Association between spirometry pattern, left ventricular diastolic function, and mortality.

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.

Effects of bihemispheric transcranial direct current stimulation on motor recovery in subacute stroke patients: a double-blind, randomized sham-controlled trial.

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).

Comparison between American Institute of Medicine Guidelines and Local Recommendation for Gestational Weight Gain in Taiwanese Primiparous Women.

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.

Feasibility of the transcatheter mitral valve repair for patients with severe mitral regurgitation and endangered heart failure.

BACKGROUND: The transcatheter edge-to-edge mitral valve repair using MitraClip has been a safe and effective treatment for severe mitral regurgitation (MR). In patients with severe MR and cardiogenic shock under hemodynamic supporting devices, emergent surgical mitral valve interventions carry extremely high risk for peri-operative morbidities and mortalities. The feasibility and efficacy of emergent MitraClip to rescue patients in critical conditions remains elucidate. METHODS: Patients with severe MR and high or prohibitive surgical risks were referred for MitraClip procedures. Emergent MitraClip were conducted in patients with unstable hemodynamics and under mechanical or inotropic support. The hemodynamic measures, transthoracic echocardiography, transesophageal echocardiography, and blood tests were performed before MitraClip procedures. Procedural success was defined as having mild mitral regurgitation immediately after MitraClip, and patients were free from in-hospital mortality. Clinical and echocardiographic outcomes were followed by telephones and clinics. RESULTS: Among 50 consecutive patients (74.7 ± 11.2 years, 74% male), 8 emergent MitraClip procedures were conducted to rescue patients with cardiogenic shock. Extracorporeal membrane oxygenations were used in 2 patients and intra-aortic balloon pump were applied in 4 patients (50%). Compare to those who underwent elective procedures, patients underwent emergent MitraClip had higher surgical risk profile (EuroSCORE II 34.8% vs 5.1% and STS score 19.7% vs 5.1%), poorer renal function and higher right atrial pressure. There was no peri-procedural death, myocardial infarction, stroke or any adverse events requiring emergent cardiac surgery in both groups. Mild mitral regurgitation was achieved in 87.5% patients from the emergent group and 95.2% patients in the elective group (P = 0.514). The Kaplan-Meier analysis showed patients who underwent emergent procedures have poorer long-term survival rate as compare to those who received elective procedures. (P value = 0.008). CONCLUSION: When open-heart surgery is not feasible, trans-catheter mitral valve repair is an alternative way to rescue patients in cardiogenic shock status.

Association Between Targeted Aortic Segment Tortuosity and Stent-Graft-Induced New Entry After Thoracic Endovascular Aortic Repair for Aortic Dissection or Intramural Hematoma.

OBJECTIVE. The aim of this study was to investigate the association between the tortuosity of the targeted aortic segment (TAS) for stent-graft implantation and distal stent-graft-induced new entry (SINE) after thoracic endovascular aortic repair (TEVAR) for aortic dissection or intramural hematoma. MATERIALS AND METHODS. We retrospectively analyzed data from 70 patients who underwent TEVAR using a single stent-graft between 2006 and 2016, and the tortuosity index of the TAS was measured. The patients were divided into high and low TAS tortuosity groups according to the median value of the tortuosity index. The incidence of distal SINE was compared between the two groups. RESULTS. The cumulative incidence of distal SINE at 2 years after TEVAR was 39% in patients in the high TAS tortuosity group and 7% in patients in the low TAS tortuosity group. The incidence of distal SINE was higher in patients in the high TAS tortuosity group than in those in the low TAS tortuosity group (p < 0.01, log-rank test). Multivariate Cox regression showed a higher risk of distal SINE in the high TAS tortuosity group (adjusted hazard ratio, 4.56 [95% CI, 1.40-14.86]; p = 0.01). CONCLUSION. Patients with high TAS tortuosity have a higher incidence of distal SINE after TEVAR. More caution must be exercised during follow-up of patients with high TAS tortuosity after TEVAR.

