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Abstract Data science is booming with big data, and machine learning provides better predictive analyses. However, conventional statistical models can effortlessly interpret the effect estimates, and the prediction models are generally in a closed form. Therefore, this research integrates the logistic regression model’s core with the Random Forest structure to create a blended novel machine learning method, the Random Logistic Machine (RLM). In this way, the new approach preserves the statistical and machine learning advantages. Computer simulation studies examined the predictive ability of RLM, random forest, and Logistic Regression under various scenarios. The results showed that the RLM delivers a comparable performance to Random Forests and Logistic Regression. An application to the Breast Cancer Wisconsin (Diagnostic) Data Set also demonstrates the superior performance of the new approach. [ABSTRACT FROM AUTHOR]

Objectives: American Institute of Medicine (IOM) recommends different ranges of gestational weight gain (GWG) based on pre-pregnancy body mass index (BMI). In Taiwan, IOM guidelines are implemented concurrently with the local recommendation for GWG (10–14 kg). This study compared between the two sets of guidelines in relation to adverse perinatal outcomes. Methods: We analyzed 31,653 primiparas with singletons from 2011 to 2016 annual National Breastfeeding Surveys. Logistic regressions for preterm birth, small for gestational age (SGA), large for gestational age (LGA), cesarean section and excessive postpartum weight retention (EPWR) were fitted separately for GWG categorized according to IOM and Taiwan ranges. Areas under the receiver–operator curves (AUC) and the predicted probabilities for each outcome were compared in each BMI group. Results: AUC for both guidelines ranged within 0.51–0.73. Compared to Taiwan recommendation, IOM ranges showed lower probabilities of SGA for underweight (0.11–0.15 versus 0.14–0.18), of LGA for obese (0.12–0.15 versus 0.15–0.18), of EPWR for overweight (0.19–0.30 versus 0.27–0.39), and obese (0.15–0.22 versus 0.25–0.36); and higher probabilities of EPWR for underweight (0.17–0.33 versus 0.14–0.22). Conclusions for practice: Discriminative performance of IOM and Taiwan recommendations was poor for the five adverse birth outcomes, and no preference for either set of recommendations could be inferred from our results. In the absence of specific GWG guidelines, health care workers may provide inconsistent information to their patients. Future research is needed to explore optimal GWG ranges that can reliably predict locally relevant perinatal outcomes for mother and child. [ABSTRACT FROM AUTHOR]

As massification of higher education developed, employment challenges in changing labour markets aroused the attention of scholars globally. An interdisciplinary approach called world-system theory is applied by scholars from the social sciences, history, anthropology and cultural studies. This study applied the theory in a bibliometric analysis of graduate employment research using R and CiteSpace. It identified the main characteristics (e.g. authors and countries) of relevant research, investigated the social and economic context of certain milestone publications and visualised research hot spots. World-system theory, as a macrosociological approach to describing the world economy and social system, is innovatively applied in illustrating the findings of the current work. Results indicate that core countries not only are economically influential but also dominating the academic research. Scholars in semi-peripheral and peripheral countries are encouraged to establish transnational networks and foster academic collaborations. [ABSTRACT FROM AUTHOR]

After the genome-wide association studies (GWAS) era, whole-genome sequencing is highly engaged in identifying the association of complex traits with rare variations. A score-based variance-component test has been proposed to identify common and rare genetic variants associated with complex traits while quickly adjusting for covariates. Such kernel score statistic allows for familial dependencies and adjusts for random confounding effects. However, the etiology of complex traits may involve the effects of genetic and environmental factors and the complex interactions between genes and the environment. Therefore, in this research, a novel method is proposed to detect gene and gene-environment interactions in a complex family-based association study with various correlated structures. We also developed an R function for the Fast Gene-Environment Sequence Kernel Association Test (FGE-SKAT), which is freely available as supplementary material for easy GWAS implementation to unveil such family-based joint effects. Simulation studies confirmed the validity of the new strategy and the superior statistical power. The FGE-SKAT was applied to the whole genome sequence data provided by Genetic Analysis Workshop 18 (GAW18) and discovered concordant and discordant regions compared to the methods without considering gene by environment interactions. [ABSTRACT FROM AUTHOR]

In recent years, machine learning methods have been applied to various prediction scenarios in time-series data. However, some processing procedures such as cross-validation (CV) that rearrange the order of the longitudinal data might ruin the seriality and lead to a potentially biased outcome. Regarding this issue, a recent study investigated how different types of CV methods influence the predictive errors in conventional time-series data. Here, we examine a more complex distributed lag nonlinear model (DLNM), which has been widely used to assess the cumulative impacts of past exposures on the current health outcome. This research extends the DLNM into an artificial neural network (ANN) and investigates how the ANN model reacts to various CV schemes that result in different predictive biases. We also propose a newly designed permutation ratio to evaluate the performance of the CV in the ANN. This ratio mimics the concept of the R-square in conventional statistical regression models. The results show that as the complexity of the ANN increases, the predicted outcome becomes more stable, and the bias shows a decreasing trend. Among the different settings of hyperparameters, the novel strategy, Leave One Block Out Cross-Validation (LOBO-CV), demonstrated much better results, and the lowest mean square error was observed. The hyperparameters of the ANN trained by the LOBO-CV yielded the minimum number of prediction errors. The newly proposed permutation ratio indicates that LOBO-CV can contribute up to 34% of the prediction accuracy. [ABSTRACT FROM AUTHOR]

