. Their findings were described, the number of overlapping studies was assessed using corrected covered area, and excess significant tests were also assessed. Finally, effect sizes of SSI and IAA were repooled. Results Ten MAs were eligible; SSI was reported in all MAs and IAA in 8 MAs. Surgical site infection rate was 48% to 70% lower in LA than OA, but conversely, IAA rate was 1.34 to 2.20 higher in LA than OA. Overlapping included studies for SSI and IAA were 61% and 54%, respectively, indicating that less information was added across MAs. However, there was no evidence of bias from excess significant tests when pooling SSI or IAA estimates. The risk ratios (95% confidence interval) comparing LA versus OA were repooled in adults and children yielding risk ratios of 0.56 (0.47-0.67) and 0.40 (0.25-0.65) for SSI, and 1.20 (0.88-1.63) and 1.05 (0.61-1.80) for IAA. Conclusion Evidence from this umbrella review indicates that LA carries a significantly lower risk of SSI but likely a higher risk of IAA than OA. Level of evidence Systematic review/meta-analysis, level I.

BackgroundBody mass index (BMI), uric acid (UA) diabetes mellitus (DM) and hypertension (HT) are known risk factors of declined kidney function, and are associated with fetuin-A. However, the causal pathways of these associations are unclear. We therefore used cohort data to explore possible causal pathways of fetuin-A and kidney function. MethodologyWe used data of the Electricity Generating Authority of Thailand cohort 2009 (n= 2305). A causal pathway was constructed, which considered fetuin-A as study factor, BMI, UA, DM, and HT as mediators, and eGFR as the outcome. A generalized-structural equation model (GSEM) with 1000-replication bootstrapping was applied to assess the causal effects adjusting for covariates. ResultsThe fetuin-A → eGFR pathway showed a direct association of fetuin-A on eGFR with the coefficient of -0.0072 (95% CI: -0.0119, -0.0025). In addition, the indirect effects of fetuin-A→ BMI → eGFR was also significant with the coefficient of 0.00086 (0.00025, 0.0016; implying that every one unit of BMI increased, resulting from increasing fetuin-A, would significantly increase eGFR 0.00086 (0.00025, 0.0016) mL/min/1.73m2. There was a negative effect of fetuin-A on eGFR through BMI and UA pathway (Fetuin-A→BMI→UA→eGFR ) as well as the HT pathway (Fetuin-A→BMI→HT→eGFR ) with average casual mediation effects (ACME) of -0.00132 (-0.00177, -0.00092) and -0.00139 (-0.00237, -0.00069). Fetuin-AàDMàHTàeGFR was also statistically significant with the ACME of -0.00223 (-0.00535, -0.00066).ConclusionOur study has shed some light on the possible role of fetuin-A in the etiology of declining renal function through the mediatory roles of BMI, UA, DM and HT in the various complex causal pathways leading to declining kidney function in our study cohort. Further studies are however recommended to examine the pathomechanisms involved in the mediational processes of these studied risk factors in the etiology of declining kidney function.

Objective. This systematic review aimed to measure the association between neutrophil lymphocyte ratio (NLR) and cardiovascular disease (CVD) risk. Methods. Relevant studies were identified from Medline and Scopus databases. Observational studies with NLR as a study factor were eligible for review. The outcomes of interest were any type of CVD including acute coronary syndrome, coronary artery disease, stroke, or a composite of these cardiovascular events. Mean differences in NLR between CVD and non-CVD patients were pooled using unstandardized mean difference (USMD). Odds ratios of CVD between high and low NLR groups were pooled using a random effects model. Results. Thirty-eight studies (n=76,002) were included. High NLR was significantly associated with the risks of CAD, ACS, stroke, and composite cardiovascular events with pooled ORs of 1.62 (95% CI: 1.38-1.91), 1.64 (95% CI: 1.30, 2.05), 2.36 (95% CI: 1.44, 2.89), and 3.86 (95% CI: 1.73, 8.64), respectively. In addition, mean NLRs in CAD, ACS, and stroke patients were significantly higher than in control groups. Conclusion. High NLR was associated with CAD, ACS, stroke, and composite cardiovascular events. Therefore, NLR may be a useful CVD biomarker.

Context Depleted nitric oxide levels in the human body play a major role in cardiovascular disease pathogenesis. Inorganic nitrate/nitrite (rich dietary sources include beetroot and spinach) can act as a nitric oxide donor because nitrate/nitrite can be metabolized to produce nitric oxide. Objective This review and meta-analysis sought to investigate the role of inorganic nitrate/nitrite in preventing or treating cardiovascular disease risk factors in humans. Data Sources Electronic databases, including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane, and Scopus, were searched. Data Extraction Experimental trials examining the effect of oral inorganic nitrate/nitrite intake on cardiovascular disease risk factors were included for systematic analysis. Results Thirty-four studies were included for qualitative synthesis, 23 of which were eligible for meta-analysis. Included studies measured the following outcomes: blood pressure, endothelial function, arterial stiffness, platelet aggregation, and/or blood lipids. Inorganic nitrate intake was found to significantly reduce resting blood pressure (systolic blood pressure: -4.80 mmHg, P

