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Study Question: Can additional genetic variants for circulating anti-Müllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women?Summary Answer: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7.What Is Known Already: AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown.Study Design, Size, Duration: We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts.Participants/materials, Setting, Methods: In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 × 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses.Main Results and the Role Of Chance: We identified four loci associated with AMH levels at P < 5 × 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored.Large Scale Data: The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/).Limitations, Reasons For Caution: Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels.Wider Implications Of the Findings: Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing.Study Funding/competing Interest(s): Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Ministère de l'Économie, de la Science et de l'Innovation du Québec' through Genome Québec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests. [ABSTRACT FROM AUTHOR]

Context: Dietary fiber intake may relate to bone health.Objective: To investigate whether dietary fiber intake is associated with bone mineral density (BMD), and the modification effect of genetic variations related to gut microbiota-derived short-chain fatty acids (SCFAs).Design: The associations of dietary fiber intake with estimated BMD derived from heel ultrasound and fractures were assessed in 224 630 and 384 134 participants from the UK Biobank.Setting: UK Biobank.Main Outcome Measures: Estimated BMD derived from heel ultrasound.Results: Higher dietary fiber intake (per standard deviation) was significantly associated with higher heel-BMD (β [standard error] = 0.0047 [0.0003], P = 1.10 × 10-54). Similarly significant associations were observed for all the fiber subtypes including cereal, fruit (dried and raw), and vegetable (cooked and raw) (all P < .05). A positive association was found in both women and men but more marked among men except for dietary fiber in cooked vegetables (all Pinteraction < .05). A protective association was found between dietary fiber intake and hip fracture (hazard ratio, 95% confidence interval: 0.94, 0.89-0.99; P = 3.0 × 10-2). In addition, the association between dietary fiber and heel BMD was modified by genetically determined SCFA propionate production (Pinteraction = 5.1 × 10-3). The protective association between dietary fiber and heel BMD was more pronounced among participants with lower genetically determined propionate production.Conclusions: Our results indicate that greater intakes of total dietary fiber and subtypes from various food sources are associated with higher heel-BMD. Participants with lower genetically determined propionate production may benefit more from taking more dietary fiber. [ABSTRACT FROM AUTHOR]

Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients. [ABSTRACT FROM AUTHOR]

Background: We aimed to compare the intraocular pressure (IOP) measurements by a dynamic Scheimpflug analyzer (Corvis ST), a non-contact tonometer, and an ocular response analyzer after hyperopic small-incision lenticule extraction (SMILE).Methods: Thirteen patients who underwent hyperopic SMILE in one eye were enrolled prospectively. IOP and corneal biomechanical parameters were measured preoperatively and at 1 week, 1 month, and 3 months postoperatively with a non-contact tonometer (IOPNCT), Corvis ST (biomechanical corrected IOP [bIOP]), and ocular response analyzer (Goldmann-correlated intraocular pressure [IOPg] and cornea compensated IOP [IOPcc]). A linear mixed model was used to compare the IOPs and biomechanical values among methods at each time point.Results: IOPNCT, IOPg, and IOPcc dropped significantly after surgery, with the amplitude being 3.15 ± 0.48 mmHg, 5.49 ± 0.94 mmHg, and 4.34 ± 0.97 mmHg, respectively, at the last follow-up visit. IOPNCT decreased by 0.11 ± 0.06 mmHg per μm of excised central corneal thickness. bIOP did not change significantly after surgery. Preoperatively, no difference was found among the four measurements (P > 0.05). Postoperatively, IOPNCT and bIOP were higher than IOPg and IOPcc. bIOP was independent of cornea thickness at last follow-up visit, whereas it correlated significantly with corneal biomechanics similar to the other three IOP values.Conclusion: bIOP is a relative accurate measure of IOP after hyperopic SMILE. [ABSTRACT FROM AUTHOR]

Background: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.Methods and Findings: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.Conclusions: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the freeze-all policy ensures a higher efficacy in terms of cumulative live birth rate (CLBR) in comparison with a conventional fresh/frozen embryo transfer (ET) approach in patients with normal ovarian response.Design: Retrospective, matched, multicenter cohort study.Setting: Private IVF centers.Patient(s): This study analyzed 564 completed IVF cycles in which an average of 12-18 oocytes were retrieved. In 435 cycles the conventional strategy was applied, with initial ET followed by frozen embryo replacements, whereas in 129 cycles the freeze-all policy was performed, with elective cryopreservation and deferred use of all viable embryos.Intervention(s): None.Main Outcome Measure(s): The primary endpoint was CLBR. The secondary endpoint was cumulative clinical pregnancy rate.Result(s): Overall, statistically comparable CLBRs were achieved in the fresh/frozen and freeze-all groups (45.5% vs. 53.5%). Stratification of data for age and number of retrieved oocytes confirmed the absence of differences between the two groups. In a subanalysis in which the day of ET and cryopreservation were taken into account, a similar outcome was achieved in cleavage-stage groups (45.6% vs. 46.4%), whereas when ET was performed at the blastocyst stage the CLBR was significantly higher in the freeze-all group (45.3% vs. 66.7%).Conclusion(s): Our CLBR analysis indicates that clinical performance of the freeze-all policy is equivalent to that of the conventional strategy when ET is carried out at the cleavage stage. However, it seems to be superior if associated with cryopreservation and transfer at the blastocyst stage. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to quantify the extent to which apparent movements of the posterior superior iliac spine and sacral base areas Gillet sacroiliac motion testing were related to (a) degree of hip flexion and (b) the examiner's palpatory pressure. Methods: A preliminary exploratory study quantified relative PSIS/S2 displacements in 10 sacroiliac joints among 5 asymptomatic subjects at 10° increments of hip flexion from 0-90°. A comprehensive follow-up asymptomatic study quantified PSIS/S2 displacements at 0° vs. 30° vs. 90° hip flexion, and for light vs. firm pressure at 30° hip flexion. Displacements measured in pixels on digital photographs were transformed to mm. Mean differences for the various test conditions were evaluated for statistical significance using paired t-testing and Wilcoxon signed rank test. Results: With light pressure, the left PSIS moved caudal for hip flexion ≤30° during right-legged stance, whereas the right PSIS moved cephalad relative to the sacral base. For hip flexion =90°, both PSISs moved cephalad. The use of firm palpatory pressure abolished the initial caudal movement of the left PSIS, as well as differences in the amount of cephalad PSIS movement at 30° vs. 90° hip flexion. Conclusions: The results are consistent with there being left-right differences in gluteus medius and biceps femoris activation among asymptomatic individuals that result in different balancing strategies during one-legged stance. This may create the appearance of relative PSIS/SB displacement, even though the results of Gillet testing can be wholly or partially explained by pelvic obliquity owing to muscle function asymmetry. This study questions the validity of the upright Gillet test for sacroiliac motion. [ABSTRACT FROM AUTHOR]

Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R2 = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R2 = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management. [ABSTRACT FROM AUTHOR]

Aims To evaluate the association of cumulative blood pressure (BP) from young adulthood to middle age with left atrial (LA) structure/function as assessed by three-dimensional echocardiography (3DE) in a large longitudinal bi-racial population study. Methods and results We conducted a prospective post hoc analysis of individuals enrolled at the Coronary Artery Risk Development in Young Adults, which is a multi-centre bi-racial cohort with 30 years of follow-up. Cumulative systolic and diastolic BP levels were defined by summing the product of average millimetres of mercury and the years between each two consecutive clinic visits over 30 years of follow-up. Multivariable linear regression analyses were used to assess the relationship between cumulative systolic and diastolic BP with 3DE LA structure and function, adjusting for demographics and traditional cardiovascular risk factors. A total of 1033 participants were included, mean age was 55.4 ± 3.5 years, 55.2% women, 43.9% blacks. Cumulative systolic BP had stronger correlations than cumulative diastolic BP. Higher cumulative systolic BP was independently associated with higher 3D LA volumes: maximum (β  = 1.74, P  = 0.004), pre-atrial contraction (β  = 1.87, P  < 0.001), minimum (β  = 0.76, P  = 0.04), total emptying (β  = 0.98, P  = 0.006), active emptying (β  = 1.12, P  < 0.001), and lower magnitude 3D LA early diastolic strain rate (β  = 0.05, P  = 0.02). Higher cumulative diastolic BP was independently associated with higher 3D LA active emptying volume (β  = 0.66, P  = 0.002), lower magnitude 3D LA early diastolic strain rate (β  = 0.05, P  = 0.004), and higher magnitude 3D LA late diastolic strain rate (β  = −0.04, P  = 0.05). Conclusion Higher cumulative BP from early adulthood throughout middle age was associated with adverse LA remodelling evaluated by 3D echocardiography. [ABSTRACT FROM AUTHOR]