An essential aspect of medical research is the prediction for a health outcome and the scientific identification of important factors. As a result, numerous methods were developed for model selections in recent years. In the era of big data, machine learning has been broadly adopted for data analysis. In particular, the Support Vector Machine (SVM) has an excellent performance in classifications and predictions with the high-dimensional data. In this research, a novel model selection strategy is carried out, named as the Stepwise Support Vector Machine (StepSVM). The new strategy is based on the SVM to conduct a modified stepwise selection, where the tuning parameter could be determined by 10-fold cross-validation that minimizes the mean squared error. Two popular methods, the conventional stepwise logistic regression model and the SVM Recursive Feature Elimination (SVM-RFE), were compared to the StepSVM. The Stability and accuracy of the three strategies were evaluated by simulation studies with a complex hierarchical structure. Up to five variables were selected to predict the dichotomous cancer remission of a lung cancer patient. Regarding the stepwise logistic regression, the mean of the C-statistic was 69.19%. The overall accuracy of the SVM-RFE was estimated at 70.62%. In contrast, the StepSVM provided the highest prediction accuracy of 80.57%. Although the StepSVM is more time consuming, it is more consistent and outperforms the other two methods. [ABSTRACT FROM AUTHOR]

Abstract: Background: Since 1992, breastfeeding promotion in Taiwan considerably raised the breastfeeding rates; however, more recent surveillance showed that breastfeeding indicators stagnated or even decreased. Methods: We analyzed 6 cross‐sectional national surveys of 69 159 postpartum women to examine the breastfeeding trends at 6 months postpartum during 2011‐2016 in Taiwan and the contributing role of maternal and environmental factors. Data were collected through telephone interviews, using structured questionnaires with randomly selected mothers, who gave birth in those years. A multinomial logistic regression was used to analyze the data. Results: Partial breastfeeding rates at 6 months postpartum increased from 2011 to 2016 (25.4%‐45.1%, crude odds ratio [OR] = 1.14 per year of study); however, the rates of exclusive breastfeeding at 6 months postpartum declined (24.5%‐14.8%, crude OR = 0.91 per year of study). During this period, increases in maternal age and educational level, employment outside the house, and prepregnancy obesity were observed. Despite a growing number of births at certified baby‐friendly hospitals, fewer mothers experienced early skin‐to‐skin contact and rooming‐in in 2016 than in 2011. Adjustment for breastfeeding‐related factors did not appreciably change the odds ratio for year of birth. Prenatal intention to breastfeed was most strongly associated with breastfeeding at 6 months postpartum (OR > 5). Conclusions: Maternal and environmental factors in the study could not explain the decline in exclusive breastfeeding. The decline in exclusive breastfeeding, accompanying the increase in partial breastfeeding, suggests that more support is needed for mothers who intend to breastfeed exclusively. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the different impacts on patient-reported vision-related quality of life (pVRQOL) outcomes in patients with primary angle-closure glaucoma(PACG) and primary open-angle glaucoma(POAG). Methods: Prospective cross-sectional study. PACG and POAG patients who had a best-corrected visual acuity(BCVA) in the better eye equal to or better than 20/60, intraocular pressure controlled at or below 25 mmHg and reliable visual field test were invited to participate. The control group included patients with BCVA in the better eye equal to or better than 20/60 and who did not have major eye disease. A validated Taiwanese version of the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25(T)) was performed to assess pVRQOL. The association between each domain of NEI VFQ-25(T) among 3 groups was determined using multivariable linear regression analysis. Results: A total of 106 PACG, 186 POAG, and 95 controls were enrolled. In multivariable regression analysis of all three groups(PACG/POAG/controls), compared to POAG, PACG showed a weakly positive association with social functioning (R2 = 0.13, β = 0.22, P = 0.04). PACG showed no significantly negative impact on pVRQOL compared to controls. Taking only glaucoma patients into consideration, PACG patients had a higher score on social functioning compared to POAG (R2 = 0.16, β = 0.27, P = 0.01). The results of other domains of NEI VFQ-25(T) between the two groups did not differ significantly(p>0.05). Conclusions: In patients with controlled disease, the impact of PACG and POAG on most domains of NEI VFQ-25(T) were similar, except for better social functioning in PACG compared to POAG. [ABSTRACT FROM AUTHOR]

While learning-oriented education has long been a global educational reform issue, an appropriate assessment tool is still lacking. This study's purpose is twofold: first, to construct indicators for monitoring learning-oriented school education and, second, to employ these indicators to evaluate how learning-oriented education has been implemented in Taiwan. To construct the indicators, we compiled relevant literature to develop a preliminary model, then consulted experts to finalize our indicator model. For evaluation, we collected 454 valid samples from 48 schools and demonstrated how importance-performance analysis data can indicate both the strengths and weaknesses of a school's learning-oriented education as well as implications for efficient leadership in school improvement. The results suggest that an indicator system for learning-oriented school education should consist of seven dimensions and 34 indicators. Among the seven dimensions, 'student learning' and 'curriculum planning and implementation' are the most important yet underperforming dimensions that need immediate improvement. • This study developed an assessment tool for learning-oriented education. • We demonstrated how the indicators with IPA helps school education improvement. • The indicator system can be a useful reference for other countries. [ABSTRACT FROM AUTHOR]

Daily temperature measures are commonly used when examining the association between temperature and mortality. In fact, temperature measures are available 24 hours a day and more detailed records may provide a better prediction of mortality compared to daily statistics. In this article, monthly stratified analysis modeling for mortality is conducted for the total population as well as the stratified elderly and younger subgroups. We identified the most significant time during the day that is associated with daily mortality. Surprisingly, the estimates of relative risk and magnitude of associations derived from the hourly temperature measures are similar or even stronger compared to those modeled by the daily statistics. This phenomenon remains true for lagged hourly temperature measures and the changing patterns of associations from January through December are revealed. In summary, people are the most vulnerable to temperature variations in the early morning around 5 am and the night time around 8 pm. [ABSTRACT FROM AUTHOR]

