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Background: Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU., Methods: We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed., Results: The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics., Conclusions: Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age., Impact: Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague-Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%-70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improved in vitro the viability of human mesangial cells . Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jankiewicz, Barnett, Stavniichuk, Hwang, Hammock, Belayet, Khan and Imig.)

Background: Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF., Methods: Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses., Results: Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLP NMR ) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLP NMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLP NMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-μmol·L -1 increase in S-HDLP NMR , p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects., Conclusions: Higher serum levels of S-HDLP NMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLP NMR may modify mortality risk in patients with IPF., Competing Interests: Conflict of interest: A.V. Barochia has nothing to disclose. Conflict of interest: M. Kaler has nothing to disclose. Conflict of interest: N. Weir has nothing to disclose. Conflict of interest: E.M. Gordon has nothing to disclose. Conflict of interest: D.M. Figueroa has nothing to disclose. Conflict of interest: X. Yao has nothing to disclose. Conflict of interest: M. Lemma WoldeHanna has nothing to disclose. Conflict of interest: M. Sampson has nothing to disclose. Conflict of interest: A.T. Remaley has nothing to disclose. Conflict of interest: G. Grant has nothing to disclose. Conflict of interest: S.D. Barnett has nothing to disclose. Conflict of interest: S.D. Nathan is a consultant and is on the speakers’ bureau for Roche-Genentech and Boehringer Ingelheim, and has received research funding from both companies. Conflict of interest: S.J. Levine has nothing to disclose., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2021. For commercial reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: Interpreting the radiologic data in conjunction with an objective clinical score could help to harmonize idiopathic pulmonary fibrosis (IPF) diagnosis and improve accuracy. Objectives: We sought to establish and validate a multivariable objective scoring model based on clinical parameters by stratifying the risk of patients having IPF diagnosed versus having other forms of interstitial lung disease (ILD) diagnosis. Methods: A clinical score was derived from review of patients evaluated at the Inova Fairfax ILD Program and validated in three distinct cohorts. On the basis of known IPF clinical characteristics, a multivariable model was created and assessed by using receiver operating characteristic curves. Results: There were 844 patients with ILD with either IPF ( n = 347, 41%) or non-IPF ILD ( n = 497, 59%) diagnosis. On the basis of calculated odds ratios, a score was assigned to each of the following clinical parameters: age, sex, smoking history, race or ethnicity, ILD family history, exposures, presence of connective tissue disease signs or symptoms, and velcro crackles. The final Fairfax IPF Clinical Score (FICS) ranged from 1 to 25. The clinical diagnostic score system was accurate in predicting IPF, as measured by the area under the curve (0.88) in the derivation cohort, with similar areas under the curve of 0.91, 0.81, and 0.71 being demonstrated in the respective validation cohorts. Conclusions: The FICS appears to be an accurate tool for estimating the pretest probability of IPF in patients with ILD. How the FICS performs in conjunction with the various high-resolution computed tomographic patterns remains to be determined. This model could ultimately be useful for increasing the degree of confidence in the final diagnosis and could help to obviate the need for lung biopsy in cases with non-usual interstitial pneumonia patterns on high-resolution computed tomographic images.

