Revisiting the Concentration Curves and Indices as Useful Tools for Assessing Relative and Attributable Risks

Accurate assessment of the association between exposure and response is central to identifying causality in medical research. The concentration index has been commonly used to study income inequality and socioeconomic related health inequality. This study generalizes applications of the concentration index to measure the relative and attributable risks for describing exposure-response relationships in medical research. Based on cumulative distribution functions, a new measure of correlation is proposed to quantify the association between exposure and response. The connection between the new and existing measures is discussed. The method enables the semi-parametric analysis of overall association and disparity by risk factors. Both grouped and continuous data situations are considered with two applications. The first example illustrates the relationships between the concentration index, relative and attributable risks. The second example demonstrates how the concentration index can assist in evaluating the association between the radiation dose and the incidence of leukaemia. Logistic regression based decomposition is compared with the new approach. We found the concentration index analysis useful not only for examining socioeconomic determinants of health, but also for assessing quantitative relations between exposures to health risks and ill-health outcomes

An Investigation of the Significance of Residual Confounding Effect

Background: Observational studies are commonly conducted in health research. However, due to their lack of randomization, the estimated associations between the outcome and the exposure can be affected by unmeasured confounding factors. It is important to determine how likely a significant association observed between an outcome variable and a noncausally related exposure may be introduced by residual confounding factors. Methods: A simulation approach is developed based on the sufficient cause model to test the likelihood of significant associations observed between a noncausally related exposure and the outcome. Results: Based on the estimates from all 500 replicates, the association between the exposure and the outcome is found to be significant in 386 (77%) replicates when all confounders (component causes) are controlled for in the model. However, when a subset of real component causes and some noncausal factors are controlled for in the model, the association between exposure and the outcome becomes significant in 487 (97%) replicates. Conclusion: Even when all confounding factors are known and controlled for using conventional multivariate analysis, the observed association between exposure and outcome can still be dominated by residual confounding effects. Therefore, an observed significant association apparently provides limited evidence for a causal relationship

A Proxy Outcome Approach for Causal Effect in Observational Studies: A Simulation Study

Background: Known and unknown/unmeasured risk factors are the main sources of confounding effects in observational studies and can lead to false observations of elevated protective or hazardous effects. In this study, we investigate an alternative approach of analysis that is operated on field-specific knowledge rather than pure statistical assumptions. Method: The proposed approach introduces a proxy outcome into the estimation system. A proxy outcome possesses the following characteristics: (i) the exposure of interest is not a cause for the proxy outcome; (ii) causes of the proxy outcome and the study outcome are subsets of a collection of correlated variables. Based on these two conditions, the confounding-effect-driven association between the exposure and proxy outcome can then be measured and used as a proxy estimate for the effects of unknown/unmeasured confounders on the outcome of interest. Performance of this approach is tested by a simulation study, whereby 500 different scenarios are generated, with the causal factors of a proxy outcome and a study outcome being partly overlapped under low-to-moderate correlations. Results: The simulation results demonstrate that the conventional approach only led to a correct conclusion in 21% of the 500 scenarios, as compared to 72.2% for the alternative approach. Conclusion: The proposed method can be applied in observational studies in social science and health research that evaluates the health impact of behaviour and mental health problems

Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice

Elevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. Here, we evaluated the involvement of interactions between neuronal nitric oxide synthase (nNOS) and the nitric oxide synthase 1 adaptor protein (NOS1AP) in pronociceptive signaling and neuropathic pain. TAT-GESV, a peptide inhibitor of the nNOS-NOS1AP complex, disrupted the in vitro binding between nNOS and its downstream protein partner NOS1AP but not its upstream protein partner postsynaptic density 95 kDa (PSD95). Putative inactive peptides (TAT-cp4GESV and TAT-GESVΔ1) failed to do so. Only the active peptide protected primary cortical neurons from glutamate/glycine-induced excitotoxicity. TAT-GESV, administered intrathecally (i.t.), suppressed mechanical and cold allodynia induced by either the chemotherapeutic agent paclitaxel or a traumatic nerve injury induced by partial sciatic nerve ligation. TAT-GESV also blocked the paclitaxel-induced phosphorylation at Ser15 of p53, a substrate of p38 MAPK. Finally, TAT-GESV (i.t.) did not induce NMDAR-mediated motor ataxia in the rotarod test and did not alter basal nociceptive thresholds in the radiant heat tail-flick test. These observations support the hypothesis that antiallodynic efficacy of an nNOS-NOS1AP disruptor may result, at least in part, from blockade of p38 MAPK-mediated downstream effects. Our studies demonstrate, for the first time, that disrupting nNOS-NOS1AP protein-protein interactions attenuates mechanistically distinct forms of neuropathic pain without unwanted motor ataxic effects of NMDAR antagonists

Habitual physical activity reduces risk of ovarian cancer: a case–control Study in Southern China