One of the greatest challenges in genetic studies is the determination of gene-environment interactions due to underlying complications and inadequate statistical power. With the increased sample size gained by using case-parent trios and unrelated cases and controls, the performance may be much improved. Focusing on a dichotomous trait, a two-stage approach was previously proposed to deal with gene-environment interaction when utilizing mixed study samples. Theoretically, the two-stage association analysis uses likelihood functions such that the computational algorithms may not converge in the maximum likelihood estimation with small study samples. In an effort to avoid such convergence issues, we propose a logistic regression framework model, based on the combined haplotype relative risk (CHRR) method, which intuitively pools the case-parent trios and unrelated subjects in a two by two table. A positive feature of the logistic regression model is the effortless adjustment for either discrete or continuous covariates. According to computer simulations, under the circumstances in which the two-stage test converges in larger sample sizes, we discovered that the performances of the two tests were quite similar; the two-stage test is more powerful under the dominant and additive disease models, but the extended CHRR is more powerful under the recessive disease model. [ABSTRACT FROM AUTHOR]

Aim: End-stage renal disease (ESRD) is a common finding in systemic lupus erythematosus (SLE) and may contribute to mortality. The purpose of the study was to investigate the incidence of ESRD and all-cause mortality and their risk factors in patients newly diagnosed with SLE in Taiwan. Methods: This nationwide cohort study used data from the National Health Insurance Research Database. We identified 4130 newly diagnosed SLE patients at risk for ESRD during 2000-2002; among them, 103 developed ESRD by the end of 2008. Additional 412 age- and sex-matched incident ESRD non-SLE patients served as controls for the survival analysis. Results: Of the newly diagnosed SLE patients, 2.5% developed ESRD. Age (adjusted hazards ratio [HR] 0.66 for each 1-year increase; 95% confidence interval [CI] 0.47-0.94) and male gender (adjusted HR 2.24; 95% CI 1.4- 3.6) were significantly associated with ESRD development. Survival analysis conducted after ESRD development revealed a higher mortality risk among the older patients (HR 1.04; 95% CI 1.02-1.05). Survival analysis in the younger population (age < 40 years) after ESRD development revealed a significant mortality risk among SLE patients (HR 2.73; 95% CI 1.22-6.07). Conclusion: In the follow-up of newly diagnosed SLE patients in Taiwan, younger age and male gender were risk factors for ESRD development. After entering ESRD, these risk factors had different impacts on mortality. Despite the overall improvement in care of patients with lupus nephritis, survival is still poorer in the younger age population. [ABSTRACT FROM AUTHOR]

In general, multiple issues are examined before the analysis of genetic data such as Hardy-Weinberg Equilibrium and Mendelian errors. Although missing genotypes are commonly observed in genetic studies, potential bias due to informative missingness is usually overlooked. Therefore, the Test of Informative Missingness (TIM) was the first attempt to determine whether or not parental genotypes are missing informatively. The TIM is a useful tool for genetic data cleaning. For example, excluding single-nucleotide polymorphisms that appear to be missing informatively may further improve the quality of genetic data. Although the TIM has decent power, its performance is discernibly weaker when the minor allele/genotype introduces informative missingness. In an effort to avoid such reduced power, the newly proposed strategy detects informative missingness by comparing inconsistent linkage disequilibrium signals between intact case-parent triads and incomplete data. Computer simulations revealed that the new method was robust to population stratifications and more powerful than the TIM in most situations. In addition, the new method demonstrated decent power in the genome-wide association study, even if the most conservative correction for multiple testing was adopted. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hemodialysis patients have higher risk of mortality and morbidity when infected with 2009 pandemic H1N1 (pH1N1/09) virus. Depending on different methodologies and criteria, previous studies reported variable response rates to adjuvanted vaccines against pH1N1/09 virus in hemodialysis patients, however, the efficacy of non-adjuvanted vaccines, which are currently used in many countries such as the USA and Asian areas, has not been comprehensively evaluated in hemodialysis population before. Methods: We evaluated the efficacy of a standard single15μg-dose of non-adjuvanted monovalent pH1N1/09 vaccine (AdimFlu-S) in vaccine-naïve 110 hemodialysis and 173 healthy participants. When enrolling, all participants had not any clinical symptom or sign suggesting pH1N1/09 infection since the index case was identified in Taiwan. Sera from all participants were tested by hemagglutination inhibition (HI) and micro-neutralization-ELISA (microNT-ELISA) tests before and 21days after vaccination. The outcome parameters were seroconversion rate (≥4-fold in HI titer with titer ≥1:40), seroprotection rate (HI titers ≥1:40), seroresponse rate (≥4-fold increase in HI or microNT-ELISA titer), fold of increase in geometric mean (GM) titers, and adverse effects. Results: In method A analyses, we included all participants’ data in final analyses, and the seroconversion rates and the fold increase of GM titer after vaccination were 25.4% and 1.8 in adult (18–60-year olds) hemodialysis subgroup, and 23.4% and 1.8 in elder (>60-year olds) hemodialysis subgroup based on HI titers, which were all significantly lower than those of the corresponding healthy control subgroups. Similar trends were observed based on microNT-ELISA titers, further validating the results. Multivariable analysis revealed hemoglobin and cholesterol levels were significant predictors for seroresponse in hemodialysis patients, suggesting the possible impacts of nutrition status and anemia. In method B analyses, we excluded participants with pre-vaccination seroprotection (based on HI or microNT-ELISA criteria) in final analyses. The response rates in various subgroups from method B analyses were also similar as those from method A analyses. No severe adverse effect was noted. Conclusions: According to the European and U.S. criteria, a single 15μg-dose of non-adjuvanted pH1N1/09 vaccination is safe but ineffective in both adult and elder hemodialysis patients. Further studies using multiple doses or higher antigen amount are warrant to define the most appropriate regimen. [Copyright &y& Elsevier]