Objectives: The ratio of mitral peak early diastolic filling to early diastolic mitral annular velocity (E/e') reflects diastolic cardiac function in adults. Dual-gate Doppler (DD) enables measurements of E/e' in the same heart beat. This study was designed to assess the utility of the DD method for measurement of fetal E/e' and determine reference ranges for normal fetuses.Methods: This prospective study comprised normal singleton pregnancies undergoing fetal echocardiography between 16 and 36 weeks of gestation. According to the DD method, E-wave velocity on pulsed-wave Doppler and e'-wave on tissue Doppler imaging were measured simultaneously on an apical or basal four-chamber view, and fetal E/e' was calculated. Spearman's correlation coefficient was used to assess the relationship between gestational age (GA) and E-wave and e'-wave velocities and E/e'.Results: A total of 133 pregnancies were included in this study and all E/e' measurements were successful. Significant correlation was observed between GA and both left ventricular (LV) E/e' (r s  = -0.666, P < 0.001) and right ventricular (RV) E/e' (r s  = -0.607, P < 0.001). The regression equations for bilateral E/e' were: LV-E/e' = 17.341 - 0.631GA + 0.008 × GA2 (mean ± SD, R 2  = 0.440 ± 1.333); and RV-E/e' = 19.156 - 0.794GA + 0.012GA2 (R 2  = 0.419 ± 1.329).Conclusions: Bilateral E/e' of normal fetuses, measured using the DD method, decreased with GA, which is considered to be related to myocardial maturity. DD is a useful and convenient method for evaluating fetal E/e' in order to assess diastolic function in the prenatal period. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown.Research Design and Methods: We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl.Results: A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11-1.42]) and fatal (1.49 [1.30-1.71]) CVD and with all-cause mortality (1.25 [1.11-1.40]), myocardial infarction (1.22 [1.02-1.45]), and amputations (1.36 [1.05-1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79-1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00-1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes.Conclusions: Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Cross-sectional studies suggest that coffee drinking is associated with better renal function. However, to our knowledge, no prospective study has examined its relation with the risk of end-stage renal disease (ESRD).Objective: We examined the relations between coffee, tea, soda, and total caffeine consumption and the risk of ESRD among middle-aged and older Chinese in Singapore.Methods: We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women aged 45-74 y at recruitment from 1993 to 1998. Baseline information on the consumption of caffeinated coffee and other caffeinated beverages (tea and sodas), habitual diet, medical history, and lifestyle factors was obtained via in-person interviews. The standard serving size of 1 cup was assigned as 237 mL in the questionnaire. Incident ESRD cases were identified via linkage with the nationwide registry. We used multivariable Cox regression models to estimate HRs and 95% CIs of ESRD risk associated with the consumption of caffeinated beverages, with adjustment for potential confounders.Results: After a mean follow-up of 16.8 y, 1143 cohort subjects developed ESRD. Compared with those who drank coffee less than daily, the HR (95% CI) was 0.91 (0.79, 1.05) for those who drank 1 cup of coffee/d and 0.82 (0.71, 0.96) for those who drank ≥2 cups/d (P-trend = 0.012). When stratified by sex, this association was observed in men but not in women. Compared with those who drank less than daily, the HR (95% CI) for drinking ≥2 cups/d was 0.71 (0.57, 0.87) among men and 0.97 (0.78, 1.19) among women (P-interaction = 0.03). Conversely, intakes of tea, soda, or total caffeine were not associated with the risk of ESRD in multivariable models.Conclusion: The consumption of ≥2 cups of coffee/d may reduce the risk of ESRD in the general population, especially among men. This study was registered at http://www.clinicaltrials.gov as NCT03356340. [ABSTRACT FROM AUTHOR]

Background: In many regions globally, buildings designed for harnessing heat during the cold exacerbate thermal exposures during heat waves (HWs) by maintaining elevated indoor temperatures even when high ambient temperatures have subdued. While previous experimental studies have documented the effects of ambient temperatures on cognitive function, few have observed HW effects on indoor temperatures following subjects' habitual conditions. The objective was to evaluate the differential impact of having air conditioning (AC) on cognitive function during a HW among residents of AC and non-AC buildings using a prospective observational cohort study.Methods: We followed 44 students (mean age = 20.2 years; SD = 1.8 years) from a university in the Greater Boston area, Massachusetts in the United States living in AC (n = 24) and non-AC (n = 20) buildings before, during, and after a HW. Two cognition tests were self-administered daily for a period of 12 days (July 9-July 20, 2016), the Stroop color-word test (STROOP) to assess selective attention/processing speed and a 2-digit, visual addition/subtraction test (ADD) to evaluate cognitive speed and working memory. The effect of the HW on cognitive function was evaluated using difference-in-differences (DiD) modelling.Findings: Mean indoor temperatures in the non-AC group (mean = 26.3°C; SD = 2.5°C; range = 19.6-30.4°C) were significantly higher (p < 0.001) than in the AC group (mean = 21.4°C; SD = 1.9°C; range = 17.5-25.0°C). DiD estimates show an increase in reaction time (STROOP = 13.4%, p < 0001; ADD = 13.3%, p < 0.001) and reduction in throughput (STROOP = -9.9%, p < 0.001; ADD = -6.3%, p = 0.08) during HWs among non-AC residents relative to AC residents at baseline. While ADD showed a linear relationship with indoor temperatures, STROOP was described by a U-shaped curve with linear effects below and above an optimum range (indoor temperature = 22°C-23°C), with an increase in reaction time of 16 ms/°C and 24 ms/°C for STROOP and ADD, respectively. Cognitive tests occurred right after waking, so the study is limited in that it cannot assess whether the observed effects extended during the rest of the day. Although the range of students' ages also represents a limitation of the study, the consistent findings in this young, healthy population might indicate that greater portions of the population are susceptible to the effects of extreme heat.Conclusions: Cognitive function deficits resulting from indoor thermal conditions during HWs extend beyond vulnerable populations. Our findings highlight the importance of incorporating sustainable adaptation measures in buildings to preserve educational attainment, economic productivity, and safety in light of a changing climate. [ABSTRACT FROM AUTHOR]

Background: While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality.Methods and Findings: We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55-74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of follow-up (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1-3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2-<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01-1.13) for never drinkers, 1.08 (1.03-1.13) for infrequent drinkers, 1.10 (1.02-1.18) for heavy drinkers, and 1.21 (1.13-1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible.Conclusions: The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death.Trial Registration: NCT00339495 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

Background: Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases.Methods: We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502 635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4-6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference.Results: Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77-0.81; HR, 0.95; 95% CI, 0.93-0.97; and HR, 0.68; 95% CI, 0.63-0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73-0.76; HR, 0.93; 95% CI, 0.91-0.95; and HR, 0.60; 95% CI, 0.56-0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group (Ptrend <0.001 in each genetic risk category). In particular, high levels of cardiorespiratory fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38-0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30-0.55) among individuals at high genetic risk for these diseases.Conclusions: Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases. [ABSTRACT FROM AUTHOR]

Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer-sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR-α and -β genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-α, TCR-β, or paired TCR-αβ amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Higher physical activity (PA) is associated with lower heart failure (HF) risk; however, the effect of changes in PA on HF risk is unknown.Methods: We evaluated 11 351 ARIC study (Atherosclerosis Risk in Communities) participants (mean age 60 years) who attended visit 3 (1993-1995) and did not have a history of cardiovascular disease. Exercise PA was assessed using a modified Baecke questionnaire and categorized according to American Heart Association guidelines as recommended, intermediate, or poor. We used Cox regression models to characterize the association of 6-year changes in PA between the first (1987-1989) and third ARIC visits and HF risk.Results: During a median of 19 years of follow-up, 1750 HF events occurred. Compared with those with poor activity at both visits, the lowest HF risk was seen for those with persistently recommended activity (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80). However, those whose PA increased from poor to recommended also had reduced HF risk (hazard ratio, 0.77; 95% confidence interval 0.63-0.93). Among participants with poor baseline activity, each 1 SD higher PA at 6 years (512.5 METS*minutes/week, corresponding to ≈30 minutes of brisk walking 4 times per week) was associated with significantly lower future HF risk (hazard ratio, 0.89, 95% confidence interval, 0.82-0.96).Conclusions: Although maintaining recommended activity levels is associated with the lowest HF risk, initiating and increasing PA, even in late middle age, are also linked to lower HF risk. Augmenting PA may be an important component of strategies to prevent HF. [ABSTRACT FROM AUTHOR]