Introduction: To characterize normative morphometric, textural and microstructural placental development by applying advanced and quantitative magnetic resonance imaging (qMRI) techniques to the in-vivo placenta., Methods: We enrolled 195 women with uncomplicated, healthy singleton pregnancies in a prospective observational study. Women underwent MRI between 16- and 40-weeks' gestation. Morphometric and textural metrics of placental growth were calculated from T2-weighted (T2W) images, while measures of microstructural development were calculated from diffusion-weighted images (DWI). Normative tables and reference curves were constructed for each measured index across gestation and according to fetal sex., Results: Data from 269 MRI studies from 169 pregnant women were included in the analyses. During the study period, placentas undergo significant increases in morphometric measures of volume, thickness, and elongation. Placental texture reveals increasing variability with advancing gestation as measured by grey level non uniformity, run length non uniformity and long run high grey level emphasis. Placental microstructure did not vary with gestational age. Placental elongation was the only metric that differed significantly between male and female fetuses., Discussion: We report quantitative metrics of placental morphometry, texture and microstructure in a large cohort of healthy controls during the second and third trimesters of pregnancy. These measures can serve as normative references of in-vivo placental development to better understand placental function in high-risk conditions and allow for the early detection of placental mal-development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Due to random motion of fetuses and maternal respirations, image quality of fetal brain MRIs varies considerably. To address this issue, visual inspection of the images is performed during acquisition phase and after 3D-reconstruction, and the images are re-acquired if they are deemed to be of insufficient quality. However, this process is time-consuming and subjective. Multi-instance (MI) deep learning methods (DLMs) may perform this task automatically., Purpose: To propose an MI count-based DLM (MI-CB-DLM), an MI vote-based DLM (MI-VB-DLM), and an MI feature-embedding DLM (MI-FE-DLM) for automatic assessment of 3D fetal-brain MR image quality. To quantify influence of fetal gestational age (GA) on DLM performance., Study Type: Retrospective., Subjects: Two hundred and seventy-one MR exams from 211 fetuses (mean GA ± SD = 30.9 ± 5.5 weeks)., Field Strength/sequence: T 2 -weighted single-shot fast spin-echo acquired at 1.5 T., Assessment: The T 2 -weighted images were reconstructed in 3D. Then, two fetal neuroradiologists, a clinical neuroscientist, and a fetal MRI technician independently labeled the reconstructed images as 1 or 0 based on image quality (1 = high; 0 = low). These labels were fused and served as ground truth. The proposed DLMs were trained and evaluated using three repeated 10-fold cross-validations (training and validation sets of 244 and 27 scans). To quantify GA influence, this variable was included as an input of the DLMs., Statistical Tests: DLM performance was evaluated using precision, recall, F-score, accuracy, and AUC values., Results: Precision, recall, F-score, accuracy, and AUC averaged over the three cross validations were 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.85 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM (without GA); 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.75 ± 0.03, 0.81 ± 0.03, for MI-VB-DLM (without GA); 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.81 ± 0.01, 0.89 ± 0.01, for MI-FE-DLM (without GA); and 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.86 ± 0.01, 0.93 ± 0.01, for MI-CB-DLM with GA., Data Conclusion: MI-CB-DLM performed better than other DLMs. Including GA as an input of MI-CB-DLM improved its performance. MI-CB-DLM may potentially be used to objectively and rapidly assess fetal MR image quality., Evidence Level: 4 TECHNICAL EFFICACY: Stage 3., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: A usual interstitial pneumonia (UIP) pattern is common in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-related interstitial lung disease (CTD-ILD). The purpose of the study was to validate imaging findings differentiating CTD-ILD from IPF in UIP., Methods: Patients with a multidisciplinary diagnosis of CTD-ILD or IPF and a UIP pattern on computed tomography and/or pathology were included in this study. Prevalence of 3 computed tomography findings shown to be associated with CTD-ILD (the straight edge sign [SES], the exuberant honeycombing sign, and the anterior upper lobe sign [AULS]) were tabulated in CTD-ILD and IPF subjects. The ability of each of these signs to discriminate between CTD-ILD and IPF was evaluated. Survival analysis was also performed using log-rank analysis., Results: The study cohort included 50 CTD-ILD and 100 IPF subjects with UIP. The SES and the AULS were more common in CTD-ILD than IPF (prevalence, 36.0% and 34.9% in CTD-ILD vs 8.3% and 17.2% in IPF, respectively [P = 0.0105 - <0.001]). The highest specificity (95.7%) of CTD-ILD diagnosis was seen with bilateral SES. Moreover, the SES was associated with improved survival (P = 0.0383), which appeared to be largely because of improvement in survival in IPF subjects. The presence of AULS was associated with pulmonary functional abnormalities., Conclusions: A radiographic UIP pattern with evidence of SES or the AULS should raise suspicion for CTD-ILD rather than IPF. Patients with IPF and SES have an attenuated disease course and might represent a different phenotype than those without the SES., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study was undertaken to select an appropriate tool to predict risk of obstructive sleep apnea (OSA) among pediatric patients in the preoperative setting., Design/methods: A retrospective chart review and a survey of nursing staff to compare two tools that were determined to be valid in assessing risk of OSA and postanesthesia complications in pediatric patients aged 6 months to 18 years was conducted. About 300 pediatric patients presenting for elective surgery were screened for OSA using STBUR (Snoring, Trouble Breathing during sleep, struggling to Breathe during Sleep, and waking UnRefreshed) and ST(1)OP-BANG (Snoring, Tonsillar hypertrophy, sleep Obstruction, BMI, Age, Neuromuscular disorders, and Genetic/congenital deformities) concurrently. Six preoperative nurses were then surveyed to compare ease of use and time to complete the screening tools., Findings: The STBUR tool was found to predict complications in 37.5% patients versus 22.7% patients with the pediatric ST(1)OP-BANG. Nursing staff found that although both tools were quick and easy to use, the STBUR tool was easier for parents to answer., Conclusions: Use of a screening tool to help predict risk of OSA and postanesthetic complications also helps to dictate anesthesia technique, nursing staffing requirements, and plans of care for postoperative management of pediatric patients., (Copyright © 2020 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Background: Minorities and women are underrepresented in cardiovascular research. Whether their higher enrollment can be predicted or influences research site performance is unclear., Methods: We evaluated 104 sites that enrolled 4,184 patients in the U.S. Platinum Diversity (PD) and Promus Element Plus (PE Plus) studies (2012 to 2016). Research sites were ranked from lowest to highest minority and female enrollment, respectively. United States Census Bureau division and core-based statistical area (CBSA) populations were determined for each site and the following study performance metrics compared across quartiles of minority and female enrollment, respectively: (1) study subject enrollment rate (SER), (2) time to first patient enrolled, (3) rate of follow-up visits not done, (4) rate of follow-up visits out of window, and (5) protocol deviation rate (PDR). Multivariable regression was used to predict SER and PDR., Results: Minority enrollment varied by region (P = .025) and population (P = .024) with highest recruitment noted in the Pacific, West South Central, South Atlantic, Mid-Atlantic and East North Central divisions. Female enrollment bore no relationship to region (P = .67) or population (P = .40). Median SER was similar in sites withi the highest vs lowest quartile of minority enrollment (SER of 4 vs 5 patients per month, respectively, P =0.78) and highest vs. lowest female enrollment (SER of 4 vs 4, respectively, P = .21). Median PDR was lower in sites within the highest vs lowest minority enrollment (0.23 vs 0.50 PDs per patient per month, respectively, P = .01) and highest vs. lowest female enrollment (0.28 vs. 0.37 PDs per patient per month, respectively, P = .04). However, this relationship did not persist after multivariable adjustment. All other site performance metrics were comparable across quartiles of minority and female enrollment., Conclusions: Minority, but not female enrollment, correlated with research site geographic region and surrounding population. High enrollment of minorities and women did not influence study performance metrics. These findings help inform future strategies aimed at increasing clinical trial diversity., Trial Registration: The PD and PE Plus studies are registered at www.clinicaltrials.gov under identifiers NCT02240810 and NCT01589978, respectively., Key Points: Question: Does the enrollment of more Blacks, Hispanics and women in US cardiovascular research studies influence the overall rate of study subject enrollment and/or other key study site performance metrics and can diverse enrollment be predicted?, Findings: In this pooled analysis of 104 sites that enrolled 4,184 patients in the Platinum Diversity and Promus Element Plus Post-Approval Studies, we found that the enrollment of higher proportions of underrepresented minorities and women was univariately associated with lower protocol deviation rates while having no effect on other site performance metrics. A site's geographic location and surrounding population predicted minority, but not female enrollment. Meaning: These findings suggest that cardiovascular research subject diversity may be predicted from site characteristics and enhanced without compromising key study performance metrics. These insights help inform future strategies aimed at improving clinical trial diversity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD., Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients., Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD., Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