Citation Wu C-H, Guo C-Y, Yang J-G, Tsai H-D, Chang Y-J, Tsai P-C, Hsu C-C, Kuo P-L. Polymorphisms of dioxin receptor complex components and detoxification-related genes jointly confer susceptibility to advanced-stage endometriosis in the Taiwanese Han population. Am J Reprod Immunol 2012; 67: 160-168 Problem To establish a multilocus model for studying the effect of dioxin receptor complex components and detoxification-related enzymes on advanced endometriosis. Method of study Six single-nucleotide polymorphisms (SNPs) and two deletion polymorphisms from eight genes (CYP1A1, CYP1B1, GSTM1, GSTT1, GSTP1, AhR, ARNT, and AhRR) were genotyped. Results In the single SNP analysis, GSTM1 null type and AhRR variant type were associated with a significantly increased risk of endometriosis [odds ratio (OR) = 2.38 and 2.45, respectively]. Using multiple SNPs in the logistic regression for covariates, wild-type AhR and mutant AhRR combination was significantly higher in patients (67.8%) than in controls (48.0%) (OR = 2.76). On the other hand, mutant AhRR in combination with GSTM1 null genotype was significantly higher in patients (35.5%) than in controls (19.3%) (OR = 6.12). Conclusion Polymorphisms of dioxin receptor complex components and detoxification-related genes jointly confer susceptibility to advanced-stage endometriosis in the Taiwanese Han population. [ABSTRACT FROM AUTHOR]

Abstract: Aims: We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation. Methods and results: We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants (n =2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998–2001. The cohort was divided into never (n =1149), former (n =1424), and current smokers with last cigarette >6h (n =134) or ≤6h (n =237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p <0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L (p <0.0001) and higher concentrations of (CRP) C-reactive protein (p =0.002). Conclusions: As opposed to never smokers, those with acute cigarette smoke exposure (≤6h) had significantly higher concentrations of all markers (p <0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state. [Copyright &y& Elsevier]

In genetic studies, the transmission/disequilibrium test (TDT) using case–parent triads has gained popularity attributable to its robustness to population admixture. Several extensions have been proposed to accommodate incomplete triads. Some strategies assume that parental genotypes are missing completely at random (MCAR) to insure an unbiased conclusion and some methods allow parental genotypes to be missing informatively, resulting in reduced power when the missing data pattern is indeed MCAR. However, these tests assumed that offspring genotypes were MCAR. Recently, Guo indicated that when offspring genotypes were missing informatively, an occurrence that can be considered as ascertainment bias, inflated type-I error and/or reduced power may occur using the TDT when incomplete triads are excluded. In an effort to avoid an erroneous conclusion, we propose a strategy called testing informative missingness (TIM) that compares conditional distributions of parental genotypes among complete triads and incomplete data with only one parent to examine the missing data pattern. Through computer simulations, TIM has decent power to detect informative missingness and is robust to population admixture. In addition, we illustrate TIM with an application to the Framingham Heart Study.European Journal of Human Genetics (2008) 16, 992–1001; doi:10.1038/ejhg.2008.38; published online 12 March 2008 [ABSTRACT FROM AUTHOR]

Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of ≥25% carotid stenosis by ultrasonography. Circulating inflammatory markers assessed from an examination 4 years later included CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoattractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory markers were significantly associated with ICA-IMT (p = 0.01), marginally with carotid stenosis (p = 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75th percentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (for ICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p = 0.0004; for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p = 0.007) after adjustment for age, gender, and established risk factors for atherosclerosis. There was a similar significant multivariate-adjusted association of CRP with ICA-IMT but not with carotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p = 0.009) and with IL-6 (p = 0.006); the association was more pronounced in current (vs former or never) smokers. In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers. [Copyright &y& Elsevier]

Investigators have suggested that inflammation may play a role in the pathogenesis of valve calcium. Participants in the Framingham Heart Study’s offspring cohort had systemic levels of C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and monocyte chemoattractant protein-1 measured at examination cycle 7. Mitral annular calcium, aortic annular calcium, aortic sclerosis, and aortic stenosis were assessed by echocardiography at examination cycle 6. Logistic regression was used to examine the odds of valvular calcium per 1 unit increase in inflammation (ISUM), a summary statistic of all normalized deviates of the individual markers. Two thousand six hundred eighty-three participants (mean age 61 ± 10 years; 52% women) were analyzed: 8.2% (n = 216) had ≥1 calcified valve or annulus; 89 had mitral annular calcium, 78 had aortic annular calcium, 135 had aortic sclerosis, and 33 had aortic stenosis. Participants with valvular calcium were older and were more likely to have hypertension and diabetes mellitus. Participants with valve calcium had higher median levels of all markers. For each log unit increase in ISUM, after adjustment for age and gender, there was an associated 1.1-fold increased odds of ≥1 calcified valve (p = 0.02); the odds ratios were no longer significant after adjustment for cardiovascular disease risk factors (odds ratio 1.0, 95% confidence interval 0.9 to 1.1). Similar results were obtained for the individual markers and the odds of ≥1 calcified valve. In conclusion, inflammatory markers were elevated in patients with valvular calcium. Our findings suggest that much of the observed association between systemic inflammatory markers and valvular calcium may be due to shared risk factors. [Copyright &y& Elsevier]