Prognostic Comparison of the Estimations of Renal Function in Patients With Acute Heart Failure.

BACKGROUND: The prognostic significance of the eGFR calculated by either the four-level Race Chronic Kidney Disease-Epidemiology Collaboration study equation (CKD-EPI4R) or the Chinese-modified Modification of Diet in Renal Disease equation (cMDRD) has not been compared in Asian populations with acute heart failure (AHF).Methods and Results:A total of 3,044 patients hospitalized for AHF were enrolled. The National Death Registry was linked to identify deaths within a 5-year follow-up. Net reclassification improvement (NRI) was calculated to compare the prognostic value of either eGFR equation. During a median follow-up of 23.3 months, 1,424 (47%) patients died. Both eGFRcMDRDand eGFRCKD-EPI4Rwere independently predictive of death in the total study population (hazard ratio and 95% confidence intervals per 1-SD: 0.76, 0.71-0.81 and 0.74, 0.70-0.79, respectively), and in the subgroups of either reduced (HFrEF) or preserved (HFpEF) ejection fraction, after accounting for important confounders. With reference to eGFRcMDRD, eGFRCKD-EPI4Rmay improve the NRI by 2.0% (0.8-3.2%) for the prediction of death. The prognostic value of the CKD stages categorized by eGFRCKD-EPI4Rsignificantly outperformed eGFRcMDRDwith a categorical NRI of 9.5% (4.7-14.3%) in the total study population, 11.5% in HFrEF, and 8.3% in HFpEF. CONCLUSIONS: Both eGFRcMDRDand eGFRCKD-EPI4Rwere independently associated with long-term survival in patients with AHF. However, the CKD stages derived from eGFRCKD-EPI4Rimproved the risk stratification of death, compared with eGFRcMDRD.

Interobserver and intraobserver variability in measuring the tortuosity of the thoracic aorta on computed tomography.

OBJECTIVE: The variability in measuring the tortuosity of the thoracic aorta has not been previously studied. This study evaluated the interobserver and intraobserver variability of major methods used for measuring the tortuosity of the thoracic aorta in patients with aortic arch or descending thoracic aortic aneurysm. METHODS: This retrospective study enrolled 66 patients with aortic arch or descending thoracic aortic aneurysm who had undergone thoracic endovascular aortic repair. Two radiologists used preoperative computed tomography images to measure the tortuosity of the thoracic aorta at multiple segments by using the fitting circle diameter, tortuosity index, and centerline angle methods; these measurements were repeated after an interval of >28 days. The variability of the methods was analyzed for interobserver and intraobserver reliability and agreement. The estimated intraclass correlation coefficient (ICC) was used to analyze the reliability. The Bland-Altman plot was used to analyze the interobserver and intraobserver agreement. The association between aortic characteristics, including calcification, luminal irregularity, shape, and diameter, and the variability of the measurements was also analyzed. RESULTS: The interobserver ICC estimates for the tortuosity index at multiple aortic segments, centerline angle methods at the supra-aortic branch orifices, and fitting circle diameter on the greater and lesser curvature sides were 0.97 to 0.98, 0.39 to 0.75, and 0.82 to 0.84, respectively. The corresponding intraobserver ICC estimates were 0.98 to 1.00, 0.44 to 0.75, and 0.82 to 0.85, respectively. In the agreement analysis, the 95% limits of agreement for the tortuosity index, centerline angle, and fitting circle diameter were -5.5% to 5.6%, -10.9% to 10.9%, and -18.0% to 24.0%, respectively. The tortuosity index had the highest ICC estimate and narrowest 99.5% limits of agreement of the three methods. Aortic characteristics, including calcification, grade of atheroma, aneurysm shape, and diameter, were not associated with the variability of the tortuosity index method in the thoracic aorta. CONCLUSIONS: The tortuosity index method has low interobserver and intraobserver variability in measuring the tortuosity of the thoracic aorta in patients with thoracic aortic aneurysm. The characteristics of the aorta and aneurysm are not associated with the interobserver or intraobserver variability of the tortuosity index.