Currently available tocolytics are ineffective at significantly delaying preterm birth. This is due in part to our failure to better understand the mechanisms that drive spontaneous preterm labor (sPTL). Cyclic nucleotides are not the primary contributors to myometrial quiescence, but instead nitric oxide (NO)-mediated protein S -nitrosation (SNO) is integral to the relaxation of the tissue. Connexin-43 (Cx43), a myometrial "contractile-associated protein" that functions as either a gap junction channel or an hemichannel (HC), was the focus of this study. Protein analysis determined that Cx43 is downregulated in sPTL myometrium. Furthermore, Cx43 is S -nitrosated by NO, which correlates with an increase of phosphorylated Cx43 at serine 368 (Cx43-pS368 -gap junction inhibition) as well as an increase in the HC open-state probability (quiescence). Pharmacologic inhibition of Cx43 with 18 β -glycyrrhetinic acid (18 β -GA) exhibits a negative inotropic effect on the myometrium in a dose-dependent manner, as does administration of nebivolol, an NO synthase activator that increases total protein SNOs. When 18 β -GA and nebivolol were coadministered at their IC 50 values, the effect on contractile dynamics was additive and all but eliminated contractions. The development of new tocolytics demands a better understanding of the underlying mechanisms of sPTL. Here it has been shown that 18 β -GA and nebivolol leverage dysregulated pathways in the myometrium, resulting in a novel approach for the treatment of sPTL. SIGNIFICANCE STATEMENT: Although there are many known causes of preterm labor (PTL), the mechanisms of "spontaneous" PTL (sPTL) remain obfuscated, which is why treating this condition is so challenging. Here we have identified that connexin-43 (Cx43), an important contractile-associated protein, is dysregulated in sPTL myometrium and that the pharmacologic inhibition of Cx43 and its S -nitrosation with 18 β -glycyrrhetinic acid and nebivolol, respectively, significantly blunts contraction in human myometrial tissue, presenting a novel approach to tocolysis that leverages maladjusted pathways in women who experience sPTL., (Copyright © 2021 by The Author(s).)