Objective: To ascertain the relationship between habitual physical activity and the risk of ovarian cancer among southern Chinese women.Method: A case–control study was conducted in Guangzhou, Guangdong Province, during 2006–2008. Information on physical activity exposure and lifestyle characteristics was obtained from 500 incident ovarian cancer patients and 500 hospital-based controls (mean age 59 years) using a validated and reliable questionnaire. Logistic regression analyses were performed to assess the association between physical activity levels and the ovarian cancer risk.Results: The control subjects reported significantly longer duration of strenuous sports and moderate activity in daily life than the ovarian cancer patients. Increased engagements in such leisure time activities were associated with reduced cancer risks after adjustment for confounding factors. A significant inverse dose–response relationship was also found for total physical activity exposure, with adjusted odds ratio 0.49 (95% confidence interval 0.35–0.68) for women engaged in 23 or more metabolic equivalent tasks (MET)-hours per week relative to those less than 12 MET-hours per week.Conclusion: The study provided evidence of an inverse association between habitual physical activity and the risk of ovarian cancer, which is important for the promotion and encouragement of leisure time exercise activities to prevent the disease

Caffeine intake and the risk of chronic obstructive pulmonary disease in Japanese adults

Background: To investigate the association between caffeine intake and the risk of developing chronic obstructive pulmonary disease (COPD) among Japanese older adults, a case–control study was conducted in central Japan. Methods: A total of 277 patients with COPD aged 50 to 75 years were referred by respiratory physicians, while 340 controls were recruited from the community. All participants had their disease status confirmed by spirometry. Information on habitual caffeine intake, demographic, and lifestyle characteristics was obtained by face-to-face interview using a validated questionnaire. Results: The COPD patients drank more coffee and had a higher mean caffeine intake (311.3, SD 176.2mg/day) than the control group (278.4, SD 188.1 mg/day), p = 0.03. Relative to nondrinkers, the risk of COPD apparently increased for those drinking at least two cups of coffee daily (adjusted odds ratio 1.58, 95% confidence interval [CI] 0.93 to 2.71). Similarly, total caffeine intake was associated with the prevalence of COPD—the adjusted odds ratio being 1.30 (95% CI 1.09 to 2.12) for consuming over 312mg/day when compared to a low intake of less than 184mg/day. Conclusions: The epidemiological evidence suggested a positive association between caffeine intake and the development of COPD in Japanese adults. Further study of the effect of caffeine on lung function and the risk of COPD should be undertaken

Effect of Cement/Wood Ratios and Wood Storage Conditions on Hydration Temperature, Hydration Time, and Compressive Strength of Wood-Cement Mixtures

This study investigated the effect of cement/wood ratios and wood storage conditions on hydration temperature, hydration time, and compressive strength of wood-cement mixtures made from six wood species: southern pine, white oak, southern red oak, yellow-poplar, sweetgum, and hickory. Cement/wood ratios varied from 13/1 to 4/1. Wood storage conditions consisted of air-dried and cold-stored wood. Results indicate that hydration temperature was drastically reduced, hydration time was prolonged, and compressive strength was reduced as cement/wood ratio was decreased. This effect was more pronounced for hardwood species and at lower cement/wood ratios. Cold storage of wood slightly increased hydration temperature and shortened hydration time of white oak and sweetgum but did not have any beneficial effect on the other four species. Results also indicate that mixtures with high cement/wood ratios used traditionally in laboratory for research purposes may not truly reflect the wood-cement compatibility at lower cement/wood ratios used in commercial production

Risk of bias and methodological issues in randomised controlled trials of acupuncture for knee osteoarthritis: A cross-sectional study

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objective To assess risk of bias and to investigate methodological issues concerning the design, conduct and analysis of randomised controlled trials (RCTs) testing acupuncture for knee osteoarthritis (KOA). Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials and four major Chinese databases were searched for RCTs that investigated the effect of acupuncture for KOA. The Cochrane tool was used to examine the risk of bias of eligible RCTs. Their methodological details were examined using a standardised and pilot-Tested questionnaire of 48 items, together with the association between four predefined factors and important methodological quality indicators. Results A total of 248 RCTs were eligible, of which 39 (15.7%) used computer-generated randomisation sequence. Of the 31 (12.5%) trials that stated the allocation concealment, only one used central randomisation. Twenty-five (10.1%) trials mentioned that their acupuncture procedures were standardised, but only 18 (7.3%) specified how the standardisation was achieved. The great majority of trials (n=233, 94%) stated that blinding was in place, but 204 (87.6%) did not clarify who was blinded. Only 27 (10.9%) trials specified the primary outcome, for which 7 used intention-To-Treat analysis. Only 17 (6.9%) trials included details on sample size calculation; none preplanned an interim analysis and associated stopping rule. In total, 46 (18.5%) trials explicitly stated that loss to follow-up occurred, but only 6 (2.4%) provided some information to deal with the issue. No trials prespecified, conducted or reported any subgroup or adjusted analysis for the primary outcome. Conclusion The overall risk of bias was high among published RCTs testing acupuncture for KOA. Methodological limitations were present in many important aspects of design, conduct and analyses. These findings inform the development of evidence-based methodological guidance for future trials assessing the effect of acupuncture for KOA

Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics.

Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) and generating nitric oxide (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS to NMDARs, the PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 µM) and ZL006 (EC50: 12.88 µM) directly inhibited binding of purified PSD95 and nNOS proteins in AlphaScreen without altering binding of PSD95 to ErbB4. Bot

Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer

Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. Anne Y Warren research time funded by: Cambridge Biomedical Research Centre.Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.Publisher PDFPeer reviewe