Context Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFAs) are widely considered as nootropic agents that may be beneficial in reversing cognitive impairment. Objective The present systematic review of randomized controlled trials was conducted to determine the changes in cognitive function after intervention with LCn-3PUFA supplementation in non-demented adults, including those with mild cognitive impairment. Data Sources Five databases (MEDLINE, CINAHL, Scopus, EMBASE, and the Cochrane Library) were searched systematically along with reference lists of selected articles. Study Selection Studies were eligible for inclusion if they measured the effect of LCn-3PUFA supplementation on cognition in non-demented adults. Data Extraction A total of 787 records were screened, of which 25 studies were eligible for inclusion. Treatment effects were summarized as global cognitive function for primary outcome and measured using the Mini-Mental State Examination and individual cognitive domains for secondary outcome. The pooled effect sizes were estimated using Hedge’s g and random-effects modeling. Data Analysis Results from randomized controlled trials indicate that LCn-3PUFAs have no effect on global cognitive function (Hedge’s g = 0.02; 95% confidence interval, −0.12 to 0.154), and among the specific cognitive domains, only memory function showed a mild benefit (Hedge’s g = 0.31; P = 0.003; z = 2.945). Conclusion The existing literature suggests that LCn-3PUFA supplementation could provide a mild benefit in improving memory function in non-demented older adults. Systematic Review Registration PROSPERO registration no. CRD42017078664.

ObjectivesTo conduct a systematic review and meta-analysis and to pool the incremental net benefits (INBs) of glucagon-like peptide 1 (GLP1) compared with other therapies in type 2 diabetes mellitus (T2DM) after metformin monotherapy failure.Research design and methodsThe study design is a systematic review and meta-analysis. We searched MEDLINE (via PubMed), Scopus and Tufts Registry for eligible cost–utility studies up to June 2018, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. We conducted a systematic review and pooled the INBs of GLP1s compared with other therapies in T2DM after metformin monotherapy failure. Various monetary units were converted to purchasing power parity, adjusted to 2017 US$. The INBs were calculated and then pooled across studies, stratified by level of country income; a random-effects model was used if heterogeneity was present, and a fixed-effects model if it was absent. Heterogeneity was assessed using Q test and I2statistic.ResultsA total of 56 studies were eligible, mainly from high-income countries (HICs). The pooled INBs of GLP1s compared with dipeptidyl peptidase-4 inhibitor (DPP4i) (n=10), sulfonylureas (n=6), thiazolidinedione (TZD) (n=3), and insulin (n=23) from HICs were US$4012.21 (95% CI US$−571.43 to US$8595.84, I2=0%), US$3857.34 (95% CI US$−7293.93 to US$15 008.61, I2=45.9%), US$37 577.74 (95% CI US$−649.02 to US$75 804.50, I2=92.4%) and US$14 062.42 (95% CI US$8168.69 to US$19 956.15, I2=86.4%), respectively. GLP1s were statistically significantly cost-effective compared with insulins, but not compared with DPP4i, sulfonylureas, and TZDs. Among GLP1s, liraglutide was more cost-effective compared with lixisenatide, but not compared with exenatide, with corresponding pooled INBs of US$4555.09 (95% CI US$3992.60 to US$5117.59, I2=0) and US$728.46 (95% CI US$−1436.14 to US$2893.07, I2=0), respectively.ConclusionGLP1 agonists are a cost-effective choice compared with insulins, but not compared with DPP4i, sulfonylureas and TZDs.PROSPERO registration numberCRD42018105193.

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.

Summary 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.

Neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, is associated with cardiovascular events (CVEs), but its causal pathway is unknown. We aimed to explore the extent to which NLR is directly associated with CVEs or mediated through diabetes mellitus (DM), hypertension (HT) and creatinine (Cr). The study used data on 2,501 subjects from the Electricity Generating Authority of Thailand cohort 2002–2012. Two causal pathways A: NLR→(DM→Cr→HT)→CVEs and B: NLR→(DM → HT→Cr)→CVEs were constructed. A generalized structural equation model and 1,000-replication bootstrapping were applied. The incidence rate of CVE was 8.8/1000/year. Prevalence rates of HT, DM, and chronic kidney disease were 45.1%, 23.6%, and 16.5%, respectively. The total effect of NLR on CVEs was explained partly (44%) by a direct effect and partly (56%) by an indirect effect through DM, HT and Cr. For pathway A, the direct OR of NLR on CVE was 1.25 (95% CI: 1.13, 1.39); the ORs for the indirect effects of NLR on CVEs mediated through DM, Cr, and poor-controlled HT were 1.06 (95% CI: 1.01, 1.11), 1.01 (95% CI: 1.00, 1.02), and 1.07 (95% CI: 1.01, 1.14) respectively. Results were similar for pathway B. Our findings demonstrate that roughly half of the relationship between NLR and CVEs may be mediated through DM, HT and Cr.

Purpose Tooth loss or periodontal disease is associated with systemic endothelial dysfunction, which has been implicated in primary open-angle glaucoma (POAG). The relationship between oral health and POAG has received limited attention. Thus, we evaluated the association between oral health history and risk of POAG and POAG subtypes. Design Prospective cohort study. Participants Health Professionals Follow-up Study participants (40 536 men) followed biennially from 1986 to 2012. At each 2-year risk period, eligible participants were aged 40+ years, were free of POAG, and reported eye examinations. Methods By using validated questions, we updated participants' status on number of natural teeth, teeth lost, periodontal disease with bone loss, and root canal treatments. Main Outcome Measures During follow-up, 485 incident cases of POAG were confirmed with medical records and classified into subtypes defined by intraocular pressure (IOP; ≥ or Results Number of natural teeth, periodontal disease, and root canal treatment were not associated with POAG. However, compared with no report of tooth loss, a report of losing teeth within the past 2 years was associated with a 1.45-fold increased risk of POAG (95% CI, 1.06–1.97); in particular, a report within the past 2 years of both losing teeth and having a prevalent diagnosis of periodontal disease was associated with a 1.85-fold increased risk of POAG (95% CI, 1.07–3.18). The associations with recent tooth loss were not significantly different for the POAG subtypes ( P for heterogeneity ≥0.36), although associations were strongest in relation to the POAG subtypes with IOP Conclusions Although the number of natural teeth was not associated with risk of POAG, recent tooth loss was associated with an increased risk of POAG. Because these findings may be due to chance, they need confirmation in larger studies.