Background: Cure rates of hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) for patients with active and inactive hepatocellular carcinoma (HCC) may differ, but well-controlled studies are limited. We aimed to evaluate DAA outcomes in a large East Asian HCV/HCC population compared with HCV/non-HCC patients., Methods: Using data from the Real-World Evidence from the Asia Liver Consortium (REAL-C) registry (Hong Kong, Japan, South Korea, and Taiwan), we used propensity score matching (PSM) to match HCC and non-HCC (1:1) groups for age, sex, cirrhosis, prior treatment, HCV genotype, treatment regimen, baseline platelet count, HCV RNA, total bilirubin, alanine aminotransferase, and albumin levels to evaluate DAA treatment outcomes in a large population of HCV/HCC compared with HCV/non-HCC patients., Results: We included 6081 patients (HCC, n = 465; non-HCC, n = 5 616) treated with interferon-free DAAs. PSM of the entire study population yielded 436 matched pairs with similar baseline characteristics. There was no statistically significant difference in the overall SVR rate of HCC (92.7%) and non-HCC (95.0%) groups. Rates of treatment discontinuation, adverse effects, and death were also similar between HCC and non-HCC groups. Among patients with HCC, those with active HCC had a lower SVR than inactive HCC cases (85.5% vs 93.7%; P = .03). On multivariable analysis, active HCC, but not inactive HCC, was significantly associated with lower SVR (OR, 0.28; P = .01) when compared with non-HCC., Conclusions: Active HCC but not inactive HCC was independently associated with lower SVR compared with non-HCC patients undergoing DAA therapy, although cure rate was still relatively high (85%) in active HCC patients., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background and Purpose: Using remote visual monitoring (RVM) technology to observe patients at high risk for falls can effectively reduce falls and sitter costs. However, RVM is underutilized by direct care nurses. This study describes the development and testing of a new tool to measure nurses' acceptance of RVM technology., Methods: The RVM Acceptance Tool (RVMAT) was tested among nurses recruited from a large health system., Results: Three factors accounted for 70.38% of the total variance: Value, Patient Selection, and Availability and Intent to Use. The overall 25-item scale had good internal consistency (Cronbach's alpha = .98)., Conclusion: The RVMAT is a theoretically grounded, valid, and reliable tool. Further research is needed to test its use in predicting nurses' acceptance and intent to incorporate new technology into daily nursing care., (© Copyright 2020 Springer Publishing Company, LLC.)