Aims: To correlate the dynamics of platelet activation with the development of thromboembolic events in patients with continuous-flow left ventricular assist device (cf-LVAD).Methods and Results: The platelet activity state (PAS) assay was utilized to evaluate platelet activation in 68 cf-LVAD patients implanted with the HeartMate II (n = 15, 22%), HeartMate 3 (n = 15, 22%), or HeartWare HVAD (n = 38, 56%). PAS was measured preoperatively, early post-implant, and at long-term follow-up (1, 3, 6, 12, 18, and 24 months post-implant). PAS was also measured at the occurrence of adverse events in patients who developed thrombotic complications. Data on patient demographics, medical history, antithrombotic therapy, and coagulation parameters were also analysed. Over a median follow-up of 602 (234-942) days, PAS values did not increase over time in the overall population (P = 0.15). However, PAS measured at event was 15-fold higher in the six patients (9%) who suffered pump thrombosis (n = 2) or ischaemic stroke (n = 4) vs. the rest of the population [6.67% (5.59%-11.98%) vs. 0.45% (0.33%-0.75%); P = 0.012], despite comparable coagulation profile. Pre-implant PAS values were 4.5-fold higher in these patients [1.90% (1.24%-3.17%) vs. 0.42% (0.32%-0.72%); P = 0.006]. Neither preoperative variables nor the type of the pump or the antiplatelet strategy were associated with a higher risk of complications.Conclusions: Thrombotic events are associated with altered PAS values. Moreover, baseline elevated PAS values in patients who developed thrombotic events suggest patient-specific tendency to post-implant thromboembolic complications. Prospectively, systematic monitoring of PAS might guide the development of refined patient-tailored antithrombotic strategies and the technological improvement of LVAD design. [ABSTRACT FROM AUTHOR]

Study Question: Can a discriminant threshold be determined for human sperm DNA oxidation?Summary Answer: A discriminant threshold was found with 65.8% of 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive sperm cells and a mean intensity of fluorescence (MIF) of 552 arbitrary units.What Is Known Already: Oxidative stress is known to interfere with sperm quality and fertilizing capacity. However, current practice does not include the routine determination of oxidative DNA damage in spermatozoa; optimized consensus protocols are lacking and no thresholds of normality have been established.Study Design, Size, Duration: Intra- and inter-method comparisons between four protocols (I-IV) were conducted to determine the most relevant and efficient means of assessing human sperm 8-OHdG content. Tests of assay repeatability, specificity, sensitivity and stability were performed to validate an optimized methodology for routine diagnostic use.Participants/materials, Setting, Methods: This prospective study compared three immuno-detection methods including immunocytochemistry, fluorescence microscopy and flow cytometry. Sperm DNA oxidation for 80 patients was determined relative to semen parameters and clinical conditions, using the selected immuno-detection protocol in comparison with a commercial kit. These patients (age 35 ± 1 years: mean ± SEM) presented with normozoospermic (n = 40) or altered parameters (necro- or/and astheno- or/and teratozoospermia or/and leukocytospermia).Main Results and the Role Of Chance: Significant positive Pearson and Spearman correlations were determined for 8-OHdG values and sperm parameters using protocol III. A notable high and positive correlation was revealed for MIF with BMI and leukocyte concentration. Protocol III was the most discriminating method regarding assay repeatability, specificity, sensitivity, stability and reliability for sperm parameter alterations, in particular leukocytospermia according to parametric or non-parametric tests, effect-size determinations and factorial analysis such as principal component analysis and factor discriminant analysis. Of interest is that 39% of the subjects with 'pathological' sperm DNA oxidation values were normozoospermic.Limitations, Reasons For Caution: The oligozoospermic population was not evaluated in this study because insufficient material was available to carry out the comparisons. However, spermatozoa concentration was taken into account in the statistical analysis.Wider Implications Of the Findings: Our study is the first validation of a protocol to determine a discriminant threshold for human sperm DNA oxidation. The protocol's detection accuracy for 8-OHdG human sperm DNA residues, stability over time, and relationship to human sperm quality were demonstrated. The assay should find application in the diagnosis of male factor infertility associated with oxidative stress.Study Funding/competing Interest(s): This work was funded by institutional grants from the CNRS, INSERM and Université Clermont Auvergne (to J.R.D.) and by Clermont-Ferrand Hospital-CECOS research funds (to L.J. and F.B.). P.G., A.M., R.J.A. and J.D. are, respectively, CEO, scientific director and scientific advisors of a US-based biotech company (Celloxess, Princeton, NJ, USA) involved in preventative medicine with a focus on the generation of antioxidant oral supplements. [ABSTRACT FROM AUTHOR]

Background: Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes.Methods and Findings: Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell's C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7-3.3) to 26.2 (95% CI: 15.4-44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6-3.1) to 20.2 (95% CI: 11.8-34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5-1.7) to 8.4 (95% CI: 4.9-14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5-3.2) to 16.5 (95% CI: 7.8-35.0) and from 0.7 (95% CI: 0.4-1.2) to 2.4 (95% CI: 1.0-5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded.Conclusion: There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial activity of green tea against Staphylococcus aureus both in vitro and in vivo has been reported recently. Studies on clinical efficacy and safety of green tea as antibacterial agent against S. aureus in human cases are rare.Objectives: To evaluate the clinical effectiveness and safety of topical green tea on primary pyoderma caused by S. aureus. We also attempted to determine the minimum inhibitory concentration of green tea against S. aureus and methicillin-resistant S. aureus.Methods: Open label, prospective, placebo-controlled study included community-acquired primary pyoderma cases caused by S. aureus. Severity grading was done on a scale of 1-5. Green tea ointment 3% and placebo ointment were used. Cure was defined on the basis of negative culture and assessment of clinical improvement. Minimum inhibitory concentration was determined by agar dilution method. Data were analyzed using Statistical Package for Social Sciences (SPSS) software version 16.Results: Of the 372 patients, 250 received green tea and 122 received placebo. Multidrug-resistant S. aureus was isolated in 89.1% in green tea group and 81.1% in placebo group, respectively. Methicillin-resistant S. aureus was isolated in 24 patients. Cure was seen in 86% in green tea group and 6.6% in placebo group which was statistically very significant. The number of days for comprehensive cure in green tea group was 9.2 ± 6.4 days. All patients with methicillin-resistant S. aureus infection in the green tea group were cured. Minimum inhibitory concentration of green tea against S. aureus was 0.0265 ± 0.008 μg/ml and against methicillin-resistant S. aureus was 0.0205 ± 0.003 μg/ml.Limitations Of the Study: Comparative trial was not conducted in the same patient with different lesions; children less than seven years were not considered as the school authorities did not permit for younger children to be included in the study and true randomization and blinding of investigators were not done.Conclusions: Green tea has a significant antibacterial effect against multidrug-resistant S. aureus. Minimum inhibitory concentration of green tea is established and is promising in methicillin-resistant S. aureus infections. [ABSTRACT FROM AUTHOR]

Objectives: The annual incidence of dengue has been increasing over the last few years in Sri Lanka with seasonal epidemics. Biological control of the vector has not been part of the integrated vector control implemented by the public health authorities of Sri Lanka so far. This pilot study assessed the effectiveness of using Bacillus thuringiensis israelensis (Bti) spray to control the Aedes mosquito vector population density.Methods: Prospective controlled effectiveness study in three administrative divisions of Colombo. Study areas were selected from urban, semiurban and rural administrative divisions within the district, and they were compared with two matching controls from the same division. Test areas received three cycles of Bti spraying 1 month apart. Control areas were not sprayed with Bti. Ovitrap and larval indices were calculated at baseline and 2 weeks after each spray cycle.Results: There was a significant improvement in the adult vector population (ovitrap index) in the test areas after three spray cycles, but this effect had disappeared after 8 weeks (no residual effect). There was no consistent positive impact on larval indices (premise, container and Breteau indices) after each spray cycle.Conclusion: Bti might have a moderate impact on adult vector populations mediated via transient reductions in larval populations. However, this effect is not sustained probably due to rapid re-infestation. Bti spray, if implemented, can only play a supplementary role to other vector control methods. [ABSTRACT FROM AUTHOR]

Background: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians.Methods: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations.Results: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 ± 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 ± 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73m2.Conclusion: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population. [ABSTRACT FROM AUTHOR]

Background: Reduced lower extremity muscle strength as well as reduced lower extremity muscle pre-activity (defined as muscular activity just prior to initial ground contact) during high-risk movements are factors related to increased risk of non-contact ACL injury in adolescent female athletes. A strong relationship exists between muscle strength and muscle activity obtained during an isometric contraction, however, whether these two measures are related when muscle activity is obtained during a movement associated with a high risk of non-contact ACL injury is not known. Absence or presence of such a relationship may have implications for which training modalities to choose in the prevention of ACL injuries. Purpose: The purpose of this study was to examine the relationship between maximal muscle strength of the hip extensors, hip abductors and knee flexors and the pre-activity of these muscle groups recorded during a sidecutting maneuver (high-risk movement) in adolescent female soccer and handball athletes. Study design: Cross-sectional study. Methods: Eighty-five adolescent (age 16.9±1.2 years) female elite handball and soccer athletes were assessed for maximal hip extensor, hip abductor and knee flexor muscle strength; and muscle pre-activity (electromyography recordings over a 10 ms time interval prior to foot ground contact) of the gluteus maximus (Gmax), gluteus medius (Gmed), biceps femoris (BF) and semitendinosus (ST) during a standardized sidecutting maneuver. Results: The results of the correlation analyses demonstrated poor and statistically non-significant correlations. Maximal hip extensor force (N/kg bw) and Gmax pre-activity [rs = 0.012 (95% CI -0.202 - 0.224), p = 0.91], maximal hip abductor force (N/kg bw) and Gmed pre-activity [rs = 0.171 (95% CI -0.044 - 0.371), p = 0.11], maximal knee flexor force (N/kg bw) and BF pre-activity [rs = 0.049 (95% CI -0.166 - 0.259), p = 0.65], and maximal knee flexor force and ST pre-activity [rs = 0.085 (95% CI -0.131 - 0.293), p = 0.44]. Conclusion: In the present exploratory study, the results imply that no relationship exists between maximal lower extremity isometric muscle strength and lower extremity muscle pre-activity during sidecutting. This means that athletes with low muscle strength may not necessarily demonstrate high (or low) muscle pre-activity during sidecutting - a well-known risk movement for sustaining non-contact ACL injury. Levels of evidence: Level 3 [ABSTRACT FROM AUTHOR]