Background We conducted a systematic review and meta-analysis of interferon regulatory factor 6 and 8q24 polymorphisms with nonsyndromic cleft lip with/without cleft palate (NSCL/P). Methods Data extraction was independently performed by two reviewers. Genotypic effects of four polymorphisms from 31 studies were pooled separately by ethnicity using a mixed-effect logit model with accounting for heterogeneity. Results For rs2235371, AA and GA carried, respectively, 51% (95% confidence interval [CI], 37%–61%) and 42% (95% CI, 32%–50%) lower risks of NSCL/P than GG genotypes in Asians, but these genotypes were not significant in Caucasians. For rs2013162, only AA was significant, that is, carried 0.65 (95% CI, 0.52–0.82) times lower odds than CC in Caucasians but not for Asians. For rs642961, AA and GA genotypes, respectively, carried 2.47 (95% CI, 1.41–4.35) and 1.40 (95% CI, 1.12–1.75) times higher odds in Asian, and 2.03 (95% CI, 1.52–2.71) and 1.58 (95% CI, 1.37–1.82) times higher odds in Caucasians compare with GG genotypes. For rs987525, AA and CA genotypes carried 2.27 (95% CI, 1.43–3.60) and 1.34 (95% CI, 1.02–1.77) times higher odds in Asian, and 5.25 (95% CI, 3.98–6.91) and 2.13 (95% CI–1.82, 2.49) times higher odds in Caucasians, and 1.42 (95% CI, 1.10–1.82) and 1.28 (95% CI, 1.09–1.50) times higher odds in mixed ethnicities compared with CC genotypes. These variant effects remained significant based on applying Bonferroni corrected-thresholds, except in the mixed ethnicity. Conclusion We show robust variant effects in NSCL/P. Considering them with other genes and risk factors might be useful to improve prediction of NSCL/P occurrence. Birth Defects Research (Part A), 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.

Background Research has shown that vaccination with Streptococcus pneumoniae reduced the extent of atherosclerosis in experimental animal models. It is thought that phosphorylcholine lipid antigens in the S. pneumoniae cell wall induce the production of antibodies that cross-react with oxidized low-density lipoprotein, a component of atherosclerotic plaques. These antibodies may bind to and facilitate the regression of the plaques. Available data provide evidence that similar mechanisms also occur in humans, leading to the possibility that pneumococcal vaccination protects against atherosclerosis. A systematic review and meta-analysis, including 8 observational human studies, of adult pneumococcal polysaccharide vaccination for preventing cardiovascular disease in people older than 65 years, showed a 17% reduction in the odds (odds ratio 0.83, 95% CI 0.71-0.97) of having an acute coronary syndrome event. Methods/Design The AUSPICE is a multicenter, randomized, placebo-controlled, double-blind, clinical trial to formally test whether vaccination with the pneumococcal polysaccharide vaccine protects against cardiovascular events (fatal and nonfatal acute coronary syndromes and ischemic strokes). Cardiovascular outcomes will be obtained during 4 to 5 years of follow-up, through health record linkage with state and national administrative data sets. Conclusion This is the first registered randomized controlled trial (on US, World Health Organization, Australia and New Zealand trial registries) to be conducted to test whether vaccination with the pneumococcal polysaccharide vaccine will reduce cardiovascular events. If successful, vaccination can be readily extended to at-risk groups to reduce the risk of cardiovascular diseases.

Background: Statins are proposed as a chemoprevention agent for breast cancer due to their anti-inflammatory effect. The effects of lipophilic and hydrophilic statins on breast cancer risk might be different due to their different pharmacologic properties. Therefore, this study aimed to assess a casual-effect of lipophilic and hydrophilic statins on breast cancer risk using a counterfactual framework approach. Methods: A cross-sectional study of 15,718 women who were screened for breast cancer at Mammographic center, Ramathibodi Hospital, Bangkok, Thailand, was conducted during September 2011 to 2012. A counterfactual framework approach was applied to assess causal effects of treatments (i.e., lipophilic and hydrophilic statins) on outcome (i.e. breast cancer). Multi-logit and logistic regression models were used for treatment and outcome models, respectively. An inverse probability weight regression analysis (IPWRA) was then applied to estimate potential outcome mean (POM) and average treatment effect (ATE) by combining the outcome and treatment models. Results: Breast cancer risks were 0.0072 (95% CI: 0.0055, 0.0089), 0.0051 (95% CI: 0.0008, 0.0095), and 0.0038 (95% CI: 0.002, 0.0056) for non-statin users, hydrophilic, and lipophilic statin users, respectively. The estimated risk differences were -0.0021 (95% CI: -0.0067, 0.0026) and -0.0034 (95% CI: -0.0059, -0.0009) for hydrophilic and lipophilic statins respectively. The number needed to treat for hydrophilic and lipophilic statins were 2.1 (95% CI: -2.6, 6.7) and 3.4 (95% CI: 1.0, 5.9) per 1000 subjected, respectively. Conclusions: Our results suggested that using lipophilic statin could significantly reduce risk of breast cancer in Thai women.