The current alanine aminotransferase (ALT) upper limit of normal was defined using selected healthy Caucasian blood donors. Given the global rise in obesity and different body habitus in Asians, we aimed to perform a systematic review and meta-analysis combined with bootstrap modeling and individual patient data validation to estimate the ALT upper threshold for Asians, including the overweight and diabetics. We included studies from PubMed, Embase, and Cochrane database searches that identified individuals without known liver diseases (i.e., viral hepatitis, alcohol, and ultrasound-detected nonalcoholic fatty liver disease). The mean ALT (U/L) was estimated using a random-effects mixed model and upper threshold (95th-percentile value, U/L) via a bootstrap model with 10,000 resamples. We screened 4,995 studies and identified 86 studies that reported ALT values for 526,641 individuals without excessive alcohol intake or known liver diseases, yielding a mean ALT of 19 and ALT upper threshold of 32. The ALT upper threshold was 37 in males versus 31 in females, 39 in overweight versus 28 in normal-weight individuals, and 36 for diabetics versus 33 for nondiabetics. We validated our study level data with individual patient level data in 6,058 individuals from five study centers in Japan. Consistent with our study-level data, we found that the ALT upper threshold in our individual patient data analysis was indeed higher in overweight versus normal-weight individuals (39 vs. 32) and in diabetics versus nondiabetics (42 vs. 33). Conclusion: We provide validated reference ranges for ALT upper threshold derived from Asians without known liver disease, including individuals with ultrasound-detected nonalcoholic fatty liver disease who are normal weight, overweight, nondiabetic, and diabetic, to inform practice., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Background: The course of idiopathic pulmonary fibrosis (IPF) is uncertain with variable patterns of disease progression. We sought to evaluate the prognostic utility of the WBC, a routinely performed lab test, in a well-defined cohort of outpatient IPF subjects., Methods: We reviewed IPF patient records from two independent ILD centers (Inova Fairfax in Falls Church, VA, USA and Ege University Hospital in Izmir, Turkey) between 2007 and 2018. Demographics, CBC data, and patient outcomes were obtained. Survival differences were analyzed., Results: There were 436 IPF outpatients in the cohort with a median WBC of 8.9 × 10 9  cells per liter. For pragmatic purposes, patients were categorized into two groups, WBC ≥9 or WBC <9. Patients with WBC <9 had a median transplant-free survival of 50.5 months from the time of the CBC, compared to 32.4 months for those with WBC ≥9 (p < 0.0001). The association between WBC and attenuated survival remained significant after adjusting for GAP stage, steroid use, and antifibrotic use when WBC was analyzed both as a continuous (HR: 1.11; 95% CI: 1.05-1.17) and a dichotomized variable (high (WBC ≥9) vs. low (WBC <9), (HR: 1.53; 95% CI:1.09-2.15). WBC and absolute neutrophil count (ANC) were highly correlated suggesting that PMNs account for most of this association (r = 0.92)., Conclusions: Baseline WBC may impart important and readily available prognostic information in outpatients with IPF. Further studies are warranted to validate this as a potential biomarker for IPF, as well as to define the biologic basis for the association., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Readmissions cost an estimated $41 billion in the United States each year. To address this, a single institution recently developed a new risk model predictive of 30-day readmission after adult cardiac surgery. The purpose of this study is to validate and refine this new readmission risk model using a statewide database., Methods: A total of 19,964 patients were analyzed using a statewide Society of Thoracic Surgeons database (2014-2017). The aforementioned multivariate model was replicated (model 1): race, hospital length of stay, chronic lung disease, operation type, and renal failure. Model 2 also included discharge location. Thirty-day readmission risk scores and low-risk (0%-10%), moderate-risk (10%-13%), and high-risk (≥13%) categories were calculated., Results: The overall 30-day readmission rate was 11.1% with both models 1 and 2 predicting readmission (odds ratio, 1.09; 95% confidence interval, 1.08-1.11 vs odds ratio, 1.10; 95% confidence interval, 1.08-1.11). Statistically significant differences were observed across all risk categories in discharge location and total cost. For models 1 and 2, 86% of low-risk patients were discharged to home vs 66.9% and 42.9% of patients in high-risk groups, respectively (P < .001). The largest increases were observed with a hospice discharge location for both model 1 (from $37,930 to $89,285) and model 2 (from $37,930 to $89,230)., Conclusions: Both risk models significantly predicted 30-day readmission in our multiinstitutional dataset, confirming the score is valid and a generalizable quality improvement tool. The addition of discharge location and total cost adds valuable information of the ongoing efforts to identify patients at high risk for readmission., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The international Registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients., Methods: ReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival., Results: Data from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide ( D LCO ) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV 1 )/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort., Conclusion: Reduced D LCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV 1 /FVC ratio was identified as an independent risk factor for worsened outcomes., Competing Interests: Conflict of interest: O.A. Shlobin reports personal fees for consultancy from United Therapeutics, Bayer and Johnson & Johnson, outside the submitted work. Conflict of interest: V. Kouranos has nothing to disclose. Conflict of interest: S.D. Barnett has nothing to disclose. Conflict of interest: E.H. Alhamad has nothing to disclose. Conflict of interest: D.A. Culver reports institutional funding for the registry from Gilead, during the conduct of the study; personal fees for advisory board work from Johnson and Johnson, outside the submitted work. Conflict of interest: J. Barney has nothing to disclose. Conflict of interest: F.C. Cordova has nothing to disclose. Conflict of interest: E.M. Carmona reports financial support for the clinical trial from Gilead, during the conduct of the study; personal fees for consultancy and developing education materials from CHEST, personal fees for editorial work from Elsevier, outside the submitted work. Conflict of interest: M.B. Scholand has performed advisory board work and been investigator in clinical trials for Boehringer Ingelheim and Genentech, and been investigator in clinical trials for Fibrogen and Global Blood Therapeutics, outside the submitted work; and has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued. Conflict of interest: M. Wijsenbeek has nothing to disclose. Conflict of interest: S. Ganesh has nothing to disclose. Conflict of interest: E.E. Lower reports grants from Gilead, Bayer and Genentech, during the conduct of the study. Conflict of interest: P.J. Engel has nothing to disclose. Conflict of interest: J. Wort reports grants and personal fees from Actelion Pharmaceuticals and Bayer Pharmaceuticals, personal fees from MSD, outside the submitted work. Conflict of interest: L. Price reports personal fees and education support from Actelion and Johnson & Johnson, during the conduct of the study. Conflict of interest: A.U. Wells reports personal fees from Boehringer Ingelheim, Roche, Intermune and Bayer, outside the submitted work. Conflict of interest: S.D. Nathan reports personal fees for consultancy from United Therapeutics, Bayer Pharmaceuticals, Bellerophon and Actelion, during the conduct of the study. Conflict of interest: R.P. Baughman reports grants from Gilead, Bayer, Genentech, Foundation for Sarcoidosis Research and National Institutes of Health, grants and personal fees for consultancy from Actelion, grants and personal fees for consultancy and lectures from Mallinckrodt, during the conduct of the study., (Copyright ©ERS 2020.)