Background: African Americans suffer disproportionately from tobacco-related illness and have more difficulty quitting smoking than other racial/ethnic groups. Previous research indicates that African American treatment-seekers are high utilizers of tobacco quitlines, yet cessation rates via quitlines are lower relative to whites. The goal of the present study is to test the effectiveness of adding a culturally specific, video-based, adjunct to standard quitline care. It is hypothesized that the integration of an evidence-based intervention (Pathways to Freedom: Leading the Way to a Smoke-Free Community©; PTF) into quitline services will increase cessation and treatment engagement compared to control conditions, and that effects will be moderated by sociocultural factors (e.g., culturally specific intervention expectancies, acculturation, and ethnic identity).Methods: This study is a 3-arm semi-pragmatic randomized controlled trial (RCT). Participants will be 1050 enrollees in the North Carolina State quitline (QuitlineNC) who self-identify as African American. Usual quitline care includes up to 4 proactive quit coaching calls, website access, and two-weeks of nicotine patch therapy. Eligible study participants will be randomized to receive (1) standard quitline services plus PTF (PTF); (2) quitline services plus a standard tobacco cessation DVD (attention control); or (3) quitline services alone (usual care). Assessments will be conducted at baseline, 3 and 6-months post-enrollment. The primary outcome will be biochemically verified 7 day ppa at 6-months. Generalized linear mixed models (GLMMs) and hierarchical logistic regression will be used to assess the effects of treatment group on cessation outcomes and to test potential moderators.Discussion: This study will answer questions regarding the implementation and effectiveness of integrating a culturally specific video intervention into a real-world, population-level tobacco intervention. It will also aid our understanding of individual-difference variables that are associated with success. If an incremental benefit is found, this trial will have implications for increasing the responsiveness of tobacco quitlines for African Americans, reducing tobacco cessation disparities, and best practices for improving minority health. In addition, the PTF intervention has the potential for widespread disseminated through quitlines, which are available across the United States.Trial Registration: Clinicaltrials.gov NCT03064971 . Registered on February 22, 2017. [ABSTRACT FROM AUTHOR]

Age-related decline in cognitive functions and dementia are major challenges in geriatric healthcare. Accumulating evidence from clinical, epidemiological and animal research suggests that tooth loss may be a risk factor for the decline of cognitive functions. This issue highlights the role of the brain-stomatognathic axis in geriatric medicine. Whether input from the stomatognathic apparatus can affect the brain remains an open debate. By revisiting the evidence published in the past five years, we argue that the hypothesis regarding the association between cognitive decline and masticatory dysfunction should be carefully interpreted. Most of the available clinical and epidemiological studies present only cross-sectional data. With respect to the prospective studies, important confounding factors, such as nutritional and physical conditions, were not fully controlled for. Animal research has revealed that hippocampal deficits may play key roles in the observed cognitive decline. However, experimental intervention and outcome assessments may not capture the condition of human subjects. Brain neuroimaging research may be suitable for bridging the gap between clinical and animal research, potentially contributing to (a) the clarification of the brain network associated with mastication, (b) the identification of brain imaging markers for exploring the mechanisms underlying long-term changes in masticatory functions, and (c) the elucidation of interactions between mastication and other cognitive-affective processing systems. Three potential models of the brain-stomatognathic axis and relevant hypotheses are summarized, focusing on the sensory feedback mechanisms, the compensation of motor control, and cerebellar deficits. Finally, we highlight four critical aspects of study and experimental design that should be considered in future research: (a) the refinement of the considered behavioral assessments, (b) the inclusion of baseline changes in mental and physical conditions, [ABSTRACT FROM AUTHOR]

Background: Conventional tests of shoulder laxity have been shown to have poor reliability due to the difficulty in palpating the subtle movements of the shoulder joint beneath the musculature. Modified drawer test that is performed while the soft tissues surrounding the shoulder are loosened has been proposed to facilitate glenohumeral joint movement and improve reliability. We hypothesised that the modified drawer test would have an improved intra- and inter-observer reproducibility in comparison to the drawer and load and shift tests. Correlation of shoulder laxity measured by these tests with generalized joint laxity was also assessed.Methods: Forty healthy volunteers underwent bilateral shoulder examination in the clinic using the three tests for anterior and posterior laxity assessment by a consultant shoulder surgeon and a resident. The examination was repeated three months later by the same examiners in the same cohort. Intra- and inter- observer reproducibility was calculated using Kappa values. The correlation of shoulder with generalized joint laxity was also investigated.Results: The modified drawer test showed significantly improved intra-observer reproducibility compared to the drawer test, but not to the load and shift (κ = 0.173, -0.042, and 0.009, respectively). There were no significant differences in the inter-observer reproducibility between the three tests (κ = 0.054, 0.055, and 0.056, respectively). Moderate correlation was noted between shoulder and generalized joint laxity when modified drawer test was used (r = 0.417).Conclusions: The modified drawer test improves intra- but not inter- observer reproducibility compared to the drawer test. Shoulder laxity assessed by the modified test correlated to generalized joint laxity. The modified drawer test has an improved reproducibility and correlation to generalized joint laxity over the conventional tests. [ABSTRACT FROM AUTHOR]

Aim: We investigated the long-term efficacy and safety of multilevel surgery (MLS) in ambulatory children with bilateral spastic cerebral palsy (CP).Method: Two hundred and thirty-one children were evaluated at short term (1.1y, SD 0.4) and long term (9.1y, SD 3.0) follow-up using clinical examination and gait analysis. MLS was investigated by studying changes in the Gait Profile Score (GPS) referenced to the minimally important clinical difference.Results: Ambulatory children aged 10 years and 7 months (SD 2y 11mo) at MLS in Gross Motor Function Classification System levels I (19), II (144), and III (68) showed a decrease (improvement) in preoperative GPS from 16.3° (SD 4.8) to 11.3° (SD 3.2) at short-term follow-up, an improvement of 5°. At long-term follow-up, GPS was maintained at 11.4° (SD 3.1). Overall, 177 (76.6%) children maintained their improvement in GPS after 9 years.Interpretation: Multilevel surgery is a safe and effective surgical intervention, which leads to a significant improvement in gait kinematics in children with bilateral spastic CP. This study improves our understanding of MLS in the long term and will help to inform families and children when planning for MLS.What This Paper Adds: Largest study of multilevel surgery (MLS) for children with bilateral spastic cerebral palsy, with longest follow-up. MLS resulted in significant long-term improvements in gait function. Minor adverse events were common, while events requiring intervention were uncommon (4% of children). Thirty-nine per cent of children required additional surgery during follow-up. 'Single-event multilevel surgery' was changed to the more realistic term 'multilevel surgery'. [ABSTRACT FROM AUTHOR]

Background: Quantitative flow ratio (QFR) is a novel angiography-based method for deriving fractional flow reserve (FFR) without pressure wire or induction of hyperemia. The accuracy of QFR when assessed online in the catheterization laboratory has not been adequately examined to date.Objectives: The goal of this study was to assess the diagnostic performance of QFR for the diagnosis of hemodynamically significant coronary stenosis defined by FFR ≤0.80.Methods: This prospective, multicenter trial enrolled patients who had at least 1 lesion with a diameter stenosis of 30% to 90% and a reference diameter ≥2 mm according to visual estimation. QFR, quantitative coronary angiography (QCA), and wire-based FFR were assessed online in blinded fashion during coronary angiography and re-analyzed offline at an independent core laboratory. The primary endpoint was that QFR would improve the diagnostic accuracy of coronary angiography such that the lower boundary of the 2-sided 95% confidence interval (CI) of this estimate exceeded 75%.Results: Between June and July 2017, a total of 308 patients were consecutively enrolled at 5 centers. Online QFR and FFR results were both obtained in 328 of 332 interrogated vessels. Patient- and vessel-level diagnostic accuracy of QFR was 92.4% (95% CI: 88.9% to 95.1%) and 92.7% (95% CI: 89.3% to 95.3%), respectively, both of which were significantly higher than the pre-specified target value (p < 0.001). Sensitivity and specificity in identifying hemodynamically significant stenosis were significantly higher for QFR than for QCA (sensitivity: 94.6% vs. 62.5%; difference: 32.0% [p < 0.001]; specificity: 91.7% vs. 58.1%; difference: 36.1% [p < 0.001]). Positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for QFR were 85.5%, 97.1%, 11.4, and 0.06. Offline analysis also revealed that vessel-level QFR had a high diagnostic accuracy of 93.3% (95% CI: 90.0% to 95.7%).Conclusions: The study met its prespecified primary performance goal for the level of diagnostic accuracy of QFR in identifying hemodynamically significant coronary stenosis. (The FAVOR [Functional Diagnostic Accuracy of Quantitative Flow Ratio in Online Assessment of Coronary Stenosis] II China study]; NCT03191708). [ABSTRACT FROM AUTHOR]

