Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Young at heart, old at work? Relations between age, (meta-)stereotypes, self-categorization, and retirement attitudes

The aims of this study were to examine how workers' negative age stereotypes (i.e., denying older workers' ability to develop) and negative meta-stereotypes (i.e., beliefs that the majority of colleagues feel negative about older workers) are related to their attitudes towards retirement (i.e., occupational future time perspective and intention to retire), and whether the strength of these relationships is influenced by workers' self-categorization as an “older” person. Results of a study among Dutch taxi drivers provided mixed support for the hypotheses. Negative meta-stereotypes, but not negative age stereotypes, were associated with fewer perceived opportunities until retirement and, in turn, a stronger intention to retire. Self-categorization moderated the relationships between negative age (meta-)stereotypes and occupational future time perspective. However, contrary to expectations, the relations were stronger among workers with a low self-categorization as an older person in comparison with workers with a high self-categorization in this regard. Overall, results highlight the importance of psychosocial processes in the study of retirement intentions and their antecedents.

Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: Systematic review and meta-analysis

Objective To assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis. Data sources Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection - Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals. - Population: sedentary individuals with or without medical diagnosis. - Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. - Comparators: usual care, no intervention, or alternative exercise referral schemes. Results Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference −0.82, −1.28 to −0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

Republished research: Effect of exercise referral schemes in primary care on physical activity and improving health outcomes: systematic review and meta-analysis

Study question Can exercise referral schemes improve health outcomes in individuals with or without pre-existing conditions? Summary answer We found weak evidence of a short term increase in physical activity and reduction in levels of depression in sedentary individuals after participation in exercise referral schemes, compared with after usual care. What is known and what this paper adds Exercise referral schemes are commonly used in primary care to promote physical activity. Evidence indicating a health benefit of these schemes is limited, so their value in primary care remains to be ascertained.

Exercise and vascular function in child obesity: A meta-analysis

CONTEXT: Conduit artery flow-mediated dilation (FMD) is a noninvasive index of preclinical atherosclerosis in humans. Exercise interventions can improve FMD in both healthy and clinical populations. OBJECTIVE: This systematic review and meta-analysis aimed to summarize the effect of exercise training on FMD in overweight and obese children and adolescents as well as investigate the role of cardiorespiratory fitness (peak oxygen consumption [Vo2peak]) on effects observed. DATA SOURCES: PubMed, Medline, Embase, and Cinahl databases were searched from the earliest available date to February 2015. STUDY SELECTION: Studies of children and/or adolescents who were overweight or obese were included. DATA EXTRACTION: Standardized data extraction forms were used for patient and intervention characteristics, control/comparator groups, and key outcomes. Procedural quality of the studies was assessed using a modified version of the Physiotherapy Evidence Base Database scale. RESULTS: A meta-analysis involving 219 participants compared the mean difference of pre- versus postintervention vascular function (FMD) and Vo2peak between an exercise training intervention and a control condition. There was a significantly greater improvement in FMD (mean difference 1.54%, P < .05) and Vo2peak (mean difference 3.64 mL/kg/min, P < .05) after exercise training compared with controls. LIMITATIONS: Given the diversity of exercise prescriptions, participant characteristics, and FMD measurement protocols, varying FMD effect size was noted between trials. CONCLUSIONS: Exercise training improves vascular function in overweight and obese children, as indicated by enhanced FMD. Further research is required to establish the optimum exercise program for maintenance of healthy vascular function in this at-risk pediatric population.

The effectiveness of SMS reminders on appointment attendance: A meta-analysis

Objective To identify the efficacy of short message service (SMS) reminders in health care appointment attendance. Materials and Methods A systematic review was undertaken to identify studies published between 2005 and 2015 that compared the attendance rates of patients receiving SMS reminders compared to patients not receiving a reminder. Each article was examined for information regarding the study design, sample size, population demographics and intervention methods. A meta-analysis was used to calculate a pooled estimate odds ratio. Results Twenty-eight (28) studies were included in the review, including 13 (46%) randomized controlled trials. The pooled odds ratio of the randomized control trials was 1.62 (1.35 – 1.94). Half of the studies reviewed sent the reminder within 48 hour prior to the appointment time, yet no significant subgroups differences with respect to participant age, SMS timing, rate or type, setting or specialty was detectable. Discussion All studies, except one with a small sample size, demonstrated a positive OR, indicating SMS reminders were an effective means of improving appointment attendance. There was no significant difference in OR when controlling for when the SMS was sent, the frequency of the reminders or the content of the reminder. Conclusion SMS appointment reminders are an effective and operative method in improving appointment attendance in a health care setting and this effectiveness has improved over the past five years. Further research is required to identify the optimal SMS reminder timing and frequency, specifically in relation to the length of time since the appointment.