People with Type 1 diabetes (T1D) have been shown to be an at-risk group for the development of disordered eating behaviours, however, the validity of tools used to assess disordered eating behaviours in T1D is unclear. This review aimed to identify tools used to screen or identify disordered eating behaviours and eating disorders in people with T1D, and evaluate the validity and reliability of these tools. A systematic search strategy was conducted to October 2019 according to the PRISMA guidelines. The search strategy retrieved 2714 articles, with 100 articles describing 90 studies included in the review. Studies were predominantly conducted in adolescent females in clinical settings. Forty-eight individual tools were used across retrieved studies. Overall, the quality of tools reported in included articles was poor, with high risk of bias due to the use of non-validated tools (n = 44 articles) and few studies comparing to the reference standard (n = 10 articles) of a diagnostic interview. This review shows that a variety of tools have been used to screen and identify disordered eating behaviours and eating disorders in people with T1D. Future research including comparison to a gold standard diagnostic interview is warranted to further evaluate the validity and reliability of available tools.

Summary Background & aims Chronic inflammation drives the development of insulin resistance and type 2 diabetes. Long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) eicosapentaenoic acid (EPA, c20:5n-3) and docosahexaenoic acid (DHA, c22:6n-3) may protect against type 2 diabetes development. The aim of this current study is to determine whether LCn-3PUFA status is associated with type 2 diabetes in the Hunter Community Study. Methods Men and women aged 55–85 years were randomly selected from the electoral roll and invited to participate. Participants were included in the current study if they had plasma phospholipid fatty acid composition data available and diabetes status could be determined. LCn-3PUFA status was determined by fatty acid composition of plasma phospholipids (EPA + DHA, %,w/w). Diabetes was determined according to World Health Organisation criteria. Insulin was measured in n = 251 participants and HOMA-IR calculated. Results In total, n = 2092 (diabetes: n = 249) participants were included. After adjusting for confounders of diabetes, LCn-3PUFA status was inversely associated with diabetes in overweight/obese females (OR [95%CI]: 0.90 [0.80, 1.00], p = 0.045) but not males (p-interactionsex = 0.041). Overweight/obese females with diabetes had significantly lower levels of DHA than those without diabetes (mean difference [95%CI]: −0.53 [−0.87, −0.20], p = 0.002), with no difference in EPA. LCn-3PUFA was inversely associated with HOMA-IR (r = −0.175, p = 0.005). Conclusions This study provides further evidence of a sex-dependent association between LCn-3PUFA and type 2 diabetes. Causal pathways between LCn-3PUFA and type 2 diabetes merits delineation.

Bone loss is characteristic of the ageing process and a common complication of many autoimmune diseases. Research has highlighted a potential role of autoantibodies in pathologic bone loss. The confounding effects of immunomodulatory drugs make it difficult to establish the contribution of autoantibodies amongst autoimmune disease sufferers. We attempted to examine the relationship between autoantibodies and bone mass in a population of 2812 elderly participants without clinical autoimmune disease. Serum samples were assayed for a panel of autoantibodies (anti-nuclear, extractable nuclear antigen, anti-neutrophil cytoplasmic, thyroid peroxidase, tissue transglutaminase, anti-cardiolipin, rheumatoid factor, and cyclic citrullinated peptide). Bone mass was measured using quantitative ultrasound (QUS) of the calcaneus. The relationship between each autoantibody and bone mass was determined using linear regression models. Anti-nuclear autoantibodies were the most prevalent, positive in approximately 11%, and borderline in roughly 23% of our sample. They were also the only autoantibody observed to be significantly associated with QUS index in the univariate analysis (n=1628; r=−0.20; 95% CI: −0.40–0.00; p=0.046). However, statistical significance was lost after adjustment for various other potential confounders. None of the other autoantibodies was associated with QUS index in either univariate or multivariate analysis. We are limited by the cross-sectional nature of the study and the low prevalence of autoantibodies in our nonclinical sample.

This study investigated whether inflammation may explain the relationship between depression and incident cardiovascular hospitalisations. Participants (55-85 years) completed baseline depression and physical assessment. Those without self-reported cardiovascular events were followed prospectively for hospital admissions for angina, myocardial infarction and cerebral infarction (median 937 days). Across 5140 person-years of risk (N = 1692), there were 47 incident cardiovascular hospitalisations (2.8 %). Controlling for age and gender, interleukin (IL)-6, C-reactive protein (CRP), body mass index (BMI) and waist-to-hip ratio were associated with future cardiovascular events. Mediation analysis showed that CRP accounted for 8.1 % and IL-6 10.9 % of the effect of depression on cardiovascular events, and including the indirect effect in the model substantially reduced the direct relationship between depression and cardiovascular hospitalisations. BMI and waist-to-hip ratio accounted for indirect effects of 7.7 and 10.4 %, respectively. Inflammatory markers partly explain the association between depression and cardiovascular events, although other shared factors also likely contribute.

SummaryLarge platelets with high haemostatic activity may lead to increased platelet aggregation.. Mean platelet volume (MPV), an indicator of platelet reactivity, may emerge as a prognostic marker in patients with coronary artery disease (CAD). It was the objective of this study to conduct a systematic review and meta-analysis to assess prognostic effects of MPV on cardiovascular events (CVE) in CAD patients. We searched MEDLINE and SCOPUS from inception to January 2, 2014. All studies that reported MPV and the incidence of cardiovascular events in CAD patients were included. Two reviewers independently extracted the data. A random-effects model was applied for pooling the mean difference of MPV between patients with vs without CVE. Among 30 eligible studies, eight studies reported mean difference of MPV between CVE groups, 11 studies reported MPV dichotomous into high vs low MPV groups, and 11 studies reported both. The pooled mean difference was 0.69 fL (95 %CI = 0.36, 1.01), i. e. patients with CVE had a MPV about 0.69 fL higher than non-CVE. Patients with higher MPV were about 12 % more likely to die than patients with lower MPV (RR 1.12; 95 %CI = 1.02–1.24). However, pooling these effects was based on high heterogeneity and the source of heterogeneity could not be identified. This might be explained by many differences among included studies (e. g. study population, outcomes of interest, analysate, time between blood collection and MPV analysis, etc). These findings suggest that MPV may be a useful prognostic marker in patients with CAD.