Background: Intraoperative use of a high-dose remifentanil may induce postoperative hyperalgesia. Low-dose naloxone can selectively reverse some adverse effects of opioids without compromising analgesia. We thus hypothesized that the intraoperative use of a high-dose remifentanil combined with a low-dose naloxone infusion reduces postoperative hyperalgesia compared with the use of remifentanil alone.Methods: Patients undergoing elective thyroid surgery were randomly assigned into one of three groups, depending on the intraoperative effect-site concentration of remifentanil, with or without a continuous infusion of naloxone: 4 ng ml-1 remifentanil with 0.05 μg kg-1 h-1 naloxone in the high-remifentanil with naloxone group, and 4 or 1 ng ml-1 remifentanil with a placebo in the high- or low-remifentanil groups, respectively. We measured the pain thresholds (primary outcome) to mechanical stimuli using von Frey filaments and incidence of hyperalgesia on the peri-incisional area 24 h after surgery. We also measured pain intensity, analgesic consumptions and adverse events up to 48 h after surgery.Results: The pain threshold presented as von Frey numbers [median (interquartile range)] was significantly lower in the high-remifentanil group (n=31) than in the high-remifentanil with naloxone (n=30) and the low-remifentanil (n=30) groups [3.63 (3.22-3.84) vs 3.84 (3.76-4.00) vs 3.80 (3.69-4.08), P=0.011]. The incidence of hyperalgesia was also higher in the high-remifentanil group than in the other groups [21/31 vs 10/30 vs 9/30, P=0.005]. Postoperative pain intensity, analgesic consumptions and adverse events were similar between groups.Conclusions: The intraoperative use of low-dose naloxone combined with high-dose remifentanil reduced postoperative hyperalgesia but not pain.Clinical trial registration: NCT02856087. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to propose the role of amniotic membrane transplantation (AMT) as an additional modulator in primary Mitomycin C (MMC)-augmented trabeculectomy.Methods: This was a randomized prospective interventional study. Forty eyes of 39 adult patients with uncontrolled primary glaucoma were randomly divided into two equal groups. Control group underwent trabeculectomy augmented with MMC while the study group underwent additional AMT. Patients were followed up for 12 months and outcomes measured were intraocular pressure (IOP), need for additional intervention, and bleb morphology.Results: Complete success (defined as IOP <16 mmHg on no medication) could be achieved in 85% eyes in study group while it was 60% in control group (P = 0.04). IOP reduced by 71.1% in study group from 41.9 ± 10.6 to 12.1 ± 2.7 mmHg and from 40.5 ± 8.5 to 12.8 ± 4.5 mmHg in control group, a decline of 68.29%. Blebs in AMT group showed better bleb morphology in terms of significantly better extent (E3) on day 1 (P = 0.03) and better height (H2 and H3) (P = 0.04), according to the Indiana Bleb Appearance Grading Scale, at all follow-up visits along with normal vascularity. The study group required significantly lesser (P = 0.03) bleb needlings as compared to control group.Conclusion: Amnion enhanced the efficacy of MMC-modulated trabeculectomy in terms of eyes with complete success and lesser interventions such as bleb needling. This reiterates the role of amnion as a safe and effective bleb modulator. A diffusely elevated bleb with healthier conjunctiva can go a long way in predicting better health and longevity of the bleb. [ABSTRACT FROM AUTHOR]

Background: The responsiveness of the Early Childhood Oral Health Impact Scale (ECOHIS) has varied greatly across studies; hence, we hypothesized that this discrepancy could be related to the complexity of dental treatment received. Thus, we aimed to evaluate the responsiveness of the ECOHIS to changes in oral health-related quality of life (OHRQoL) following dental treatments of varying complexity in preschool children.Methods: Preschool children aged 3 to 6 years were selected; their parents responded to the ECOHIS at baseline. The parents responded to the ECOHIS again and a global transition question 30 days after the children were treated. The type of treatment received by the children was categorized according to complexity, as follows: 1) non-operative treatment only, 2) restorative treatment, and 3) endodontic treatment and/or tooth extraction. Change scores and effect sizes (ES) were calculated for total scores, as well as considering the different treatment types and global transition question responses.Results: Of the 152 children who completed the study, the ECOHIS yielded large ES for total scores (0.89). The children showed increasing ES values associated with better perception of improvement, assessed by the global transition question. The magnitude of ES after treatment was related to treatment complexity (0.53, 0.92 and 1.43, for children who received non-operative treatment only, restorative treatment, and endodontic treatment and/or tooth extraction, respectively).Conclusions: Parents whose children required more complex dental treatment are more likely to perceive treatment-related changes to OHRQoL assessed with the ECOHIS. [ABSTRACT FROM AUTHOR]

Background: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients.Methods: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch.Results: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038).Conclusions: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired - as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients. [ABSTRACT FROM AUTHOR]

Background: Stroke is the prime cause of morbidity and mortality in the general population, and hypertension will increase the recurrence and mortality of stroke. We report a protocol of a pragmatic randomized controlled trial (RCT) using blood pressure (BP)-lowering acupuncture add-on treatment to treat patients with hypertension and stroke.Methods: This is a large-scale, multicenter, subject-, assessor- and analyst-blinded, pragmatic RCT. A total of 480 patients with hypertension and ischemic stroke will be randomly assigned to two groups: an experimental group and a control group. The experimental group will receive "HuoXueSanFeng" acupuncture combined with one antihypertensive medication in addition to routine ischemic stroke treatment. The control group will only receive one antihypertensive medication and basic treatments for ischemic stroke. HuoXueSanFeng acupuncture will be given for six sessions weekly for the first 6 weeks and three times weekly for the next 6 weeks. A 9-month follow-up will, thereafter, be conducted. Antihypertensive medication will be adjusted based on BP levels. The primary outcome will be the recurrence of stroke. The secondary outcomes including 24-h ambulatory BP, the TCM syndrome score, the Short Form 36-item Health Survey (SF-36), the National Institute of Health Stroke Scale (NIHSS), as well as the Barthel Index (BI) scale will be assessed at baseline, 6 weeks and 12 weeks post initiating treatments; cardiac ultrasound, carotid artery ultrasound, transcranial Doppler, and lower extremity ultrasound will be evaluated at baseline and 12 weeks after treatment. The safety of acupuncture will also be assessed.Discussion: We aim to determine the clinical effects of controlling BP for secondary prevention of stroke with acupuncture add-on treatment.Trial Registration: ClinicalTrials.gov, ID: NCT02967484 . Registered on 13 February 2017; last updated on 27 June 2017. [ABSTRACT FROM AUTHOR]

Background: A low-calorie diet (LCD) reduces fat mass excess, improves insulin sensitivity, and alters adipose tissue (AT) gene expression, yet the relation with clinical outcomes remains unclear. Objective: We evaluated AT transcriptome alterations during an LCD and the association with weight and glycemic outcomes both at LCD termination and 6 mo after the LCD. Design: Using RNA sequencing (RNAseq), we analyzed transcriptome changes in AT from 191 obese, nondiabetic patients within a multicenter, controlled dietary intervention. Expression changes were associated with outcomes after an 8-wk LCD (800-1000 kcal/d) and 6 mo after the LCD. Results were validated by using quantitative reverse transcriptase-polymerase chain reaction in 350 subjects from the same cohort. Statistical models were constructed to classify weight maintainers or glycemic improvers. Results: With RNAseq analyses, we identified 1173 genes that were differentially expressed after the LCD, of which 350 and 33 were associated with changes in body mass index (BMI; in kg/m2) and Matsuda index values, respectively, whereas 29 genes were associated with both endpoints. Pathway analyses highlighted enrichment in lipid and glucose metabolism. Classification models were constructed to identify weight maintainers. A model based on clinical baseline variables could not achieve any classification (validation AUC: 0.50; 95% CI: 0.36, 0.64). However, clinical changes during the LCD yielded better performance of the model (AUC: 0.73; 95% CI: 0.60, 0.87]). Adding baseline expression to this model improved the performance significantly (AUC: 0.87; 95% CI: 0.77, 0.96; Delong's P = 0.012). Similar analyses were performed to classify subjects with good glycemic improvements. Baseline- and LCD-based clinical models yielded similar performance (best AUC: 0.73; 95% CI: 0.60, 0.86). The addition of expression changes during the LCD improved the performance substantially (AUC: 0.80; 95% CI: 0.69, 0.92; P = 0.058).Conclusions: This study investigated AT transcriptome alterations after an LCD in a large cohort of obese, nondiabetic patients. Gene expression combined with clinical variables enabled us to distinguish weight and glycemic responders from nonresponders. These potential biomarkers may help clinicians understand intersubject variability and better predict the success of dietary interventions. This trial was registered at clinicaltrials.gov as NCT00390637. [ABSTRACT FROM AUTHOR]