Background: Spirometric abnormalities have been related to incident heart failure in general population, who generally have preserved left ventricular ejection fraction (LVEF). We aimed to investigate the association between spirometric indices, cardiac functions and clinical outcomes. Methods: Subjects presenting with exertional dyspnoea and received spirometry and echocardiography were eligible for this study. Forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1)/FVC ratio were measured to define the spirometry patterns: normal (FEV1/FVC ≥ 70%, FVC ≥ 80%), obstructive (FEV1/FVC < 70%, FVC ≥ 80%), restrictive pattern (FEV1/FVC ≥ 70%, FVC < 80%) and mixed (FEV1/FVC < 70%, FVC < 80%). The diastolic dysfunction index (DDi) was the counts of the indicators, including septal e′ velocity <7 cm/s, septal E/e′ > 15, pulmonary artery systolic pressure > 35 mmHg and left atrial dimension >40 mm. Results: Among a total of 8669 participants (65.8 ± 16.3 years, 56% men), 3739 (43.1%), 829 (9.6%), 3050 (35.2%) and 1051 (12.1%) had normal, obstructive, restrictive and mixed spirometry pattern, respectively. Subjects with restrictive or mixed spirometry pattern had higher DDi and worse long‐term survival than those with obstructive or normal ventilation. FVC but not FEV1/FVC was predictive of 5‐year mortality, independent of age, sex, renal function, LVEF, DDi, body mass index, and comorbidities (hazard ratio, 95% confidence intervals:.981,.977–.985). Furthermore, there was an inverse nonlinear relationship between FVC and DDi, suggesting the declined FVC may mediate 43% of the prognostic hazard of left ventricular diastolic dysfunction. Conclusions: The restrictive spirometry pattern or the declined FVC was associated with left ventricular diastolic dysfunction, which aggravated the long‐term mortality in the ambulatory dyspnoeic subjects. [ABSTRACT FROM AUTHOR]

In recent years, governmental policy changes have exerted significant impact on the structural transformation, role diversity and commercialisation of national quality assurance agencies in many nations. Due to policy change, ongoing structural transformation and emerging roles, four national quality assurance agencies in Australia, Japan, Malaysia and Taiwan were selected as case studies. The study presents three major findings. First, although a state-controlled governance model remained popular in all cases, the university-led and supermarket models were chosen due to changes in policy. Second, case agencies intended to develop new roles in order to respond to policy change and public demands, particularly enhancing professionalism, redefining the relationship with universities as partners, strengthening the linkage with international quality assurance networks, providing quality assurance services with foreign providers. Third, autonomy and independence remain a considerable challenge for quality assurance agencies. [ABSTRACT FROM AUTHOR]

Frailty is a well-recognized geriatric syndrome with various definitions and conceptual frameworks. This study aimed to use latent class analysis to discover potential subtypes of pre-frail and frail older people. Data from the I-Lan Longitudinal Aging Study (ILAS), a community-based cohort study was used for analysis. Latent class analysis was applied to characterize classes or subgroups with different frailty phenotypes among ILAS participants targeting older adults aged 65 and above, capable of completing a 6-meter walk, without severe major or life threatening diseases, and not institutionalized. Latent class analysis identified three distinct subgroups with different frailty phenotypes: non-mobility-type (weight loss and exhaustion), mobility-type frailty (slowness and weakness), and low physical activity. Comparing these groups with the robust group, people with mobility-type frailty had poorer body composition, worse bone health, poorer cognitive function, lower survival (hazard ratio: 6.82, p = 0.019), and poorer overall health outcomes (hazard ratio: 1.67, p = 0.040). People in the non-mobility-type group had poorer bone health and more metabolic serum abnormalities. In conclusion, mobility-type frailty was a better predictor of adverse outcomes. However, further investigation is needed to evaluate how these phenotypic subgroups may help in predicting prognosis or in developing interventions. [ABSTRACT FROM AUTHOR]

Background: Bihemispheric transcranial direct current stimulation (tDCS) of the primary motor cortex (M1) can simultaneously modulate bilateral corticospinal excitability and interhemispheric interaction. However, how tDCS affects subacute stroke recovery remains unclear. We investigated the effects of bihemispheric tDCS on motor recovery in subacute stroke patients. Methods: We enrolled subacute inpatients who had first-ever ischemic stroke at subcortical regions and moderate-to-severe baseline Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score 2–56. Participants between 14 and 28 days after stroke were double-blind, randomly assigned (1:1) to receive real (n = 13) or sham (n = 14) bihemispheric tDCS (with ipsilesional M1 anode and contralesional M1 cathode, 20 min, 2 mA) during task practice twice daily for 20 sessions in two weeks. Residual integrity of the ipsilesional corticospinal tract was stratified between groups. The primary efficacy outcome was the change in FMA-UE score from baseline (responder as an increase ≥ 10). The secondary measures included changes in the Action Research Arm Test (ARAT), FMA-Lower Extremity (FMA-LE) and explorative resting-state MRI functional connectivity (FC) of target regions after intervention and three months post-stroke. Results: Twenty-seven participants completed the study without significant adverse effects. Nineteen patients (70%) had no recordable baseline motor-evoked potentials (MEP-negative) from the paretic forearm. Compared with the sham group, the real tDCS group showed enhanced improvement of FMA-UE after intervention (p < 0.01, effect size η2 = 0.211; responder rate: 77% vs. 36%, p = 0.031), which sustained three months post-stroke (p < 0.01), but not ARAT. Interestingly, in the MEP-negative subgroup analysis, the FMA-UE improvement remained but delayed. Additionally, the FMA-LE improvement after real tDCS was not significantly greater until three months post-stroke (p < 0.01). We found that the individual FMA-UE improvements after real tDCS were associated with bilateral intrahemispheric, rather than interhemispheric, FC strengths in the targeted cortices, while the improvements after sham tDCS were associated with predominantly ipsilesional FC changes after adjustment for age and sex (p < 0.01). Conclusions: Bihemispheric tDCS during task-oriented training may facilitate motor recovery in subacute stroke patients, even with compromised corticospinal tract integrity. Further studies are warranted for tDCS efficacy and network-specific neuromodulation. Trial registration: This study is registered with ClinicalTrials.gov: (ID: NCT02731508). [ABSTRACT FROM AUTHOR]