Background Chronic kidney disease (CKD) is a leading cause of death before and after onset of end-stage renal disease (ESRD). Knowing treatments that can delay disease progression will lead to reduced mortality. We therefore aimed to estimate the effectiveness of renin angiotensin aldosterone system (RAAS) blockade on CKD progression. Methods We conducted a retrospective CKD cohort at Ubon Ratchathani province, Thailand from 1997 to 2011. ESRD was defined as estimated glomerular filtration rate (eGFR) 1 year (RAAS2). An augmented inverse-probability weighting (AIPW) method was used to estimate potential-outcome mean (POM) and average treatment-effect (ATE). Multi-logit and Poisson regressions were used for treatment and outcome models, respectively. Analyses were stratified by ESRD, death before/after ESRD for diabetic and non-diabetic groups. STATA 14.0 was used for statistical analyses. Results Among 15,032 diabetic patients, 2346 (15.6%), 2351 (18.5%), and 1607 (68.5%) developed ESRD, died before ESRD, and died after ESRD, respectively. Only RAAS2 effect was significant on ESRD, death before and after ESRD. The ESRD rates were 12.9%, versus 20.0% for RAAS2 and non-RAAS, respectively, resulted in significant risk differences (RD) of −7.2% (95% CI: -8.8%, −5.5%), and a numbers needed-to-treat (NNT) of 14. Death rates before ESRD for these corresponding groups were 14.4% (12.9%, 15.9%) and 19.6% (18.7%, 20.4%) with a NNT of 19. Death rates after ESRD in RAAS2 was lower than non-RASS group (i.e., 62.8% (55.5%, 68.9%) versus 68.1% (65.9%, 70.4%)) but this was not significant. RAAS2 effects on ESRD and death before ESRD were persistently significant in non-diabetic patients (n = 17,074) but not for death after ESRD with the NNT of about 15 and 16 respectively. Conclusions Receiving RAAS blockade for 1 year or longer could prevent both CKD progression to ESRD and premature mortality. Electronic supplementary material The online version of this article (10.1186/s12882-017-0753-9) contains supplementary material, which is available to authorized users.

Vitamin D supplementation effects with or without calcium in pregnancy for reducing risk of preeclampsia and gestational or pregnancy induced hypertension are controversial. Literature was systematically searched in Medline, Scopus and Cochrane databases from inception to July 2017. Only randomized controlled trials (RCTs) in English were selected if they had any pair of interventions (calcium, vitamin D, both, or placebo). Systematic review with two-step network-meta-analysis was used to indirectly estimate supplementary effects. Twenty-seven RCTs with 28,000 women were eligible. A direct meta-analysis suggested that calcium, vitamin D, and calcium plus vitamin D could lower risk of preeclampsia when compared to placebo with the pooled risk ratios (RRs) of 0.54 (0.41, 0.70), 0.47 (0.24, 0.89) and 0.50 (0.32, 0.78), respectively. Results of network meta-analysis were similar with the corresponding RRs of 0.49 (0.35, 0.69), 0.43 (0.17, 1.11), and 0.57 (0.30, 1.10), respectively. None of the controls were significant. Efficacy of supplementation, which was ranked by surface under cumulative ranking probabilities, were: vitamin D (47.4%), calcium (31.6%) and calcium plus vitamin D (19.6%), respectively. Calcium supplementation may be used for prevention for preeclampsia. Vitamin D might also worked well but further large scale RCTs are warranted to confirm our findings.

Objectives To assess the cost effectiveness of renin-angiotensin aldosterone system (RAAS) blockade in the progression of chronic kidney disease using Thai clinical data in 2014. Methods A Markov model for cost-effectiveness analysis was applied to estimate from a societal perspective the cost per quality-adjusted life-year (QALY) gained and the incremental cost-effectiveness ratio of RAAS versus non-RAAS used in preventing the progression of end-stage renal disease and death stratified by diabetic and nondiabetic patients. Input parameters related to clinical outcomes were obtained from a cohort study of treatment effectiveness, whereas costs were retrieved from the Ramathibodi Hospital electronic database in 2015 and the Health Intervention and Technology Assessment Program in Thailand. One-way analysis and probabilistic sensitivity analysis were performed to evaluate uncertainty surrounding model parameters. Results From the model, using RAAS improved QALY from 2.41 to 3.16 years and from 2.37 to 3.20 years in diabetic and nondiabetic groups, respectively. The incremental cost-effectiveness ratios for these groups were 78,250 baht (US $2,353.39) and 66,674 baht (US $2,005.22), respectively. Conclusions Using RAAS in patients with chronic kidney disease improved QALY in both diabetic and nondiabetic patients and proved to be cost-effective.