Objective: This study investigated school self-efficacy and sense of school membership (collectively "school self-concept") as potential influences on impaired school function among adolescents with chronic pain, including comparison of adolescents with primary pain to those with disease-based pain and pain-free peers.Methods: In all, 264 adolescents (12-17 years old) with primary pain conditions, juvenile idiopathic arthritis, or no pain completed measures of functional disability, school functioning, pain characteristics, and school self-concept, the Self-Efficacy Questionnaire for School Situations (SEQ-SS), and Psychological Sense of School Membership (PSSM).Results: Both the SEQ-SS and PSSM demonstrated reliability and some validity, with the SEQ-SS more strongly supported. As a group, adolescents with primary pain conditions reported poorer school self-concept. School self-efficacy, but not school belongingness, predicted school functioning later in the school year.Conclusions: School self-concept, especially as assessed with the SEQ-SS, is relevant and important to assess when addressing school functioning in youth with chronic pain. [ABSTRACT FROM AUTHOR]

Background: Recent evidence suggests that impaired central sensorimotor integration may contribute to deficits in movement control experienced by people with chronic ankle instability (CAI). This study compared the effects of dual-task and walking speed on gait variability in individuals with and without CAI.Methods: Sixteen subjects with CAI and 16 age- and gender-matched, able-bodied controls participated in this study. Stride time variability and stride length variability were measured on a treadmill under four different conditions: self-paced walking, self-paced walking with dual-task, fast walking, and fast walking with dual-task.Results: Under self-paced walking (without dual-task) there was no difference in stride time variability between CAI and control groups (P = 0.346). In the control group, compared to self-paced walking, stride time variability decreased in all conditions: self-paced walking with dual-task, fast speed, and fast speed with dual-task (P = 0.011, P = 0.016, P = 0.001, respectively). However, in the CAI group, compared to self-paced walking, decreased stride time variability was demonstrated only in the fast speed with dual-task condition (P = 1.000, P = 0.471, P = 0.008; respectively). Stride length variability did not change under any condition in either group.Conclusions: Subjects with CAI and healthy controls reduced their stride time variability in response to challenging walking conditions; however, the pattern of change was different. A higher level of gait disturbance was required to cause a change in walking in the CAI group compared to healthy individuals, which may indicate lower adaptability of the sensorimotor system. Clinicians may use this information and employ activities to enhance sensorimotor control during gait, when designing intervention programs for people with CAI. The study was registered with the Clinical Trials network (registration NCT02745834, registration date 15/3/2016). [ABSTRACT FROM AUTHOR]

Background: Clinicians, afraid of missing intracranial injuries, liberally obtain computed tomographic (CT) head imaging in blunt trauma patients. Prior work suggests that clinical criteria (National Emergency X-Radiography Utilization Study [NEXUS] Head CT decision instrument [DI]) can reliably identify patients with important injuries, while excluding injury, and the need for imaging in many patients. Validating this DI requires confirmation of the hypothesis that the lower 95% confidence limit for its sensitivity in detecting serious injury exceeds 99.0%. A secondary goal of the study was to complete an independent validation and comparison of the Canadian and NEXUS Head CT rules among the subgroup of patients meeting the inclusion and exclusion criteria.Methods and Findings: We conducted a prospective observational study of the NEXUS Head CT DI in 4 hospital emergency departments between April 2006 and December 2015. Implementation of the rule requires that patients satisfy 8 criteria to achieve "low-risk" classification. Patients are excluded from "low-risk" classification and assigned "high-risk" status if they fail to meet 1 or more criteria. We examined the instrument's performance in assigning "high-risk" status to patients requiring neurosurgical intervention among a cohort of 11,770 blunt head injury patients. The NEXUS Head CT DI assigned high-risk status to 420 of 420 patients requiring neurosurgical intervention (sensitivity, 100.0% [95% confidence interval [CI]: 99.1%-100.0%]). The instrument assigned low-risk status to 2,823 of 11,350 patients who did not require neurosurgical intervention (specificity, 24.9% [95% CI: 24.1%-25.7%]). None of the 2,823 low-risk patients required neurosurgical intervention (negative predictive value [NPV], 100.0% [95% CI: 99.9%-100.0%]). The DI assigned high-risk status to 759 of 767 patients with significant intracranial injuries (sensitivity, 99.0% [95% CI: 98.0%-99.6%]). The instrument assigned low-risk status to 2,815 of 11,003 patients who did not have significant injuries (specificity, 25.6% [95% CI: 24.8%-26.4%]). Significant injuries were absent in 2,815 of the 2,823 patients assigned low-risk status (NPV, 99.7% [95% CI: 99.4%-99.9%]). Of our patients, 7,759 (65.9%) met the inclusion and exclusion criteria of the Canadian Head CT rule, including 111 patients (1.43%) who required neurosurgical intervention and 306 (3.94%) who had significant intracranial injuries. In our study, the Canadian criteria for neurosurgical intervention identified 108 of 111 patients requiring neurosurgical intervention to yield a sensitivity of 97.3% (95% CI: 92.3%-99.4%) and exhibited a specificity of 58.8% (95% CI: 57.7%-59.9%). The NEXUS rule, when applied to this same cohort, identified all 111 patients requiring neurosurgical intervention, yielding a sensitivity of 100% (95% CI: 96.7%-100.0%) with a specificity of 32.6% (95% CI: 31.5%-33.6%). Our study found that the Canadian medium-risk factors identified 301 of 306 patients with significant injuries (sensitivity = 98.4%; 95% CI: 96.2%-99.5%), while the NEXUS rule identified 299 of these patients (sensitivity = 97.7%; 95% CI: 95.3%-99.1%). In our study, the Canadian medium-risk rule exhibited a specificity of 12.3% (95% CI: 11.6%-13.1%), while the NEXUS rule exhibited a specificity of 33.3% (95% CI: 32.3%-34.4%). Limitations of the study may arise from application of the rule by different clinicians in different environments. Clinicians may vary in their interpretation and application of the instrument's criteria and risk assignment and may also vary in deciding which patients require intervention. The instrument's specificity is also subject to spectrum bias and may change with variations in the proportion of "low-risk" patients seen in other centers.Conclusions: The NEXUS Head CT DI reliably identifies blunt trauma patients who require head CT imaging and could significantly reduce the use of CT imaging. [ABSTRACT FROM AUTHOR]

