Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune challenge-induced oxidative damage may be mitigated by biliverdin

ABSTRACT An effective immune response results in the elimination of pathogens, but this immunological benefit may be accompanied by increased levels of oxidative damage. However, organisms have evolved mechanisms to mitigate the extent of such oxidative damage, including the production and mobilization of antioxidants. One potential mechanism of mitigating immune challenge-induced changes in oxidative physiology is increasing biliverdin production. Biliverdin is chemically an antioxidant, but within-tissue correlations between biliverdin concentration and oxidative damage have never been directly examined. To test how biliverdin tissue concentrations are associated with physiological responses to an immune challenge, we exposed northern bobwhite quail (Colinus virginianus) to one of four treatments: injection of a non-pathogenic antigen – either lipopolysaccharide or phytohemagglutinin, control injection of phosphate-buffered saline or a sham procedure with no injection. Twenty-four hours later, we quantified oxidative damage and triglyceride concentration in the plasma, and biliverdin concentration in the plasma, liver and spleen. We found that both types of immune challenge increased oxidative damage relative to both non-injected and vehicle-injected controls, but treatment had no effects on any other metric. However, across all birds, oxidative damage and biliverdin concentration in the plasma were negatively correlated, which is consistent with a localized antioxidant function of biliverdin. Additionally, we uncovered multiple links between biliverdin concentration, change in mass during the immune challenges and triglyceride levels, suggesting that pathways associated with biliverdin production may also be associated with aspects of nutrient mobilization. Future experiments that manipulate biliverdin levels or oxidative damage directly could establish a systemic antioxidant function or elucidate important physiological impacts on body mass maintenance and triglyceride storage, mobilization or transport. Summary: In quail, plasma levels of oxidative damage and biliverdin concentration are negatively correlated, consistent with a localized antioxidant function of biliverdin.
Trajectories of Emotional and Conduct Problems and Their Association With Early High School Achievement and Engagement for Adolescents With ADHD

Objective: This study aimed to (a) identify longitudinal trajectories of emotional and conduct problems from middle childhood to early adolescence in a sample of 130 adolescents diagnosed with ADHD and (b) examine trajectories in relation to early adolescent academic achievement and engagement. Method: Group-based trajectory models (GBTMs) were constructed from the parent-rated strengths and difficulties questionnaire (SDQ) subscales of emotional and conduct problems at three time points, mean ages 10.7 years, 11.6 years, and 13.7 years. Associations between trajectories and adolescent academic achievement and engagement were examined using multivariate regression. Results: Four distinct trajectories were identified within each domain. High-persistent problem trajectories in each domain were associated with poorer achievement and lower school engagement compared with adolescents following persistent-low problem trajectories. Conclusion: Findings highlight the importance of early assessment and management of comorbid emotional and conduct problems for children with ADHD as they predict school difficulties during early high school. (J. of Att. Dis. XXXX; XX(X) XX-XX)
Sexual orientation, disclosure, and cardiovascular stress reactivity

Abstract Stigma may strain the heart health of lesbian, gay, and bisexual (LGB) individuals. To date, however, LGB-related differences in cardiovascular diagnosis, risk factors, and basal biomarkers are inconsistently reported. Using a laboratory-based stress paradigm, the current study assessed whether cardiovascular stress reactivity differs as a function of sexual orientation and disclosure status (“coming out”) in a sample of healthy young LGB and heterosexual adults. Eighty-seven participants aged 18–45 (M = 24.61 ± 0.61 SE) identifying as LGB and heterosexual (47%) were exposed to the Trier Social Stress Test, a well-validated laboratory stressor involving public speaking and mental arithmetic. Throughout a two-hour session, ambulatory recordings for heart rate and blood pressure were collected. Self-report questionnaires were also administered to assess psychosocial and demographic variables. Gay/bisexual men showed higher heart rate and lesbian/bisexual women showed marginally higher mean arterial blood pressure in response to a stressor, compared to sex- and age-matched heterosexuals. No significant differences emerged when comparing LGB individuals who had completely disclosed and those that had not completely disclosed their sexual orientation to family and friends. Compared to heterosexuals, heart rate is higher among gay/bisexual men and blood pressure is marginally higher among lesbian/bisexual women when exposed to a laboratory-based stressor. These preliminary findings contribute to small literature on sexual orientation differences in stress reactive biomarkers that requires further exploration. Lay abstract In response to stress exposure in a laboratory, gay/bisexual men showed higher heart rate than heterosexual men. By contrast, lesbian/bisexual showed a non-significant tendency towards higher blood pressure than heterosexual women. These preliminary findings suggest that the heart health of LGB individuals might be strained by stigma exposure.
Complexin cooperates with Bruchpilot to tether synaptic vesicles to the active zone cytomatrix