To unlock the full potential of disease modifying treatments, it is essential to develop early biomarkers for Alzheimer's disease (AD). For practical reasons, blood-based markers that could provide a signal at the stage of mild cognitive impairment (MCI) or even earlier would be ideal. Using the proteomic approach of isobaric tagging for relative and absolute quantitation (iTRAQ), we compared the plasma protein profiles of MCI, AD, and cognitively normal control subjects from two independent cohorts: the Sydney Memory and Ageing Study (261 MCI subjects, 24 AD subjects, 411 controls) and the Hunter Community Study (180 MCI subjects, 153 controls). The objective was to identify any proteins that are differentially abundant in MCI and AD plasma in both cohorts, since they might be of interest as potential biomarkers, or could help direct future mechanistic studies. Proteins representative of biological processes relevant to AD pathology, such as the complement system, the coagulation cascade, lipid metabolism, and metal and vitamin D and E transport, were found to differ in abundance in MCI. In particular, levels of complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, and vitamin D-binding protein were significantly decreased in MCI participants from both cohorts. Several apolipoproteins, including apolipoprotein AIV, B-100, and H were also significantly decreased in MCI. Most of these proteins have previously been reported as potential biomarkers for AD; however, we show for the first time that a significant decrease in plasma levels of two potential biomarkers (fibronectin and C1 inhibitor) is evident at the MCI stage.

Background Platelets with high hemostatic activity play an important role in the pathophysiology of coronary artery disease(CAD) and mean platelet volume(MPV) has been proposed as an indicator of platelet reactivity. Thus, MPV may emerge as a potential marker of CAD risk. The aim of this study was to conduct a systematic review and meta-analysis comparing mean difference in MPV between patients with CAD and controls and pooling the odds ratio of CAD in those with high versus low MPV. Methods Medline and Scopus databases were searched up to 12 March 2013. All observational studies that considered MPV as a study's factor and measured CAD as an outcome were included. Two reviewers independently selected the studies and extracted the data. Results Forty studies were included in this meta-analysis. The MPV was significantly larger in patients with CAD than controls with the unstandardized mean difference of 0.70fL (95% CI: 0.55, 0.85). The unstandardized mean difference of MPV in patients with acute coronary event and in patients with chronic stable angina was 0.84fL (95% CI: 0.63, 1.04) and 0.46fL (95% CI: 0.11, 0.81) respectively. Patients with larger MPV (≥7.3fL) also had a greater odds of having CAD than patients with smaller MPV with a pooled odds ratio of 2.28 (95% CI: 1.46, 3.58). Conclusion Larger MPV was associated with CAD. Thus, it might be helpful in risk stratification, or improvement of risk prediction if combining it with other risk factors in risk prediction models.

Background: Autoimmunity is considered an uncommon but under-recognised cause of cognitive decline. Methods: Serum samples from 3,253 randomly selected subjects enrolled in the Hunter Community Study, aged 55-85 years, were assayed for thyrotropin stimulatory hormone, anti-thyroid peroxidase antibodies (TPO-Ab), anti-nuclear antibodies (ANA) and extractable nuclear antigens (ENA). Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) tool. Results: TPO-Ab were found in 8.4% and ANA in 27.9% of the study population, of whom 3% had positive ENA findings. No relationship was found between the ARCS score and either TPO-Ab (coefficient = 0.133; 95% CI -0.20, 0.82, p = 0.616), ANA at a low (coefficient = 1.01; 95% CI -2.58, 0.55, p = 0.203) or a high titre (coefficient = -0.65; 95% CI -2.59, 1.28, p = 0.508), or ENA antibodies (coefficient = 5.12; 95% CI -0.53, 10.77; p = 0.076). Conclusions: Autoantibody findings are common in an aging population and are not associated with cognitive decline.

Tenascin-C (Tn-C) is an endogenous ligand of toll-like receptor-4 (TLR-4); a key signalling molecule associated with chronic inflammatory conditions. Both Tn-C and TLR-4 are increased in unstable human atheroma, but their effects on local inflammatory conditions have not been investigated. The aim of the present study was to investigate the association and functional implications of Tn-C/TLR-4 signalling in large artery atherosclerotic stroke. Plasma Tn-C was measured by ELISA and found to be higher in recent stroke patients (n = 336; median 12.77 μg/mL, inter-quartile range 10.23–15.74 μg/mL) than in controls (n = 321; median 11.31 μg/mL, inter-quartile range 8.89–13.90 μg/mL), P

Background:This study measured serum concentrations of vascular risk factors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in a representative sample of older community-dwelling adults and determined their associations with objective and subjective memory impairment. Methods: Data on clinical, lifestyle, and demographic characteristics, serum ADMA, SDMA, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. Objective memory was measured with the Audio Recorded Cognitive Screen (ARCS) neuropsychological battery and subjective memory impairment was measured using the Memory Complaint Questionnaire (MAC-Q). Results: Multivariate analysis revealed that SDMA and diabetes were significantly associated with objective memory impairment (Adjusted Odd ratio (AOR) = 3.90; 95% CI. 1.21 – 12.52 for fourth quartile (Q4) of SDMA. ADMA, SDMA, education, number of general practitioner visits and atrial fibrillation were all significantly associated with subjective memory impairment. (AOR = 1.82; 95% CI. 1.04 – 3.18 for Q4 ADMA. Conclusions: Higher serum SDMA was associated with objective and subjective memory impairment while higher serum ADMA was associated with subjective memory impairment.

Background Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l -arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up. Methods Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l -arginine (measured using LC–MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60–70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥16 or use of antidepressant medications. Results In adjusted analyses ADMA (Q3), SDMA (Q2), l -arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25–9.99). Limitations Limitations of our study include the use of a subjective self-reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression. Conclusions After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up.