Background: The impact of hospitalization on patient outcomes is increasingly recognized and considered in the prognostication of many pulmonary disorders. We sought to evaluate the impact of hospitalization on survival in connective tissue disease-interstitial lung disease (CTD-ILD) patients., Methods: A chart review of patients with CTD-ILD followed at a tertiary care center was performed. Patients were stratified into two groups based on hospitalization status. Outcomes of the groups were compared using Kaplan-Meier survival analyses as well as multivariate competing risk analysis., Results: There were 137 patients identified with confirmed CTD-ILD. Patients who underwent hospitalization for any reason had a significant decrease in transplant-free survival compared to the never hospitalized cohort (3-year survival 60% vs. 94%; p = 0.0001). Hospitalization for ≥7 days was associated with worse outcomes than those hospitalized for <7 days (median survival 1.59 years vs. 7.17 years, p = 0.0012). Based on multivariate competing risk analysis, factors associated with death, with lung transplantation as a competing risk, were age (HR = 1.05 [95% 1.01-1.09]; P = 0.0443), male gender (HR = 4.94 [95% CI: 1.58-15.41]; P = 0.006), and all cause hospitalization (HR = 11.97 [95% CI: 1.36-105.49]; P = 0.0253)., Conclusion: This study highlights the impact of hospitalization on subsequent outcomes in the CTD-ILD population with a significantly reduced transplant-free survival demonstrated, especially after cardiopulmonary hospitalization events., (Published by Elsevier Ltd.)

Introduction: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was designed to assess the impact of the adverse effects of heart failure (HF). Numerous reports suggest an additional third factor with the proposed third factor representing a social dimension. The purpose of this study was to use confirmatory factor analysis (CFA) to validate the factor structure of the MLWHFQ, and examine a proposed third factor structure., Methods: Participants were 1290 individuals with open heart surgery for isolated valve repair or replacement between September 2005 and May 2016. Confirmatory factor analysis was used to assess both initial and proposed alternate factor structures., Results: CFA indicated a poor fit for the original proposed 2-factor solution [root mean square error of approximation (RMSEA) = 0.116], whereas separate proposed 3-factor solutions with varying item scoring fit marginally well (RMSEA = 0.080, 0.089). The CFA suggests the existence of a third dimension, social, beyond the established original two-factor solution. Results suggest in a direct comparison of proposed social dimensions, both Garin's four item solution and Munyombwe's six-item solution provide similar results., Conclusions: Results suggest support for an additional third factor among patients undergoing isolated valve replacement surgery. We suggest given the inclusion of items important to our population, relatively strong fit indices, and correlation with the SF-12, the social dimension proposed by Munyombwe best fits our population.

Objectives: To examine community reintegration problems among Veterans and military service members with mild or moderate/severe traumatic brain injury (TBI) at 1 year postinjury and to identify unique predictors that may contribute to these difficulties., Setting: VA Polytrauma Rehabilitation Centers., Participants: Participants were 154 inpatients enrolled in the VA TBI Model Systems Program with available injury severity data (mild = 28.6%; moderate/severe = 71.4%) and 1-year postinjury outcome data., Design: Prospective, longitudinal cohort., Main Measures: Community reintegration outcomes included independent driving, employability, and general community participation. Additional measures assessed depression, posttraumatic stress, and cognitive and motor functioning., Results: In the mild TBI (mTBI) group, posttraumatic stress disorder and depressive symptoms were associated with lower levels of various community reintegration outcomes. In the moderate/severe TBI group, cognition and motor skills were significantly associated with lower levels of community participation, independent driving, and employability., Conclusion: Community reintegration is problematic for Veterans and active duty service members with a history of TBI. Unique comorbidities across injury severity groups inhibit full reintegration into the community. These findings highlight the ongoing rehabilitation needs of persons with TBI, specifically evidence-based mental healthcare, in comprehensive rehabilitation programs consistent with a chronic disease management model.