Evaluation of factors contributing to the decline in exclusive breastfeeding at 6 months postpartum: The 2011-2016 National Surveys in Taiwan.

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.

Determinants and Prognostic Impact of Hyperuricemia in Hospitalization for Acute Heart Failure.

BACKGROUND: Hyperuricemia is a prognostic factor in patients with chronic heart failure, but whether uric acid level can predict clinical outcome of acute heart failure (AHF) remains to be elucidated. We therefore investigated the association of uric acid with mortality in patients hospitalized for AHF. METHODS AND RESULTS: Data for patients hospitalized for AHF were drawn from an intramural registry. Biochemistry data, echocardiographic characteristics, and uric acid level were collected. National Death Registry was linked for the identification of mortality data. Among a total of 1,835 participants (age, 75 ± 13 years, 68% men), 794 patients died during follow-up. Patients who died were older, had lower hemoglobin and estimated glomerular filtration rate, and higher pulmonary artery systolic pressure, NT-proBNP, and uric acid. Uric acid was a significant predictor of mortality on univariate analysis (HR per 1 SD, 1.18; 95% CI: 1.11-1.26) and in multivariate Cox models (HR, 1.15; 95% CI: 1.02-1.29). Survival analysis showed an increasing risk of death along the quartile distribution of uric acid level. Given renal function, cardiac performance, and kidney perfusion as major determinants of hyperuricemia, the prognostic impact of uric acid level was diminished as renal function deteriorated. CONCLUSIONS: Uric acid level was an independent predictor of mortality in patients hospitalized for AHF, but the prognostic impact of hyperuricemia was attenuated by worsening renal function.

Endometriosis Might Be Inversely Associated with Developing Chronic Kidney Disease: A Population-Based Cohort Study in Taiwan.

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of endometriosis and 27,973 multivariable-matched controls (1:1) from 2000 to 2010 were selected. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of CKD among women with endometriosis. The incidence rates (IR, per 10,000 person-years) of CKD among women with and without endometriosis were 4.64 and 7.01, respectively, with a significantly decreased risk of CKD (crude HR 0.65, 95% CI 0.53-0.81; adjusted HR 0.69, 95% CI 0.56-0.86) among women with endometriosis. The IR of CKD progressively increased with age, but the trend of lower CKD risk among women with endometriosis was consistent. However, the lower risk of CKD in women with endometriosis was no longer statistically significant after adjusting for menopausal status (adjusted HR 0.85, 95% CI 0.65-1.10). The results suggest that endometriosis is inversely associated with CKD, but this effect was mediated by menopause. The possible mechanism of this association is worthy of further evaluation.

A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization.

Extremes of the electrocardiographic QT interval, a measure of cardiac repolarization, are associated with increased cardiovascular mortality. We identified a common genetic variant influencing this quantitative trait through a genome-wide association study on 200 subjects at the extremes of a population-based QT interval distribution of 3,966 subjects from the KORA cohort in Germany, with follow-up screening of selected markers in the remainder of the cohort. We validated statistically significant findings in two independent samples of 2,646 subjects from Germany and 1,805 subjects from the US Framingham Heart Study. This genome-wide study identified NOS1AP (CAPON), a regulator of neuronal nitric oxide synthase, as a new target that modulates cardiac repolarization. Approximately 60% of subjects of European ancestry carry at least one minor allele of the NOS1AP genetic variant, which explains up to 1.5% of QT interval variation.

The logistic regression model for gene-environment interactions using both case-parent trios and unrelated case-controls.

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.

An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis.