Background and Purpose— Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. Methods— A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. Results— The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 ( P =1.4×10 −8 ). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97–1.07; P =0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97–1.16; P =0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89–1.07; P =0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97–1.17; P =0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants ( P =0.18). Conclusions— We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

We investigated the contribution of polymorphisms in cytokine genes (TNFa-308, IL10-1082 and -592, TGFb1-c10 and c25, and IFNg + 874) on the risk of graft rejection in liver transplantation. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. In total, 12 studies were eligible and included in the study. Data extraction and assessments for risk of bias were independently performed by two reviewers. Data for allele frequencies, allelic, and genotypic effects were pooled. Heterogeneity and publication bias were assessed. Pooled minor allele frequencies for TNFa-308, IL10-1082, TGFb1-c10, TGFb1-c25, IFNg + 874, and IL10-592 were 0.140 (95% CI: 0.083, 0.198), 0.432 (95% CI: 0.392, 0.472), 0.387 (95% CI: 0.307, 0.467), 0.090 (95% CI: 0.056, 0.123), 0.460 (95% CI: 0.392, 0.528), and 0.224 (95% CI: 0.178, 0.269), respectively. OnlyTNFa-308 and IL10-1082 polymorphisms were significantly associated with graft rejection. Patients who carried minor homozygous genotypes for these two polymorphisms were at 3.5 and 1.69 times higher risk of graft rejections than patients who carried major homozygous genotypes. The estimated lambdas were 0.41 and 0.47, suggesting an additive mode of effect was most likely. However, we could not detect the associations of TGFb1at c10 and c25, INFg + 874, and IL10-592 polymorphisms and graft rejection. In summary, our systematic review has demonstrated that TNFa-308 and IL10-1082 are potential risk factors of poor outcomes in liver transplantation. Future updated meta-analysis studies to confirm the power of these genotypes in association with allograft rejection are needed.

Summary This review aims to evaluate the performance of obstructive sleep apnea (OSA) screening questionnaires during pregnancy. A systematic review and meta-analysis was performed using MEDLINE Scopus, CINAHL, and the Cochrane library. A bivariate meta-analysis was applied for pooling of diagnostic parameters. Six of the total 4719 articles met the inclusion criteria. The Berlin questionnaire (BQ, N = 604) and Epworth sleepiness scale (ESS, N = 420) were the most frequently used screening tools during pregnancy. The pooled prevalence of OSA during pregnancy was 26.7% (95%CI: 16.9%, 34.4%, I 2 = 83.15%). BQ performance was poor to fair with pooled sensitivity and specificity of 0.66 (95%CI: 0.45, 0.83; I 2 = 78.65%) and 0.62 (95%CI: 0.48, 0.75; I 2 = 81.55%), respectively. BQ performance was heterogeneous depending on type of reference test and pregnancy. Sensitivity increased if diagnosis was based on polysomnography (0.90), and respiratory disturbance index (0.90). However, sensitivity decreased if screening was performed in early pregnancy (≤20 weeks gestation: 0.47), and high-risk pregnancy (0.44). Performance of ESS was poor with pooled sensitivity and specificity of 0.44 (95%CI: 0.33, 0.56; I 2 = 32.8%) and 0.62 (95%CI: 0.48, 0.75; I 2 = 81.55%), respectively. In conclusion, BQ and ESS showed poor performance during pregnancy, hence a new OSA screening questionnaire is needed. Registration: PROSPERO registration CRD42015025848.

Apolipoproteins play a crucial role in lipid metabolism with implications in cardiovascular disease, obesity, diabetes, Alzheimer's disease, and longevity. We quantified 7 apolipoproteins in plasma in 1067 individuals aged 56-105 using immunoassays and explored relationships with APOE polymorphism e2/3/4, vascular health, frailty, and cognition. ApoA1, ApoA2, ApoB, ApoC3, ApoE, ApoH, and ApoJ decreased from mid-life, although ApoE and ApoJ had U-shaped trends. Centenarians had the highest ApoE levels and the lowest frequency of APOE e4 allele relative to younger groups. Apolipoprotein levels trended lower in APOE e4 homozygotes and heterozygotes compared with noncarriers, with ApoE and ApoJ being significantly lower. Levels of all apolipoproteins except ApoH were higher in females. Sex- and age-related differences were apparent in the association of apolipoproteins with cognitive performance, as only women had significant negative associations of ApoB, ApoE, ApoH, and ApoJ in mid-life, whereas associations at older age were nonsignificant or positive. Our findings suggest levels of some apolipoproteins, especially ApoE, are associated with lifespan and cognitive function in exceptionally long-lived individuals.

Background Chronic kidney disease (CKD) is a major contributor to mortality in the general population. Understanding the factors that drive this process will help delay progression of CKD. The study aimed to estimate the risks of kidney failure and death prior to and after the development of kidney failure among patients with pre-existing CKD, and to identify potential prognostic factors. Method Data were obtained from patients with CKD from Ubon Ratchathani province, Thailand from 1997 to 2011. The probability of each transition (i.e., CKD➔death (T1), CKD➔kidney failure (T2), and kidney failure➔death (T3)) was estimated using a competing risk model. A parametric survival model with restricted cubic spline function was applied to assess prognostic factors. Illness-death models were constructed for the 3 transitions. Among 32,106 patients with CKD, 5576 (17.4%), 4768 (14.9%), and 3056 (9.5%) respectively moved through T1, T2, and T3. Results Diabetics had 22.6%, 13.5%, and 60.7% higher risks of T1, T2, and T3 than non-diabetics respectively (p