Information processing by the nervous system depends on the release of neurotransmitter from synaptic vesicles (SVs) at the presynaptic active zone. Molecular components of the cytomatrix at the active zone (CAZ) regulate the final stages of the SV cycle preceding exocytosis and thereby shape the efficacy and plasticity of synaptic transmission. Part of this regulation is reflected by a physical association of SVs with filamentous CAZ structures. However, our understanding of the protein interactions underlying SV tethering by the CAZ is far from complete. The very C-terminal region of Bruchpilot (Brp), a key component of the Drosophila CAZ, participates in SV tethering. Yet so far, no vesicular or cytoplasmic molecules have been reported to engage in an interaction with Brp’s C-terminus. Here, we carried out an in vivo screen for molecules that link the Brp C-terminus to SVs. This strategy identified the conserved SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) regulator Complexin (Cpx) as a vesicular interaction partner of Brp. We show that Brp and Cpx interact genetically and functionally. Interfering with Cpx targeting to SVs mirrored distinctive features of a C-terminal Brp truncation: impaired SV recruitment to the CAZ and enhanced short-term synaptic depression. Extending the study beyond Drosophila synapses, we interrogated active zones of mouse rod bipolar cells. Here, too, we collected evidence for an evolutionarily conserved role of Cpx upstream of SNARE complex assembly where it participates in SV tethering to the CAZ.
Does Routine Pressure Wire Assessment Influence Management Strategy at Coronary Angiography for Diagnosis of Chest Pain?: The RIPCORD Study

Background—The use of coronary angiography (CA) for diagnosis and management of chest pain (CP) has several flaws. The assessment of coronary artery disease using fractional flow reserve (FFR) is a well-validated technique for describing lesion-level ischemia and improves clinical outcome in the context of percutaneous coronary intervention. The impact of routine FFR at the time of diagnostic CA on patient management has not been determined. Methods and Results—Two hundred patients with stable CP underwent CA for clinical indications. The supervising cardiologist (S.C.) made a management plan based on CA (optimal medical therapy alone, percutaneous coronary intervention, coronary artery bypass grafting, or more information required) and also recorded which stenoses were significant. An interventional cardiologist then measured FFR in all patent coronary arteries of stentable diameter (≥2.25 mm). S.C. was then asked to make a second management plan when FFR results were disclosed. Overall, after disclosure of FFR data, management plan based on CA alone was changed in 26% of patients, and the number and localization of functional stenoses changed in 32%. Specifically, of 72 cases in which optimal medical therapy was recommended after CA, 9 (13%) were actually referred for revascularization with FFR data. By contrast, of 89 cases in whom management plan was optimal medical therapy based on FFR, revascularization would have been recommended in 25 (28%) based on CA. Conclusions—Routine measurement of FFR at CA has important influence both on which coronary arteries have significant stenoses and on patient management. These findings could have important implications for clinical practice. Clinical Trial Registration—URL: http://www.clinicaltrial. gov. Unique identifier: NCT01070771.
Validity and reliability of lower‐limb pulse‐wave velocity assessments using an oscillometric technique

What is the central question of this study? There is growing interest in the effects of sedentarism on central and peripheral cardiovascular health. To permit further investigation, including larger epidemiological studies, there is a need to identify arterial health assessment tools that are valid (accurate) and reliable (precise), yet practical. What is the main finding and its importance? Lower‐limb vascular health (femoral–ankle pulse‐wave velocity) can be determined in a supine position with accuracy and precision using an oscillometrically based device. This technology might help to improve our understanding of the pathological mechanisms linking cardiovascular disease to sedentarism, including the interaction between peripheral and central vasculature.
Walk Score® and Its Associations with Older Adults’ Health Behaviors and Outcomes