Background: The optimal regimen for perioperative antimicrobial prophylaxis is controversial. Use of combination prophylaxis with a beta-lactam plus vancomycin is increasing; however, the relative risks and benefits associated with this strategy are unknown. Thus, we sought to compare postoperative outcomes following administration of 2 antimicrobials versus a single agent for the prevention of surgical site infections (SSIs). Potential harms associated with combination regimens, including acute kidney injury (AKI) and Clostridium difficile infection (CDI), were also considered.Methods and Findings: Using a multicenter, national Veterans Affairs (VA) cohort, all patients who underwent cardiac, orthopedic joint replacement, vascular, colorectal, and hysterectomy procedures during the period from 1 October 2008 to 30 September 2013 and who received planned manual review of perioperative antimicrobial prophylaxis regimen and manual review for the 30-day incidence of SSI were included. Using a propensity-adjusted log-binomial regression model stratified by type of surgical procedure, the association between receipt of 2 antimicrobials (vancomycin plus a beta-lactam) versus either single agent alone (vancomycin or a beta-lactam) and SSI was evaluated. Measures of association were adjusted for age, diabetes, smoking, American Society of Anesthesiologists score, preoperative methicillin-resistant Staphylococcus aureus (MRSA) status, and receipt of mupirocin. The 7-day incidence of postoperative AKI and 90-day incidence of CDI were also measured. In all, 70,101 procedures (52,504 beta-lactam only, 5,089 vancomycin only, and 12,508 combination) with 2,466 (3.5%) SSIs from 109 medical centers were included. Among cardiac surgery patients, combination prophylaxis was associated with a lower incidence of SSI (66/6,953, 0.95%) than single-agent prophylaxis (190/12,834, 1.48%; crude risk ratio [RR] 0.64, 95% CI 0.49, 0.85; adjusted RR 0.61, 95% CI 0.46, 0.83). After adjusting for SSI risk, no association between receipt of combination prophylaxis and SSI was found for the other types of surgeries evaluated, including orthopedic joint replacement procedures. In MRSA-colonized patients undergoing cardiac surgery, SSI occurred in 8/346 (2.3%) patients who received combination prophylaxis versus 4/100 (4.0%) patients who received vancomycin alone (crude RR 0.58, 95% CI 0.18, 1.88). Among MRSA-negative and -unknown cardiac surgery patients, SSIs occurred in 58/6,607 (0.9%) patients receiving combination prophylaxis versus 146/10,215 (1.4%) patients who received a beta-lactam alone (crude RR 0.61, 95% CI 0.45, 0.83). Based on these associations, the number needed to treat to prevent 1 SSI in MRSA-colonized patients is estimated to be 53, compared to 176 in non-MRSA patients. CDI incidence was similar in both exposure groups. Across all types of surgical procedures, risk of AKI was increased in the combination antimicrobial prophylaxis group (2,971/12,508 [23.8%] receiving combination versus 1,058/5,089 [20.8%] receiving vancomycin alone versus 7,314/52,504 [13.9%] receiving beta-lactam alone). We found a significant association between absolute risk of AKI and receipt of combination regimens across all types of procedures. If the observed association is causal, the number needed to harm for severe AKI following cardiac surgery would be 167. The major limitation of our investigation is that it is an observational study in a predominantly male population, which may limit generalizability and lead to unmeasured confounding.Conclusions: There are benefits but also unintended consequences of antimicrobial and infection prevention strategies aimed at "getting to zero" healthcare-associated infections. In our study, combination prophylaxis was associated with both benefits (reduction in SSIs following cardiac surgical procedures) and harms (increase in postoperative AKI). In cardiac surgery patients, the difference in risk-benefit profile by MRSA status suggests that MRSA-screening-directed prophylaxis may optimize benefits while minimizing harms in this selected population. More information about long-term outcomes and patient and societal preferences regarding risk of SSI versus risk of AKI is needed to improve clinical decision-making. [ABSTRACT FROM AUTHOR]

Aims: To assess the clinical value of measuring right atrial pressure (RAP) using near-infrared spectroscopy (NIRS) in patients with chronic heart failure (CHF).Methods and Results: RAP was measured non-invasively using NIRS over the external jugular vein (Venus 1000, Mespere LifeSciences, Canada) in ambulatory patients with CHF enrolled in the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF) programme. Comparing 243 patients with CHF (mean age 71 years; mean left ventricular ejection fraction (LVEF) 45%, median NT-proBNP 788 ng/L) to 49 controls (NT-proBNP ≤125 ng/L), RAP was 7 [interquartile range (IQR) 4-11] mmHg vs. 4 (IQR 3-8) mmHg (P < 0.001). Those with RAP ≥10 mmHg (n = 75) were older, had more severe clinical congestion and renal dysfunction, higher plasma NT-proBNP, larger left atrial volume, higher systolic pulmonary pressure and were more often in atrial fibrillation but their LVEF was similar to patients with lower RAP. During a median follow-up of 595 (IQR: 492-714) days, 49 patients (20%) died or were hospitalized for worsening CHF. Compared with patients with RAP ≤5 mmHg, those with RAP ≥10 mmHg had a greater risk of an event (hazard ratio 2.38, 95% confidence interval 1.19-4.75, P = 0.014). RAP measured by NIRS predicted outcome, competing with NT-proBNP in multivariable models.Conclusions: Measuring RAP using NIRS identifies ambulatory patients with CHF who have more severe congestion and a worse outcome. The device might be a useful objective method of monitoring RAP, especially for those inexperienced in eliciting physical signs or when measurement of natriuretic peptides is not immediately available. [ABSTRACT FROM AUTHOR]

Objectives: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome.Methods: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome.Results: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes.Conclusion: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Background: Supraventricular tachycardia is common after heart transplantation. Adenosine, the standard therapy for treating supraventricular tachycardia in children and adults without transplantation, is relatively contraindicated after transplantation because of a presumed risk of prolonged atrioventricular block in denervated hearts. This study tested whether adenosine caused prolonged asystole after transplantation and if it was effective in blocking atrioventricular nodal conduction in these patients.Methods: This was a single-center prospective clinical study including healthy heart transplant recipients 6 months to 25 years of age presenting for routine cardiac catheterization during 2015 to 2016. After catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose-escalation protocol until atrioventricular block was achieved. The incidence of clinically significant asystole (≥12 seconds after adenosine) was quantified. The effects of patient characteristics on adenosine dose required to produce atrioventricular block and duration of effect were also measured.Results: Eighty patients completed adenosine testing. No patient (0%; 95% confidence interval, 0-3) required rescue ventricular pacing. Atrioventricular block was observed in 77 patients (96%; 95% confidence interval, 89-99). The median longest atrioventricular block was 1.9 seconds (interquartile range, 1.4-3.2 seconds), with a mean duration of adenosine effect of 4.3±2.0 seconds. No patient characteristic significantly predicted the adenosine dose to produce atrioventricular block or duration of effect. Results were similar across patient weight categories.Conclusions: Adenosine induces atrioventricular block in healthy pediatric and young adult heart transplant recipients with minimal risk when low initial doses are used (25 μg/kg; 1.5 mg if ≥60 kg) and therapy is gradually escalated.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02462941. [ABSTRACT FROM AUTHOR]

Background: Although some studies found improved coronary flow and myocardial salvage when stent implantation was deferred, the DANAMI-3-DEFER (Third DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) did not show any improvement in clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) and deferred stenting.Objectives: This study sought to evaluate the effect of deferred stent implantation on infarct size, myocardial salvage, and microvascular obstruction (MVO) in patients with STEMI.Methods: In the present DANAMI-3 substudy, a total of 510 patients with STEMI were randomized to PCI with deferred versus immediate stent implantation. The patients underwent a cardiac magnetic resonance examination before discharge after the index procedure and again 3 months later. The primary endpoint was final infarct size.Results: Deferred stenting did not reduce final infarct size (9% left ventricle [LV]; interquartile range [IQR]: 3% to 18% vs. 10% LV; IQR: 3% to 18%; p = 0.67). Similarly, deferred stenting was not associated with myocardial salvage index (66%; IQR: 50% to 89% vs. 67%; IQR: 49% to 88%; p = 0.80) or presence of MVO (43% vs. 42%; p = 0.78). In a post hoc analysis, stent length was the only subgroup of 7 that had an effect on outcome. In patients with a stent length ≥24 mm, deferred stenting reduced the final infarct size (6% LV; IQR: 2% to 18% vs. 13% LV; IQR: 7% to 23%; p = 0.006; and p for interaction = 0.005).Conclusions: In the DANAMI-3-DEFER cardiac magnetic resonance substudy, routine deferred stenting did not reduce infarct size or MVO and did not increase myocardial salvage. These results do not support the use of routine deferred stenting in STEMI patients treated with primary PCI. (DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction [DANAMI-3]; NCT01435408). [ABSTRACT FROM AUTHOR]

Background: Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT.Objectives: This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT.Methods: In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year.Results: Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm3 vs. 177.3 ± 94.3 mm3, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group.Conclusions: Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363). [ABSTRACT FROM AUTHOR]

Background: We evaluated the prognosis of deferred and revascularized coronary stenoses after fractional flow reserve (FFR) measurement to assess its revascularization threshold in clinical practice.Methods: The IRIS-FFR registry (Interventional Cardiology Research In-cooperation Society Fractional Flow Reserve) prospectively enrolled 5846 patients with ≥1coronary lesion with FFR measurement. Revascularization was deferred in 6468 lesions and performed in 2165 lesions after FFR assessment. The primary end point was major adverse cardiac events (cardiac death, myocardial infarction, and repeat revascularization) at a median follow-up of 1.9 years and analyzed on a per-lesion basis. A marginal Cox model accounted for correlated data in patients with multiple lesions, and a model to predict per-lesion outcomes was adjusted for confounding factors.Results: For deferred lesions, the risk of major adverse cardiac events demonstrated a significant, inverse relationship with FFR (adjusted hazard ratio, 1.06; 95% confidence interval, 1.05-1.08; P<0.001). However, this relationship was not observed in revascularized lesions (adjusted hazard ratio, 1.00; 95% confidence interval, 0.98-1.02; P=0.70). For lesions with FFR ≥0.76, the risk of major adverse cardiac events was not significantly different between deferred and revascularized lesions. Conversely, in lesions with FFR ≤0.75, the risk of major adverse cardiac events was significantly lower in revascularized lesions than in deferred lesions (for FFR 0.71-0.75, adjusted hazard ratio, 0.47; 95% confidence interval, 0.24-0.89; P=0.021; for FFR ≤0.70, adjusted hazard ratio 0.47; 95% confidence interval, 0.26-0.84; P=0.012).Conclusions: This large, prospective registry showed that the FFR value was linearly associated with the risk of cardiac events in deferred lesions. In addition, revascularization for coronary artery stenosis with a low FFR (≤0.75) was associated with better outcomes than the deferral, whereas for a stenosis with a high FFR (≥0.76), medical treatment would be a reasonable and safe treatment strategy.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01366404. [ABSTRACT FROM AUTHOR]