Legionnaires’ disease (LD) is an acute form of pneumonia, and changing weather is considered a plausible risk factor. Yet, the relationship between weather and LD has rarely been investigated, especially using long-term daily data. In this study, daily data was used to evaluate the impacts of precipitation, temperature, and relative humidity on LD occurrence in Taiwan from 1995–2011. A time-stratified 2:1 matched-period case-crossover design was used to compare each case with self-controlled data using a conditional logistic regression analysis, and odds ratios (ORs) for LD occurrence was estimated. The city, gender and age were defined as a stratum for each matched set to modify the effects. For lag day- 0 to 15, the precipitation at lag day-11 significantly affected LD occurrence (p<0.05), and a 2.5% (95% CIs = 0.3–4.7%) increased risk of LD occurrence was associated with every 5-mm increase in precipitation. In addition, stratified analyses further showed that positive associations of precipitation with LD incidence were only significant in male and elderly groups and during the warm season ORs = 1.023–1.029). However, such an effect was not completely linear. Only precipitations at 21–40 (OR = 1.643 (95% CIs = 1.074–2.513)) and 61–80 mm (OR = 2.572 (1.106–5.978)) significantly increased the risk of LD occurrence. Moreover, a negative correlation between mean temperature at an 11-day lag and LD occurrence was also found (OR = 0.975 (0.953–0.996)). No significant association between relative humidity and LD occurrence was identified (p>0.05). In conclusion, in warm, humid regions, an increase of daily precipitation is likely to be a critical weather factor triggering LD occurrence where the risk is found particularly significant at an 11-day lag. Additionally, precipitation at 21–40 and 61–80 mm might make LD occurrence more likely. [ABSTRACT FROM AUTHOR]

Background. Inflammation and chronic kidney disease (CKD) are both associated with cardiovascular disease (CVD). Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood.Methods. The sample comprised Framingham Offspring cohort participants (n = 3294, mean age 61, 53% women) who attended the seventh examination cycle (1998–2001). Inflammatory biomarkers [C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha, interleukin-6, TNF receptor 2 (TNFR2), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD-40 ligand, osteoprotegerin, urinary isoprostanes, myeloperoxidase and fibrinogen] were measured on fasting blood samples. Serum creatinine-based estimated glomerular filtration rate (eGFR) and serum cystatin C concentration were used to assess kidney function. Urinary albumin-to-creatinine ratio (UACR) was used to assess albuminuria. Linear or logistic regression was used to test associations between biomarkers and kidney measures.Results. Chronic kidney disease (CKD), defined as eGFR < 59/64 mL/min/1.73 m2 in women/men, was present in 8.8% (n = 291) of participants. TNF-alpha, interleukin-6, TNFR2, MCP-1, osteoprotegerin, myeloperoxidase and fibrinogen were higher among individuals with CKD; all biomarkers except for urinary isoprostanes were elevated in higher cystatin C quartiles; and TNF-alpha, interleukin-6, TNFR2, ICAM-1 and osteoprotegerin were elevated in higher UACR quartiles—all assessed after multivariable adjustment. Almost 6% and 17% of variability in TNFR2 were explained by CKD status and higher cystatin C quartiles, respectively.Conclusions. Biomarkers of inflammation are associated with kidney function and albuminuria. In particular, substantial variability in soluble TNFR2 is explained by CKD and cystatin C. [ABSTRACT FROM AUTHOR]

Abstract: Background: Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers. Methods: In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n =2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using (1) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and (2) stepwise multivariable logistic regression with forward selection of markers with separate models for (1) ankle-brachial index (ABI) category (<0.9, 0.9–1.0, >1.0) and (2) presence of clinical PAD (intermittent claudication or lower extremity revascularization). Results: The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p =0.01 and p =0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p =0.005) and 1.19 (p =0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD. Conclusion: Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway. [Copyright &y& Elsevier]

Background: The prognostic value of chronic obstructive pulmonary disease (COPD) as a comorbidity in heart failure has been well documented. However, the role of pulmonary function indices in patients with heart failure and preserved ejection fraction (HFpEF) remains to be elucidated. Methods: Subjects with HFpEF received pulmonary function tests and echocardiogram. Total lung capacity (TLC), residual volume (RV), forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75), forced expiratory volume in the 1st second (FEV1), forced vital capacity (FVC), and vital capacity (VC) were measured. Echocardiographic indices, including pulmonary artery systolic pressure (PASP), the ratio of early ventricular filling flow velocity to the septal mitral annulus tissue velocity (E/e'), and left ventricular mass (LVM), were recorded. National Death Registry was linked for the identification of mortality. Results: A total of 1194 patients (72.4±13.2 years, 59% men) were enrolled. PASP, E/e' and LVM were associated with either obstructive (RV/TLC, FEV1 and FEF25-75) or restrictive (VC and TLC) ventilatory indices. During a mean follow-up of 23.0±12.8 months, 182 patients died. Subjects with COPD had a lower survival rate than those without COPD. While VC, FVC, RV/TLC, and FEV1 were all independently associated with all-cause mortality in patients without COPD, only FEF25-75 was predictive of outcomes in those with COPD. Conclusions: The abnormalities of pulmonary function were related to the cardiac hemodynamics in patients with HFpEF. In addition, these ventilatory indices were independently associated with long-term mortality, especially in those without COPD. [ABSTRACT FROM AUTHOR]