This study aimed to investigate the associations between Walk Score® and lifestyle behaviors and health outcomes in older Taiwanese adults. A nationwide survey was conducted through telephone-based interviews with older adults (65 years and older) in Taiwan. Data on Walk Score®, lifestyle behaviors (physical activity, sedentary behavior, healthy eating behavior, alcohol use, and smoking status), health outcomes (overweight/obesity, hypertension, type 2 diabetes, and cardiovascular disease), and personal characteristics were obtained from 1052 respondents. A binary logistic regression adjusting for potential confounders was employed. None of the Walk Score® categories were related to the recommended levels of total physical activity. The categories “very walkable” and “walker’s paradise” were positively related to total sedentary time and TV viewing among older adults. No significant associations were found between Walk Score® and other lifestyle health behaviors or health outcomes. While Walk Score® was not associated with recommended levels of physical activity, it was positively related to prolonged sedentary time in the context of a non-Western country. The different associations between the walk score and health lifestyle behaviors and health outcomes in different contexts should be noted.
Reverse Epidemiology of Blood Pressure in Peritoneal Dialysis Associated with Dynamic Deterioration of Left Ventricular Function

♦ Background: Reverse epidemiology of blood pressure (BP) in end-stage kidney disease (ESKD) is manifested as higher mortality at lower blood pressure. We hypothesize that this phenomenon is partially mediated by deterioration of cardiac structure and function. ♦ Methods: Seventy-seven prevalent ESKD patients starting renal replacement therapy on peritoneal dialysis (PD) from 2007 to 2012 were evaluated for the primary outcome of all-cause mortality. Longitudinal data were obtained from 1,930 patient-encounters including monthly clinic BP and serial echocardiograms. Generalized linear mixed models using data from the last observation moving backward, and time-to-event analysis using time-varying Cox-survival models to estimate mortality risk at different blood pressure categories were applied. ♦ Results: There were 39 males (50.6%). Mean age was 51 years (standard deviation [SD] = 15). During follow-up, 20 patients (25%) died. As compared to systolic blood pressure (SBP) of 140 – 159 mmHg, unadjusted risk of mortality was 7.3 (95% confidence interval [CI]: 1.5 – 35.7, p = 0.008) at level < 120 mmHg. Systolic BP trended down to an average of 117 mmHg prior to death in non-survivors as compared to 141 mmHg in survivors (p < 0.05). In non-survivors, percentage with concentric left ventricular hypertrophy (LVH) decreased by 20% at the expense of a 20% reciprocal increase in eccentric hypertrophy associated with a 30% increase in percentage with low ejection fraction (EF) (< 50%). After adjusting for EF, risk of mortality at SBP < 120 mmHg attenuated to 3.4 (95% CI: 0.7 – 17.7, p = 0.14). ♦ Conclusion: We conclude that higher mortality associated with lower BP may be mediated in part by worsening heart function in ESKD patients receiving PD.
Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE

Glioblastoma (GBM) is a deadly disease with few effective therapies. Although much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is composed of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage to support registration. Therapeutic arms with biomarkers may be added to the trial over time, while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice. Clin Cancer Res; 24(4); 737–43. ©2017 AACR.
Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

ABSTRACT Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.
18F-Fluoroestradiol PET Imaging of Activating Estrogen Receptor-α Mutations in Breast Cancer

The purpose of this study was to determine the effect of estrogen receptor-α gene (ESR1) mutations at the tyrosine (Y) 537 amino acid residue within the ligand binding domain on 18F-fluoroestradiol (18F-FES) binding and in vivo tumor uptake compared with wild-type (WT)-estrogen receptor α (ER). Methods: ER-negative MDA-MB-231 breast cancer cells were used to generate stable cell lines that express WT-ER, Y537S, or Y537C mutant ER. Receptor expression and localization were confirmed by Western blot and immunofluorescence, respectively. ER transcriptional function was measured using an estrogen response element-luciferase reporter gene assay and quantitative polymerase chain reaction analysis of ER-regulated endogenous target genes. Saturation binding and competition assays were performed to determine equilibrium dissociation constant (Kd) and half maximal inhibitory concentration (IC50) values. 18F-FES uptake was measured in tumor xenografts grown in female athymic nude mice by small-animal PET/CT imaging and tissue biodistribution using 5.55 MBq (150 μCi) of 18F-FES. A 10-fold-lower injected dose of 0.555 MBq (15 μCi) of 18F-FES was also used for tissue biodistribution. Statistical significance was determined using ANOVA. Results: Y537S and Y537C mutations resulted in increased ER transcriptional activity in the absence of estrogen compared with WT-ER (11.48 ± 2.42 fold; P = 0.0002, and 5.89 ± 0.94 fold; P = 0.04, respectively). Constitutive ER activation of two target genes (PGR and TFF1) in the absence of estrogen was also observed in Y537S- and Y537C-ER cells compared with WT-ER. Kd values for 18F-FES were 0.98 ± 0.54 nM for Y537S-ER (P = 0.27) and 0.24 ± 0.03 nM for Y537C-ER (P = 0.95) compared with 0.07 ± 0.03 nM for WT-ER. IC50 values were 0.22 ± 0.09 nM for Y537S-ER (P = 0.97), 0.18 ± 0.09 nM for Y537C-ER (P = 0.99), and 0.19 ± 0.11 nM for WT-ER. Tumor xenografts expressing Y537S-ER (mean percentage injected dose per gram, 1.45 ± 0.06; P = 0.77) and Y537C-ER (2.09 ± 0.20; P = 0.21) had similar 18F-FES uptake compared with WT-ER (1.68 ± 0.12). Comparable 18F-FES uptake between Y537S-, Y537C-, and WT-ER xenografts was also observed using a 10-fold-lower injected dose with the tissue biodistribution assay. Conclusion: Since tumoral uptake of 18F-FES is not significantly impacted by Y537S-ER or Y537C-ER mutations, the potential diagnostic utility of 18F-FES PET imaging is expected to be equally valid for patients with or without these activating ESR1 mutations.
Machine-Learning-Based Laboratory Developed Test for the Diagnosis of Sepsis in High-Risk Patients