Background: Return to work is associated with positive rehabilitation outcomes for persons with spinal cord injury (SCI); however, more research is needed on vocational support for persons with disabilities seeking employment., Objective: The association between facilitators and barriers of employment and employment outcome was examined among Veterans with SCI who participated in an evidence-based supported employment (EBSE) program., Methods: Using a mixed-methods, nested case-control design, data on facilitators and barriers to employment were extracted from qualitative interviews and quantitative measures administered in person to 34 Veterans with SCI who completed 12 months of an EBSE program. Participants who did (case) and did not (control) obtain competitive employment were matched on time since SCI. Facilitators and barriers to employment were compared between the groups., Results: Self-report measures administered at baseline were examined; there were no statistically significant factors that predicted employment outcomes after 12 months of EBSE program participation. Qualitative interview data revealed program-specific facilitators and Veteran characteristics that were associated with employment outcomes., Conclusions: Qualitative data illustrate how the integration of the vocational rehabilitation specialist on the medical team is helpful for addressing identified disability-specific barriers, including practical matters such as transportation and caregiving schedules, to facilitate employment outcomes.

Background: Designing effective vocational programs for persons with spinal cord injury (SCI) is essential for improving return to work outcome following injury. The relationship between specific vocational services and positive employment outcome has not been empirically studied., Objective: To examine the association of specific vocational service activities as predictors of employment., Method: Secondary analysis of a randomized, controlled trial of evidence-based supported employment (EBSE) with 12-month follow-up data among 81 Veteran participants with SCI., Results: Primary activities recorded were vocational counseling (23.9%) and vocational case management (23.8%). As expected, job development and employment supports were the most time-consuming activities per appointment. Though the amount of time spent in weekly appointments did not differ by employment outcome, participants obtaining competitive employment averaged significantly more individual activities per appointment. Further, for these participants, job development or placement and employment follow-along or supports were more likely to occur and vocational counseling was less likely to occur. Community-based employment services, including job development or placement and employment follow-along or supports as part of a supported employment model, were associated with competitive employment outcomes. Office-based vocational counseling services, which are common to general models of vocational rehabilitation, were associated with a lack of employment., Conclusions: Vocational services that actively engage Veterans with SCI in job seeking and acquisition and that provide on-the-job support are more likely to lead to employment than general vocational counseling that involves only job preparation.

Purpose: To investigate the impact of social support at home on health-related quality of life (HRQOL) as measured by the VR-6D utility index for spinal cord injury (SCI) veterans participating in a program of supported employment (SE)., Methods: We calculated a preference-based utility index called the VR-6D from the responses from a 36-item instrument called the VR-36. We estimated a growth curve model to examine the change in the VR-6D utility index over time adjusting for social support status, demographics, and chronic comorbidities., Results: Study participants experienced an increase in HRQOL over time. The initial level and the rate of increase in HRQOL varied by groups based on their support status. The rate of increase in HRQOL diminished over time. Participants reporting no support at home experienced lower initial HRQOL but reached the same level of those who reported having support at home by the ninth month of follow-up. Quality-adjusted life-years, as measured by the area under the curves, were approximately the same for both groups after 2 years., Conclusions: Differences in the rate of change in HRQOL by support status have important implications for evaluations of SE programs. Participants in this program of SE experienced improvement in HRQOL beyond 12 months and extending to 2 years. Follow-up times for evaluations should extend beyond 12 months to assess complete improvements in HRQOL. Future comparison groups in comparative effectiveness evaluations of SE need to be balanced carefully on support status in addition to other factors.

Objective: We theorized that ability to direct and control a horse will lead to a sense of empowerment, facilitate a relationship between horse and veteran, lead to a decrease in anxiety, and improve physical and social functioning., Methods: This case study utilizes the Connection methodology: nonverbal language of the horse in a predictable, sequential, and repeatable method. Psychological testing occurred immediately pre- and post-Connection with follow-up occurring at 2, 4, 6, and 12 wks post-Connection., Participant: Twice-deployed combat medic who served in Operation Iraqi Freedom (OIF)., Setting: Saratoga Springs, New York., Primary Outcome Measures: Beck Depression Inventory-II (BDI-II); Posttraumatic Stress Disorder Checklist (PCL-C); the Response to Stressful Experiences Scale (RSES); the Quality of Life Inventory (QOLI); and the Modified Social Support Survey (MSSS)., Results: The participant demonstrated significant improvement in measures of psychological functioning (eg, over 12 wks); both PCL-C and RSES scores decreased 58% and 44%, respectively. Participant further reported an increase in sleep quality., Conclusion: The results of this case study strongly support the potential for the intervention and indicate the need for a controlled, randomized study that might more stringently investigate the impact of the intervention.