BACKGROUND: Epidemiological evidence of relationships between endometriosis and epithelial ovarian cancer (EOC) has been obtained mainly from Western countries. Our goal was to determine the risk of EOC due to endometriosis in Taiwanese women. METHODS: A retrospective cohort study was performed by linking to the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 5,945 women with a new surgico-pathological diagnosis of endometriosis from 2000 to 2010 and 23,780 multivariable-matched controls (1:4) were selected. The Cox regression model adjusted for potential confounders was used to assess the risk of EOC due to endometriosis. RESULTS: The EOC incidence rate (IR) of the women with and without endometriosis was 11.64 and 2.66 per 10,000 person-years, contributing to a crude hazard ratio (HR) of 4.48 (95% confidence interval [CI] 2.84-7.06), and HR after adjustment for all confounders (adjusted HR) of 5.62 (95% CI 3.46-9.14); the risk was higher in clear-cell carcinoma subtypes (adjusted HR 7.36, 95% CI 1.91-28.33). The EOC IR of women with endometriosis consistently increased with increasing age, ranging from 4.99 (<30 years) to 35.81 (≥50 years) per 10,000 person-years, contributing to a progressively increased risk of EOC (crude HRs ranging from 2.80 to 6.74 and adjusted HRs ranging from 3.34 to 9.63) compared to age-matched women without endometriosis, whose EOC IR also increased with age. The older women (≥50 years) with endometriosis had a risk of EOC that was higher than both the age-matched women without endometriosis (adjusted HR 9.63, 95% CI 3.27-28.37) and the youngest women (<30 years) with endometriosis (adjusted HR 4.97, 95% CI 1.03-24.09). CONCLUSIONS: These significant findings corroborate the previously reported association between endometriosis and increased risk of EOC. Since the risk of EOC in women with a new surgico-pathological diagnosis of endometriosis constantly increased with age and this increased risk of EOC was more significant in women aged ≥50 years, active and intensive surgical intervention should be taken into consideration for older women with endometriosis.

Right ventricular scalloping index as cardiac magnetic resonance-derived marker for diagnosis of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: The cardiac magnetic resonance (CMR) evaluation of right ventricular (RV) morphologic abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is subjective. Here, we aimed to use a quantitative index, the right ventricular scalloping index (RVSI), to standardize the measurement of RV free wall scalloping and aid in the imaging diagnosis. METHODS: We retrospectively included 15 patients with definite ARVC and 45 age- and sex-matched patients with idiopathic right ventricular outflow tract ventricular arrhythmia (RVOT-VA) as controls. The RVSI was measured from cine images on four-chamber view to evaluate its ability to distinguish between ARVC and RVOT-VA patients. Other cardiac functional parameters including strain analysis were also performed. RESULTS: The RVSI was significantly higher in the ARVC than RVOT-VA group (1.56 ± 0.23 vs 1.30 ± 0.08, p < 0.001). The diagnostic performance of the RVSI was superior to the RV global longitudinal, circumferential, and radial strains, RV ejection fraction, and RV end-diastolic volume index. The RVSI demonstrated high intraobserver and interobserver reliability (intraclass correlation coefficient, 0.94 and 0.96, respectively). RVSI was a strong discriminator between ARVC and RVOT-VA patients (area under curve [AUC], 0.91; 95% CI, 0.82-0.99). A cutoff value of RVSI ≥1.49 provided an accuracy of 90.0%, specificity of 97.8%, sensitivity of 66.7%, positive predictive value (PPV) of 90.9%, and a negative predictive value (NPV) of 89.8%. In a multivariable analysis, a family history of ARVC or sudden cardiac death (odds ratio, 38.71; 95% CI, 1.48-1011.05; p = 0.028) and an RVSI ≥1.49 (odds ratio, 64.72; 95% CI, 4.58-914.63; p = 0.002) remained predictive of definite ARVC. CONCLUSION: RVSI is a quantitative method with good performance for the diagnosis of definite ARVC.