Sepsis, a dysregulated host response to infection, is a major health burden in terms of both mortality and cost. The difficulties clinicians face in diagnosing sepsis, alongside the insufficiencies of diagnostic biomarkers, motivate the present study. This work develops a machine-learning-based sepsis diagnostic for a high-risk patient group, using a geographically and institutionally diverse collection of nearly 500,000 patient health records. Using only a minimal set of clinical variables, our diagnostics outperform common severity scoring systems and sepsis biomarkers and benefit from being available immediately upon ordering.
Disasters and youth: a meta-analytic examination of posttraumatic stress.

OBJECTIVE Meta-analyze the literature on posttraumatic stress (PTS) symptoms in youths post-disaster. METHOD Meta-analytic synthesis of the literature (k = 96 studies; Ntotal = 74,154) summarizing the magnitude of associations between disasters and youth PTS, and key factors associated with variations in the magnitude of these associations. We included peer-reviewed studies published prior to 1/1/2009 that quantitatively examined youth PTS (≤ 18 years at event) after a distinct and identifiable disaster. RESULTS Despite variability across studies, disasters had a significant effect on youth PTS (small-to-medium magnitude; rpooled = .19, SEr = .03; d = 0.4). Female gender (rpooled = .14), higher death toll (disasters of death toll ≤ 25: rpooled = .09; vs. disasters with ≥ 1,000 deaths: rpooled = .22), child proximity (rpooled = .33), personal loss (rpooled = .16), perceived threat (rpooled = .34), and distress (rpooled = .38) at time of event were each associated with increased PTS. Studies conducted within 1 year post-disaster, studies that used established measures, and studies that relied on child-report data identified a significant effect. CONCLUSION Youths are vulnerable to appreciable PTS after disaster, with pre-existing child characteristics, aspects of the disaster experience, and study methodology each associated with variations in the effect magnitude. Findings underscore the importance of measurement considerations in post-disaster research. Areas in need of research include the long-term impact of disasters, disaster-related media exposure, prior trauma and psychopathology, social support, ethnicity/race, prejudice, parental psychopathology, and the effects of disasters in developing regions of the world. Policy and clinical implications are discussed.
Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint inhibitors (ICIs) in nonsmall cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD), compared to those without COPD. This study aimed to investigate the clinical impact of COPD on the treatment response to ICIs in a large number of patients with NSCLC. In total, 133 patients with spirometry test results were retrospectively identified among those who received palliative pembrolizumab for NSCLC. COPD was defined as pre‐bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.7. Overall survival (OS), progression‐free survival (PFS), and objective response rate were analyzed according to the presence of COPD. Spirometry‐based COPD was present in 59 (44%) patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45; 95% confidence interval [CI], 0.26–0.78) and PFS (HR for disease progression or death, 0.50; 95% CI, 0.31–0.79) than those without COPD. These associations persisted after adjusting for potential confounders including smoking history. The response rate was also higher in patients with COPD than in those without COPD (38.2% vs. 20.5%, p = 0.028). Spirometry‐defined COPD was associated with a significantly longer OS and PFS in patients with NSCLC treated with palliative pembrolizumab. Identifying coexisting COPD could predict favorable treatment outcomes in patients with NSCLC treated with pembrolizumab.