Background: Heart failure with mid-range ejection fraction (HFmrEF) has been proposed as a new phenotype of heart failure. We therefore investigated the pulsatile hemodynamic characteristics and outcomes in patients with HFmrEF, in comparison with those with reduced (HFrEF) or preserved (HFpEF) ejection fraction. Methods: The study was composed of two cohorts of patients hospitalized due to acute heart failure. Pulsatile hemodynamic measures, including carotid-femoral pulse wave velocity (cf-PWV), carotid pulse pressure (cPP), amplitude of the backward pressure wave (Pb) and carotid augmentation index (cAIx), were recorded on admission and before discharge in Cohort A (n = 230, mean age 69.9 ±15.4 years), and long-term follow-up was performed in Cohort B (n = 2677, mean age 76.3 ± 33.4 years). Results: In Cohort A, patients with HFmrEF had persistently greater cf-PWV, cPP, Pb, and cAI than those with HFrEF, both on admission and before discharge. In contrast, patients with HFmrEF and HFpEF had similar pulsatile hemodynamic characteristics. In cohort B, patients with HFmrEF and HFrEF had similar three-year mortality rates and both were significantly higher than that in patients with HFpEF (both P values < 0.05). Conclusions: Patients with HFmrEF were characterized by a worse left ventricular systolic function than patients with HFpEF and excessive wave reflections than patients with HFrEF. Future studies are required to confirm that the unfavorable ventriculo-arterial coupling in HFmrEF might play a role in the pathogenesis of high long-term mortality in these patients. [ABSTRACT FROM AUTHOR]

Study Type - Aetiology (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Genetic linkage to distinguish loci for VUR has been previously described in several autosomal chromosomes. Although there are numerous explanations for the dissimilar findings, e.g. multifactorial etiology of VUR and hereditary miscellany among studied populations, clinical diversity between males and females may indicate a central gender-specific genetic susceptibility. Early studies suggested the presence of modified VUR gene(s) on the X-chromosome, accounting for the higher incidence of this disorder among female members in the pedigrees studied. On the other hand male-to-male transmission and a higher ratio of females to males argued against X-linked inheritance. More recently, additional chromosomal regions (i.e. chromosomes 1-7, 10-13, and 18-22) have been identified for VUR by using single nucleotide polymorphism-genome-wide linkage analysis. This is the first study to show that there is autosomal difference in VUR expression in males and females. This genotype variability may be the basis for the clinical differences between genders in children with VUR. OBJECTIVE To assess gender-specific genetic differences in the susceptibility loci for vesico-ureteric reflux (VUR) in families who have two or more affected children., PATIENTS AND METHODS A genome-wide linkage analysis of VUR with high-density single nucleotide polymorphisms was conducted in 98 families with two or more affected children., A total of 221 affected offspring (123 sibling pairs) were included in the analysis., Genomic DNA was extracted from blood or saliva from all the patients., Data was stratified and analysed according to clinical presentation and gender of the proband and affected siblings., RESULTS Using the affected sib-pair method, statistically significant peaks were found on chromosomes 1 (logarithm of odds, base10 [LOD] 4.4) and 5 (LOD 3.7) in males and on chromosomes 3 (LOD 3.5), 13 (LOD 4.5), and 15 (LOD 3.4) in females., CONCLUSION This genotype variability might be the basis for the clinical differences between genders in children with VUR. Our data might be the first step to understanding the genetic background behind the gender-specific differences of VUR and more clearly defining the genetically different subgroups of VUR. [ABSTRACT FROM AUTHOR]

Background: Home blood pressure (BP) and unattended automated BP (uAOBP) monitoring have been recommended by guidelines for the care of hypertensive subjects. However, BP measurements in the peripheral arteries cannot serve as direct substitutes for their central counterparts. Moreover, the comparative effectiveness and safety of BP-guided strategies using these BP measuring devices have never been evaluated.Methods/design: Patients with uncontrolled or newly diagnosed hypertension aged 20-90 years will be recruited via outpatient clinics and allocated into three arms by stratified randomization (baseline systolic BP 130-155 mmHg and 155-180 mmHg): home BP, uAOBP, and central BP-guided treatment. At each scheduled visit to the clinic, a patient's BP will be measured by each of the three methods of measuring BP. The blood pressure from three different methods will be confirmed available at each visit. Patients and physicians will be blinded to the allocated interventions because they will use measured BP values in the clinic through a standardized report format. A common BP target for systolic blood pressure (SBP) of 130 mmHg is adopted for these BP-guided strategies. The primary outcome is the change of 24-h mean ambulatory SBP at 3 months. A key secondary outcome is to determine the percentage achieving their target BPs at 3 months and the decrease of left ventricular mass at 12 months.Discussion: To our knowledge, this is the first prospective double-blind randomized controlled trial to assess the optimal guiding strategy for hypertension. It will help to define which BP monitoring method is the most effective for guiding the clinical management of hypertension. It will provide good evidence to support future guideline recommendations for BP monitoring devices.Trial Registration: ClinicalTrials.gov, NCT03578848 . Registered on 4 June 2018. [ABSTRACT FROM AUTHOR]

Red cell distribution width (RCDW) has not been fully investigated for its prognostic impact in patients with acute heart failure (AHF) with or without the cardiorenal anemia syndrome (CRAS). A total of 978 patients (age 75 ± 14 years, 70% men, 43% with CRAS) hospitalized for AHF were enrolled. During a median follow-up duration of 31 months, 472 subjects (48%) died. The postdischarge mortality was positively associated with the increasing RCDW. After accounting for age, gender, co-morbidities, hemoglobin, renal function, sodium level, and N-terminal probrain natriuretic peptide, RCDW remained an independent predictor of mortality (hazard ratio [HR] and 95% CI for a 1% increase of RCDW: 1.09, 1.00 to 1.17, p = 0.04). In the subgroups of patients with or without CRAS, RCDW was an independent predictor of total mortality for both subgroups (HR 1.05, 95% CI 1.00 to 1.10 and HR 1.11, 95% CI 1.07 to 1.15, respectively). In conclusion, elevated RCDW was independently associated with mortality in patients hospitalized for AHF, with or without CRAS. [ABSTRACT FROM AUTHOR]