A retrospective study of vase life determinants for cut Acacia holosericea foliage

Short and variable vase life of cut Acacia holosericea foliage stems limits its commercial potential. Retrospective evaluation of factors affecting the vase life of this cut foliage line was assessed using primary data collected from 30 individual experiments. These data had been collected by four different researchers over 17 months, from late Summer to mid Winter across two consecutive years. Vase life data of cut A. holosericea stems held in deionised water (DIW) was analysed for general vase life variation and to define the most influential factor affecting vase life of the cut stems. Meanwhile, vase life of cut stems exposed to various chemical and physical postharvest treatments was analysed using meta-analysis to evaluate their efficacy in prolonging vase life of the stems. The overall mean vase life (±standard deviation) of cut A. holosericea stems was 6.4 ± 1.2 days (n = 30 trials). Longer vase life of ≥7 days was obtained from cut stems harvested at vegetative and flowering stage, which was between Summer and Autumn. Cut stems harvested at fruiting stage, between Winter and Spring displayed shorter vase life of ≤5.5 days. Mixed model analysis indicated that vase life variation of the cut stems was mostly determined by season (P < 0.001). In averaged, postharvest treatments increased vase life 1.4-fold compared to stems in DIW, with 68.32% had a large positive treatment effect size (d). Among the treatments, nano silver (NS) and copper (Cu2+) were the most beneficial to vase life. Retrospective analysis was found to be beneficial for identifying conditions and targeting practices to maximise the vase life of cut A. holosericea and, potentially for other species.

Family-based interventions in preventing children and adolescents from using tobacco: A systematic review and meta-analysis

- Background Tobacco is the main preventable cause of death and disease worldwide. Adolescent smoking is increasing in many countries with poorer countries following the earlier experiences of affluent countries. Preventing adolescents starting smoking is crucial to decreasing tobacco-related illness. - Objective To assess effectiveness of family-based interventions alone and combined with school-based interventions to prevent children and adolescents from initiating tobacco use. - Data Sources 14 bibliographic databases and the Internet, journals hand-searched, experts consulted. - Study Eligibility Criteria, Participants, and Interventions Randomised controlled trials (RCTs) with children or adolescents and families, interventions to prevent starting tobacco use, follow-up ≥ 6 months. - Study Appraisal/Synthesis methods Abstracts/titles independently assessed and data independently entered by two authors. Risk-of-bias assessed with the Cochrane Risk-of-Bias tool. - Results Twenty-seven RCTs were included. Nine trials of never-smokers compared to a control provided data for meta-analysis. Family intervention trials had significantly fewer students who started smoking. Meta-analysis of twoRCTs of combined family and school interventions compared to school only, showed additional significant benefit. The common feature of effective high intensity interventions was encouraging authoritative parenting. - Limitations Only 14 RCTs provided data for meta-analysis (about 1/3 of participants). Of the 13 RCTs which did not provide data for meta-analysis eight compared a family intervention to no intervention and one found significant effects, and five compared a family + school intervention to a school intervention and none found additional significant effects. - Conclusions and Implications of Key Findings There is moderate quality evidence that family-based interventions prevent children and adolescents starting to smoke.

Identification of IDUA and WNT16 phosphorylation-related non-synonymous polymorphisms for bone mineral density in meta-analyses of genome-wide association studies

Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10–6 (0.05/9593) and 1.00 × 10–4, respectively. In stage 2, nine stage 1–discovered phosSNPs (based on α = 1.00 × 10–4) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10–3, 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10–10, p = 5.26 × 10–10, and p = 3.01 × 10–10, respectively) and HIP-BMD (p = 3.26 × 10–6, p = 1.97 × 10–6, and p = 1.63 × 10–12, respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants. © 2015 American Society for Bone and Mineral Research.

Multistage genome-wide association meta-analyses identified two new loci for bone mineral density

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10-8) level: 14q24.2 (rs227425, P-value 3.98 × 10-13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10-9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n 5 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis. © The Author 2013. Published by Oxford University Press.

A retrospective case-control study on the prescribing practices of antidepressants administered to cancer patients and non-cancer patients in Australia

Comorbidity of depression risks is common among cancer patients. The pharmacological treatment of depression is antidepressants. However, antidepressants may interact with anticancer drugs or cause adverse reactions. The prescription practice of antidepressants to cancer patients in Australia is not well documented. Our systematic review and meta-analysis identified that the overall prevalence rate of antidepressants was 15.6% varied widely by world-region and gender. A retrospective case-control study was undertaken to determine the recent prescription practice of antidepressants to cancer and non-cancer patients in Australia. Mirtazapine was the highly prescribed antidepressants to cases, whereas Desvenlafaxine was prescribed to controls. Considerable variation in the prescribing patterns of antidepressants was identified. Prospective studies are needed to ascertain whether patients are being treated optimally.