Background: Multicenter longitudinal objective data for survival into adulthood of patients who have undergone Fontan procedures are lacking.Objectives: This study sought to describe transplant-free survival and explore relationships between laboratory measures of ventricular performance and functional status over time.Methods: Exercise testing, echocardiography, B-type natriuretic peptide, functional health assessment, and medical history abstraction were repeated 9.4 ± 0.4 years after the Fontan Cross-Sectional Study (Fontan 1) and compared with previous values. Cox regression analysis explored risk factors for interim death or cardiac transplantation.Results: From the original cohort of 546 subjects, 466 were contacted again, and 373 (80%) were enrolled at 21.2 ± 3.5 years of age. Among subjects with paired testing, the percent predicted maximum oxygen uptake decreased (69 ± 14% vs. 61 ± 16%; p < 0.001; n = 95), ejection fraction decreased (58 ± 11% vs. 55 ± 10%; p < 0.001; n = 259), and B-type natriuretic peptide increased (median [interquartile range] 13 [7 to 25] pg/mol vs. 18 [9 to 36] pg/mol; p < 0.001; n = 340). At latest follow-up, a lower Pediatric Quality of Life Inventory physical summary score was associated with poorer exercise performance (R2 adjusted = 0.20; p < 0.001; n = 274). Cumulative complications since the Fontan procedure included additional cardiac surgery (32%), catheter intervention (62%), arrhythmia treatment (32%), thrombosis (12%), and protein-losing enteropathy (8%). Since Fontan 1, 54 subjects (10%) have received a heart transplant (n = 23) or died without transplantation (n = 31). The interval risk of death or/cardiac transplantation was associated with poorer ventricular performance and functional health status assessed at Fontan 1, but it was not associated with ventricular morphology, the subject's age, or the type of Fontan connection.Conclusions: Interim transplant-free survival over 12 years in this Fontan cohort was 90% and was independent of ventricular morphology. Exercise performance decreased and was associated with worse functional health status. Future interventions might focus on preserving exercise capacity. (Relationship Between Functional Health Status and Ventricular Performance After Fontan-Pediatric Heart Network; NCT00132782). [ABSTRACT FROM AUTHOR]

Background: Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection.Methods and Findings: Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; γ-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits.Conclusions: In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients. [ABSTRACT FROM AUTHOR]

Background& Aims: Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for infant neurodevelopment. The nutritional adequacy of dietary LC-PUFAs depends not only on the LC-PUFAs intake but also on the n-6 to n-3 fatty acid ratio (n-6/n-3 PUFAs). This study aimed to identify the association between the maternal dietary n-6/n-3 PUFAs and motor and cognitive development of infants at 6 months of age.Methods: We used data from 960 participants in the Mothers and Children's Environmental Health (MOCEH) study, which is a multi-center prospective cohort study. Dietary intake of pregnant women was assessed by a one-day 24-h recall method. Food consumption of infants was estimated based on the volume of breast milk and weaning foods. The duration of each feed was used to estimate the likely volume of milk consumed. Dietary intake of infants at 6 months was also assessed by a 24-h recall method. Cognitive and motor development of infants at 6 months of age was assessed by the Korean Bayley scales of infant development edition II (BSID-II) including the mental developmental index (MDI) and the psychomotor developmental index (PDI).Results: Maternal intakes of n-6/n-3 PUFAs and linoleic acid (LA)-to-α-linolenic acid (ALA) ratio (LA/ALA) were 9.7 ± 6.3 and 11.12 ± 6.9, respectively. Multiple regression analysis, after adjusting for covariates, showed that n-6/n-3 PUFAs was negatively associated with both the MDI (β = -0.1674, P = 0.0291) and PDI (β = -0.1947, P = 0.0380) at 6 months of age. These inverse associations were also observed between LA/ALA and both the MDI and PDI (MDI; β = -0.1567; P = 0.0310, PDI; β = -0.1855; P = 0.0367). Multiple logistic regression analysis, with the covariates, showed that infants whose mother's LA/ALA were ranked in the 2nd, 3rd, and 4th quartile were at approximately twice the risk with more than twice the risk of delayed performance on the PDI compared to the lowest quartile (1st vs. 2nd; OR = 2.965; 95% CI = 1.376 - 6.390, 1st vs. 3rd; OR = 3.047; 95% CI = 1.374 - 6.756 and 1st vs. 4th; OR = 2.551; 95% CI = 1.160 - 5.607).Conclusions: Both the maternal dietary n-6/n-3 PUFAs and LA/ALA intake were significantly associated with the mental and psychomotor development of infants at 6 months of age. Thus, maintaining low n-6/n-3 PUFAs and LA/ALA is encouraged for women during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Regular physical activity (PA) promotes and excessive sedentary behavior (SB) deteriorates health. Yet the Finnish working-aged population spends most of the day sitting. A 1-year Moving To Business (MTB) -intervention supported small and medium-size workplaces to combat sedentariness. This paper reports the changes in employees' PA and SB from before MTB (baseline) to 1 year after baseline (follow-up).Methods: Twelve workplaces with a total of 396 employees participated. Each workplace nominated a team to promote PA and reduce SB at organizational, working unit and employee level. The teams were mentored regionally through meetings, workshop and tools. Changes in PA and SB were assessed with a questionnaire and an accelerometer. Wald Confidence Interval (Cl) for a difference of proportions with matched pairs was used in the questionnaire data (%-points with 95% CI) and linear mixed model in the accelerometer data (minutes and % of wear-time with 95% CI).Results: The mean age of the respondents to the questionnaire (N = 296; 75%) was 42.6 (SD 10.9), 64% were women, 95% had some education after high school, 74% worked in the day shift, 71% did sedentary work and 51% were overweight. The mean number of actions implemented in the workplaces was 6.8 and the multilevel approach was fully applied in 6 workplaces. Based on the questionnaire the time spent in SB decreased from baseline to follow-up 16% (95% CI -29 to -3) in total and 22% (-41 to -3) at work. The accelerometer showed daily increases of 33.7 min (15.3 to 52.1) and 6.8% (3.1 to 10.4) in total PA, 30.9 min (15.3 to 46.5) and 6.1% (2.9 to 9.2) in light PA and 673 (209 to 1139) more steps at work. Daily SB at work decreased 44.9 min (-68.0 to -21.8) and 7.6% (-11.9 to -3.2). Daily leisure PA declined 11.0 min (-24.9 to 2.9) and 3.2% (-6.2 to -0.2). Number of levels or actions had no effect on changes.Conclusions: Employees' PA increased and SB reduced at work during the intervention. At the same time leisure PA decreased slightly. Workplaces can achieve meaningful changes in employees' PA and SB if assisted systematically. Controlled studies are needed to confirm the present findings.Trial Registration: NCT01999205 , registration date 11/01/2013. [ABSTRACT FROM AUTHOR]

Background: Lung cancer aetiology and clinical aspects have been mainly studied in men, although specific risk factors probably exist in women. Here we present the rationale, design and organization of the WELCA study (Women Epidemiology Lung CAncer) that has been launched to investigate lung cancer in women, focusing particularly on hormonal and occupational factors.Methods/design: WELCA is a population based case-control study and planned to recruit 1000 cases and 1000 controls in three years, based on study power calculation. Eligible cases are female patients newly diagnosed with lung cancer, living in Paris and the Ile de France area and aged up to 75 years. Almost all Parisian pneumology and oncology clinical departments are involved. The control group is a random sample of the population living in the same area, frequency-matched on age and additionally stratified on the distribution of socio-professional categories of women residing there. After acquisition of written consent, research nurses administer standardized computer assisted questionnaires to all the subjects in face-to-face interviews and acquire anthropometric measures. Besides usual socio-demographic characteristics, information is gathered about menstrual and reproductive factors, hormonal treatments, lifestyle and leisure characteristics, occupational history, personal and familial medical history. Biological samples are also collected, in order to establish a biobank for molecular epidemiology studies. Molecular characteristics of the tumours will be obtained and patients will be followed up for five years.Discussion: The WELCA study aims to answer key questions in lung cancer aetiology and clinical characteristics specifically in women. The role of hormonal impregnation is investigated, and the interactions with cigarette smoking or body mass index (BMI) will be analyzed in detail. The occupational history of the subjects is carefully reconstructed, focusing in particular on the service sector. The creation of a biobank for collection of serum, plasma, DNA and tumour tissue will allow the genetic and biochemical characterization of both the subjets and the tumours. The follow-up of the patients will help in disentangling the role of hormonal factors and tumour molecular characteristics in survival. [ABSTRACT FROM AUTHOR]