Cardiovascular Risk in Patients With Treated Isolated Diastolic Hypertension and Isolated Low Diastolic Blood Pressure.

BACKGROUND: The prognosis of high or markedly low diastolic blood pressure (DBP) with normalized on-treatment systolic blood pressure on major adverse cardiovascular events (MACEs) is uncertain. This study examined whether treated isolated diastolic hypertension (IDH) and treated isolated low DBP (ILDBP) were associated with MACEs in patients with hypertension. METHODS AND RESULTS: A total of 7582 patients with on-treatment systolic blood pressure <130 mm Hg from SPRINT (Systolic Blood Pressure Intervention Trial) were categorized on the basis of average DBP: <60 mm Hg (n=1031; treated ILDBP), 60 to 79 mm Hg (n=5432), ≥80 mm Hg (n=1119; treated IDH). MACE risk was estimated using Cox proportional-hazards models. Among the SPRINT participants, median age was 67.0 years and 64.9% were men. Over a median follow-up of 3.4 years, 512 patients developed a MACE. The incidence of MACEs was 3.9 cases per 100 person-years for treated ILDBP, 1.9 cases for DBP 60 to 79 mm Hg, and 1.8 cases for treated IDH. Comparing with DBP 60 to 79 mm Hg, treated ILDBP was associated with an 1.32-fold MACE risk (hazard ratio [HR], 1.32, 95% CI, 1.05-1.66), whereas treated IDH was not (HR, 1.18 [95% CI, 0.87-1.59]). There was no effect modification by age, sex, atherosclerotic cardiovascular disease risk, or cardiovascular disease history (all P values for interaction >0.05). CONCLUSIONS: In this secondary analysis of SPRINT, among treated patients with normalized systolic blood pressure, excessively low DBP was associated with an increased MACE risk, while treated IDH was not. Further research is required for treated ILDBP management.

Innate immune function and mortality in critically ill children with influenza: a multicenter study.

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.

Symptom-limited exercise capacity is associated with long-term survival.

The prognostic value of exercise capacity has been demonstrated in subjects with established cardiovascular diseases. We aim to evaluate the independence of exercise capacity measured by treadmill exercise test (TET) in predicting long-term outcomes among various comorbidities. This study was conducted from January 2003 to December 2012 in a tertiary medical center in Taiwan. Subjects referred for symptom-limited TET were recruited. Peak achieved metabolic equivalents (METs) were determined by treadmill grade and speed at peak exercise. The main outcomes were cardiovascular and all-cause mortality by linking to the National Death Registry. A total of 18,954 participants (57.8 ± 12.8 years, 62% men) achieved a mean peak METs of 9.2. Subjects in the lowest tertile of peak METs were older, had poorer renal function, lower hemoglobin, and more comorbidities. During a median follow-up of 4.3 years, there were 642 mortalities and 132 cardiovascular deaths. Peak METs significantly predicted cardiovascular death and all-cause mortality in the multivariable Cox regression models [hazard ratio (95% confidence intervals): 0.788 (0.660-0.940) and 0.835 (0.772-0.903), respectively]. The prognostic influence of peak METs consistently appeared in the subgroups, regardless of age, gender, body weight, comorbidities, use of beta-blockers, or the presence of exercise-induced ischemia. The fitness was more predictive of long-term outcomes in young or those with ischemic changes during TET (P for interaction: 0.035 and 0.018, respectively). The benefit of fitness was nonlinearly associated with long-term survival. The prognostic impacts of exercise capacity were universally observed in subjects with or without various comorbidities.

A novel test of informative missingness using inconsistent linkage disequilibrium signals between case-parent triads and incomplete data.

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.

Genome gender diversity in affected sib-pairs with familial vesico-ureteric reflux identified by single nucleotide polymorphism linkage analysis.

UNLABELLED: 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.

The adult galactosemic phenotype.

BACKGROUND: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. METHODS: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. RESULTS: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. CONCLUSIONS: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.