Schizencephaly is a rare malformation of cortical development characterized by congenital clefts extending from the pial surface to the lateral ventricle that are lined by heterotopic gray matter. The clinical presentation is variable and can include motor or cognitive impairment and epilepsy. The causes of schizencephaly are heterogeneous and can include teratogens, prenatal infection, or maternal trauma. Reported genetic causes include chromosomal aneuploidy, EMX2 mutations, and possible autosomal recessive familial cases based on recurrence in siblings. In an effort to identify risk factors for schizencephaly, we conducted a survey of 48 parents or primary caretakers of patients with schizencephaly born between 1983 and 2004. We discovered that young maternal age, lack of prenatal care, and alcohol use were all significantly associated with risk of schizencephaly. Our results suggest that there are important nongenetic, intrauterine events that predispose to schizencephaly. [ABSTRACT FROM AUTHOR]

Objective: To prospectively evaluate relationships among serum cytokine levels, innate immune responsiveness, and mortality in a multicenter cohort of critically ill children with influenza infection.Design: Prospective, multicenter, observational study.Setting: Fifteen pediatric ICUs among members of the Pediatric Acute Lung Injury and Sepsis Investigators network.Patients: Patients ≤18 yrs old admitted to a PICU with community-acquired influenza infection. A control group of outpatient children was also evaluated.Interventions: ICU patients underwent sampling within 72 hrs of ICU admission for measurement of a panel of 31 serum cytokine levels and quantification of whole blood ex vivo lipopolysaccharide-stimulated tumor necrosis factor-α production capacity using a standardized stimulation protocol. Outpatient control subjects also underwent measurement of tumor necrosis factor-α production capacity.Measurements and Main Results: Fifty-two patients (44 survivors, eight deaths) were sampled. High levels of serum cytokines (granulocyte macrophage colony-stimulating factor, interleukin-6, interleukin-8, interferon-inducible protein-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1α) were associated with mortality (p < 0.0016 for each comparison) as was the presence of secondary infection with Staphylococcus aureus (p = 0.007), particularly methicillin-resistant S. aureus (p < 0.0001). Nonsurvivors were immunosuppressed with leukopenia and markedly reduced tumor necrosis factor-α production capacity compared with outpatient control subjects (n = 21, p < 0.0001) and to ICU survivors (p < 0.0001). This association remained after controlling for multiple covariables. A tumor necrosis factor-α response <250 pg/mL was highly predictive of death and longer duration of ICU stay (p < 0.0001). Patients with S. aureus coinfection demonstrated the greatest degree of immunosuppression (p < 0.0001).Conclusions: High serum levels of cytokines can coexist with marked innate immune suppression in children with critical influenza. Severe, early innate immune suppression is highly associated with both S. aureus coinfection and mortality in this population. Multicenter innate immune function testing is feasible and can identify these high-risk children. [ABSTRACT FROM AUTHOR]

Cystatin C (CysC) is associated with cardiovascular disease (CVD) and chronic kidney disease (CKD). We examined the clinical correlates and heritability of CysC and determined if associations between CVD risk factors and CysC differed by CKD status. Among Framingham Heart Study offspring (examined from 1998-2001, n = 3,241, mean age 61 years, 54% women), the 95(th) percentile cut-point was developed for CysC in a healthy subset (n = 779) after excluding participants with diabetes, hypertension, low high-density lipoproteins, obesity, smoking, high triglycerides, prevalent CVD, and CKD (as defined by glomerular filtration rate <60 mL/min per 1.73 m(2)). Multivariable logistic regression was used to evaluate the association between CVD risk factors and high CysC (CysC > or =95(th) percentile cut-point). In a family-based subset (n = 1,188), we estimated CysC heritability using the variance-components method. The cut-point for high CysC was 1.07 mg/L. Age, hypertension treatment, low diastolic blood pressure, body mass index, low high-density lipoprotein cholesterol, and smoking were associated with high CysC in multivariable models. These factors and estimated glomerular filtration rate (egFR) explained 39.2% of CysC variability (R(2)). Excluding CKD did not materially change associations. Multivariable-adjusted heritability for CysC was 0.35 (p <0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD. [ABSTRACT FROM AUTHOR]

The prognostic factors and pharmacological effects of the very elderly patients (aged ≥80 years) with acute heart failure (AHF) remain unclear. The study, therefore, investigated the prognostic impacts of the guideline-recommended pharmacological therapy in these patients. A cohort of 1297 very elderly patients [85.1 ± 4.0 years, 69.7% male, 32.6% heart failure with reduced left ventricular ejection fraction (LVEF), HFrEF], hospitalized for AHF, was studied. The percentage of the recommended prescription for HFrEF at discharge, including renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists, was calculated as guideline adherence indicator (GAI). Among the 1233 survivors at discharge, 495 subjects (40.1%) died during a mean follow-up of 27.1 ± 23.9 months. Mean GAIs in HFrEF and HFpEF were 70.6 ± 34.9% and 64.1 ± 35.9%, respectively. A higher GAI was associated with less overall mortality [hazard ratio and 95% confidence interval per-1SD: 0.781, 0.655-0.930] and cardiovascular death (0.718, 0.558-0.925), independent of age, gender, diabetes, hypertension, mean blood pressure, LVEF, eGFR, sodium, and NT-proBNP. A GAI of 100% was associated with a better survival in both HFrEF and HFpEF. A prescription of the three recommended medications for HFrEF to the very elderly AHF patients was associated with a better survival after discharge. [ABSTRACT FROM AUTHOR]