Antioxidants and fatty acids are associated with depression and inflammation, and inflammation appears to predict depression risk; hence, the associations between these nutrients and depression may be mediated by inflammation. We hypothesized that inflammatory markers interleukin (IL)-6 and C-reactive protein (CRP) mediate the associations between antioxidant and fatty acid intakes, and depression. Participants were from the Hunter Community Study, a longitudinal cohort of adults aged 55-85 years. Dietary intake was assessed using the Older Australian's Food Frequency Questionnaire. Fasting blood samples were drawn for analysis of nutrient and inflammatory biomarkers. Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies-Depression scale at baseline and at 5-year follow-up. Linear mixed models were used to investigate longitudinal associations between dietary intakes and depression, and mediation analyses were carried out to determine if IL-6 and/or CRP were the mediators. Analyses were conducted on men and women separately and adjusted for potential confounders. Fruit and monounsaturated fat intakes were negatively associated with depression, whereas total fat and saturated fat intakes were positively associated with depression in both sexes. Omega-3 polyunsaturated fat was inversely associated with depression in men only. IL-6 was a significant mediator of the association between fruits with low carotenoid content and depression in women. CRP significantly mediated the relationship between total fat, saturated fat, and monounsaturated fat intakes and depression in women, and saturated fat intake and depression in men. Our findings raise the possibility that the association between fatty acid intake and depression is partially mediated by inflammatory markers.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.

The authors performed a systematic review of the association of complement component 2(C2)/complement factor B (CFB) gene polymorphisms with age-related macular degeneration (AMD). In total, data from 19 studies published between 2006 and 2011 were pooled for 4 polymorphisms: rs9332739 and rs547154 in the C2 gene and rs4151667 and rs641153 in the CFB gene. Data extraction and assessments for risk of bias were independently performed by 2 reviewers. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6% for all polymorphisms, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI): 0.46, 0.65) and 0.47 (95% CI: 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI: 0.45, 0.64) and 0.41 (95% CI: 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0%–6.0%. This meta-analysis provides a robust estimate of the protective association of C2/CFB with AMD.

Review /Objective To synthesise the best available evidence on the association between dietary pattern and the development of Type 2 diabetes (T2DM). Inclusion Criteria Type of Participants The population of interest for this review will consist of adults without history of type2 diabetes mellitus at the baseline of the study. Phenomenon of Interest The review will aim to determine the relationship (if any) between overall dietary patterns, and the risk of developing type 2 diabetes. Type of outcome The outcome of interest in this review is the strength and direction of the association (if any) between dietary pattern and the risk (incidence) of developing type 2 diabetes. The relationships will be measured by measurement of association, such as the relative risk (RR) or odds ratio (OR).

Review Objective To synthesise the best available evidence on the association between macronutrients intake and the development of Type 2 diabetes mellitus. Inclusion Criteria Type of Participants The population of increase in this review will be adults aged 18 or over without history of type2 diabetes mellitus in the baseline of the study. Phenomenon of Interest The review will aim to determine the relationship (if any) between macronutrients including subtypes of macronutrients: fat (saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), trans fatty acids (TFA) and long chain omega-3 (n-3) fatty acids) carbohydrates and protein (animal and vegetable protein), and the risk of developing type 2 diabetes. Type of outcome The outcome of interest in this review is the strength and direction of the association (if any) between dietary macronutrients and the risk (incidence) of developing type 2 diabetes. The relationships will be measured by measurement of association, such as the relative risk (RR) or odds ratio (OR).

Genome-Wide Association Study Identifies Two Novel Genomic Regions in Irritable Bowel Syndrome

Objectives: The incidence of endometrial cancer has recently increased substantially and studies have shown that altered levels of exogenous and endogenous hormones are associated with individual variation in endometrial cancer risk. The environmental and reproductive risk factors that influence these hormones are well known, however, genetic variants involved in hormone biosynthesis and estrogen metabolism have not been well established in endometrial cancer. Methods: To determine whether polymorphisms in genes of the steroid hormone biosynthesis and metabolism pathways are associated with endometrial cancer risk, 28 polymorphisms in 18 genes were genotyped in 191 endometrial cancer cases and 291 healthy controls. Results: The GSTM1 deletion and the variant (GG) genotype of the CYP1B1 rs1800440 polymorphism were associated with a decreased risk of developing endometrial cancer. Furthermore, combinations of haplotypes in CYP1A1, CYP1B1 and GSTs were associated with a decreased risk. The analysis of the repeat polymorphisms revealed that women with the long repeat allele length of the ESR1 (GT)n repeat polymorphism were at an increased risk of developing endometrial cancer. Conversely, women with two long repeat length alleles of the (CAG)n repeat polymorphism in the AR correlated with a decrease in endometrial cancer risk compared to women with one or two alleles with the short repeat length. Conclusions: The findings are consistent with our hypothesis that variability in genes involved in steroidogenesis and estrogen metabolism may alter the risk of developing endometrial cancer, suggesting that they may be useful as biomarkers for genetic susceptibility to endometrial cancer.

Hearing loss is highly prevalent in older people, affecting around 25 percent of American adults aged 65 to 74 and 50 percent of those aged 75 and older (NIH, 2016). The number of people affected by this disability continues to rise, as does the associated cost that affects individuals in terms of their quality of life and society. Several co-morbidities often accompany age-related hearing loss, including endothelial dysfunction and increased cardiovascular risk, and there is evidence of significantly higher rates of cardiovascular disease among people with hearing loss (Circulation. 2016;134:A19010). Hearing loss has significantly negative effects on quality of life, mental health, and physical function. Therefore, finding potentially modifiable risk factors and markers for hearing loss should be a public health priority. Our world-first study investigated the association between hearing loss and circulating markers for endothelial dysfunction that are potentially modifiable through lifestyle and drug interventions (Otol Neurotol. 2018 Apr;39(4):e280).