Prevalence of foot disease and risk factors in general inpatient populations: A systematic review and meta-analysis

Objective: To systematically review studies reporting the prevalence in general adult inpatient populations of foot disease disorders (foot wounds, foot infections, collective ‘foot disease’) and risk factors (peripheral arterial disease (PAD), peripheral neuropathy (PN), foot deformity). Methods: A systematic review of studies published between 1980 and 2013 was undertaken using electronic databases (MEDLINE, EMBASE and CINAHL). Keywords and synonyms relating to prevalence, inpatients, foot disease disorders and risk factors were used. Studies reporting foot disease or risk factor prevalence data in general inpatient populations were included. Included study's reference lists and citations were searched and experts consulted to identify additional relevant studies. 2 authors, blinded to each other, assessed the methodological quality of included studies. Applicable data were extracted by 1 author and checked by a second author. Prevalence proportions and SEs were calculated for all included studies. Pooled prevalence estimates were calculated using random-effects models where 3 eligible studies were available. Results: Of the 4972 studies initially identified, 78 studies reporting 84 different cohorts (total 60 231 517 participants) were included. Foot disease prevalence included: foot wounds 0.01–13.5% (70 cohorts), foot infections 0.05–6.4% (7 cohorts), collective foot disease 0.2–11.9% (12 cohorts). Risk factor prevalence included: PAD 0.01–36.0% (10 cohorts), PN 0.003–2.8% (6 cohorts), foot deformity was not reported. Pooled prevalence estimates were only able to be calculated for pressure ulcer-related foot wounds 4.6% (95% CI 3.7% to 5.4%)), diabetes-related foot wounds 2.4% (1.5% to 3.4%), diabetes-related foot infections 3.4% (0.2% to 6.5%), diabetes-related foot disease 4.7% (0.3% to 9.2%). Heterogeneity was high in all pooled estimates (I2=94.2–97.8%, p<0.001). Conclusions: This review found high heterogeneity, yet suggests foot disease was present in 1 in every 20 inpatients and a major risk factor in 1 in 3 inpatients. These findings are likely an underestimate and more robust studies are required to provide more precise estimates.

The influence of OLR1 and PCSK9 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis

It has been reported that both OLR1 and PCSK9 genes are related to various vascular diseases such as atherosclerosis, cardiovascular disease, peripheral artery disease and stroke, in particular ischemic stroke. The prevalence of PCSK9 rs505151 and OLR1 rs11053646 variants in ischemic stroke were 0.005 and 0.116, respectively. However, to date, association between OLR1 rs11053646 and PCSK9 rs505151 polymorphisms and the risk of ischemic stroke remains unclear and inconclusive. Therefore, this first meta-analysis was carried out to clarify the presumed influence of genetic polymorphisms on ischemic stroke, by analyzing the complete coverage of all relevant studies. All eligible case-control and cohort studies that met the search term were retrieved in multiple scientific databases. Data of interest such as demographic data and genotyping methods were extracted from each study, and the meta-analysis was performed using RevMan 5.3 and Metafor R 3.2.1. The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using both fixed- and random-effect models. A total of seven case-control studies encompassing 1897 ischemic stroke cases and 2119 healthy controls were critically evaluated. Pooled results from the genetic models indicated that OLR1 rs11053646 dominant (OR=1.33. 95%CI:1.11-1.58) and co-dominant models (OR=1.24, 95%CI:1.02-1.51) were significantly associated with ischemic stroke. For PCSK9 rs505151 polymorphism, the OR of co-dominant model (OR=1.36, 95%CI:1.01-1.58) was found to be higher among ischemic stroke patients. In conclusion, the current meta-analysis highlighted that variant allele of OLR1 rs11053646 G>C and PCSK9 rs505151 A>G may contribute to the susceptibility risk of ischemic stroke.

The unusual formation of methyl alpha-(5,6-dimethoxycarbonyl-2,3-dimethoxyazepin-7-ylidene)-alpha-[5-methoxycarbonyl-2,3-dimethoxypyrid-6-yl)acetate during the pyrolysis of ''azido-meta-hemipinate'' - First example of a reaction involving a concomitant ring expansion and ring extrusion

he ortho methoxycarbonyl substituent constitutes a sole exception in the ring closure reactions of ortho substituted aryl azides, as it provides no rate acceleration to this reaction. Pyrolysis of ''azido-meta-hemipinate'', an aryl azide containing such a substituent, led us to the title compound, a new azepinylidenepyridylacetic ester, whose structure has been established unambiguously by a single crystal X-ray diffraction study. This is the first report of a reaction involving both a ring expansion to an azaheptafulvalene and a ring extrusion to a pyridyl ring residue.