Background: Patients with pleural effusions who reside in geographic areas with a high prevalence of tuberculosis frequently have similar clinical manifestations of other diseases. The aim of our study was to develop a simple but accurate clinical score for differential diagnosis of tuberculosis pleural effusion (TPE) from non-TB pleural effusion (NTPE)., Methods: This was an unblinded, prospective study of Turkish patients 18 years of age or older with pleural effusion of indeterminate etiology conducted from June 2003 to June 2005. Unconditional logistic regression models were used to discriminate TPE cases from NTPE cases. Standard errors for the area under the curve (AUC) were calculated using the Mann-Whitney method. Data were statistically significance if two-tailed P < 0.05., Results: A total of 63.3% (157/248) of the patients had TPE while 36.7% (91/248) of the patients had other etiologies for pleural effusions. We were able to provide a predictive model of TPE that included age <47 years and either pleural fluid adenosine deaminase enzyme (PADA) >35 U/l or pleural serum protein ratio >0.710. However, only the combination of age <47 and PADA >35 U/l was significant (odds ratio [OR]: 7.46; 95% confidence interval [CI]: 3.99-13.96). The generated summary score (range = 0-6) was significantly predictive of TPE (OR: 2.91; 95% CI: 2.18-3.89) and with high AUC (0.79)., Conclusion: We propose an affordable model that includes age <47 years and PADA >35 U/l for timely diagnosis of TPE in geographical regions with a high prevalence of TB.

Objective: : Several risk models exist to predict operative outcomes after cardiac surgery and are used in selecting patients for alternative procedures such as transcatheter valve implantation. We sought to evaluate the performance of the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) model in accurately identifying patients at high risk for aortic valve replacement (AVR)., Methods: : Three hundred and ninety four consecutive patients who underwent isolated AVR from January 1, 2001, to July 1, 2007, at a tertiary care center were analyzed using the STS database. Patients were stratified into tertiles according to operative surgical risk calculated by the four models [STS-PROM, European system for cardiac operative risk evaluation (EuroSCORE), Ambler, and Providence]. Vital status at 1 year was determined using the National Death Index and Social Security Death Index., Results: : There were 310 low-risk patients, 56 intermediate-risk patients, and 28 high-risk patients with respect to the STS-PROM. The predicted risk of death for the low-risk, intermediate-risk, and high-risk groups were 2.4% ± 1.1%, 6.9% ± 1.4%, 15.8% ± 7.6% (P < 0.001) with respect to the STS-PROM model. Actual operative mortality for each respective group was 1.94%, 5.36%, 14.29% (P < 0.001) and 1-year mortality was 3.23%, 12.50%, 21.43% (P < 0.001), respectively., Conclusions: : High-risk patients have significantly high mortality after AVR. The STS-PROM accurately predicts operative mortality and can be used to predict 1-year survival as well. This risk model may be preferentially used instead of the EuroSCORE.

The effect of increased body mass index (BMI) on survival following open heart surgery is unclear. We explored the relationship between BMI, survival following elective open heart surgery, and health-related quality of life. Our results suggest that increased BMI need not be a deterrent for undergoing open heart surgery. Patients with increased BMI can expect similar complication rates, significant gains in health-related quality of life at 1 year, and comparable intermediate survival.

The release of 2 landmark reports by the Institute of Medicine titled, "To Err Is Human: Building a Safer Health System" and "Crossing the Quality Chasm" were instrumental in the identification of safety and quality issues. Since their release, federal and state programs of public reporting of performance measures have attempted to close the quality gap of care that is inappropriate, not timely, or lacking an evidence base. Cardiac surgery has long been the focus of public scrutiny, and now, as we move from an era of managed care to public reporting, reimbursement for cardiac surgery procedures will be tied to performance. However, the question is whether public reporting and pay for performance will ultimately improve the quality of patient care, safety, and provide the consumer with enough information to make surgeon and institutional choices. Will the cost and focus of achieving perfection with performance standards overshadow any real improvement in clinical outcomes?