bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Remote Ischemic Perconditioning on Renal Water and Salt Handling in Rats Subjected to Renal Ischemia/Reperfusion
Authors: Kristensen Marie Louise , Lassen Casper , Birn Henrik , Nørregaard Rikke 
Published: June 2021

Renal ischemia/reperfusion (I/R) can lead to acute kidney injury, characterized by increased urine output and fractional excretion of sodium (FE(Na)). Previous studies have shown an improvement of these parameters when applying local ischemic preconditioning (IPC) to ischemic kidneys. Here we investigate the effect of remote ischemic perconditioning (rIPeC) on the renal water and salt handling in ischemic rat kidneys.Male Wistar rats were subjected to 37 min of unilateral renal ischemia and three days reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine was collected on day 2 and 3 post‐operatively for clearance studies. The expression and localization of renal aquaporins (AQP1, AQP2, phosphorylated S256‐AQP2 and AQP3) and the sodium transports Na‐K‐ATPase and NKCC2 was analyzed using immunoblotting and immunohistochemistry (IHC). Finally, the renal injury was evaluated by morphological examination and detection of renal injury markers.As previously shown, renal I/R resulted in an increase in urine output and FE(Na) and a decrease in urine osmolality compared to Sham group. rIPeC attenuated all these parameters. The protein level of AQPs, Na‐K‐ATPase and NKCC2 was down regulated in the I/R group compared to Sham, and this reduction was attenuated in the I/R+rIPeC group. IHC showed weak labeling of AQP2 and pAQP2 in collecting ducts in I/R kidneys compared to sham kidneys. rIPeC increased the labeling and showed more apical localization of AQP2 and pAQP2.In conclusion, data suggests that rIPeC prevents dysregulation of renal water and salt handling by attenuating down regulation of aquaporins and sodium transporters in ischemic rat kidneys.
n‐6 Fatty Acids Instead of n‐3 and Saturated Fatty Acids Correlate with Body Fat Distribution From Subcutaneous Adipose Tissue to Visceral Adipose Tissue in Healthy and Overweight Subjects
Authors: Jiao Jingjing , Zhu Shankuan 
Published: June 2021

ObjectiveOur aim was to investigate the association between the plasma phospholipid (PPL) fatty acid profile and fat distribution in both healthy and overweight subjects.MethodsTotally 108 of 1066 Chinese adults stratified by gender and body mass index (BMI) were enrolled. The subjects received lifestyle questionnaire survey, physical examination and magnetic resonance imaging (MRI) scan. The PPL fatty acid profile was determined by gas chromatography. The fat distribution including subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), intramuscular adipose tissue (IMAT) and skeletal muscle (SM) was measured by MRI.ResultsPPL n‐3 PUFA levels were inversely associated with SAT in healthy but not overweight subjects. However, no correlation between PPL n‐3 PUFA levels and VAT was observed. PPL n‐6 PUFA levels were directly correlated with SAT and VAT in healthy subjects, while PPL SFA levels were positively associated with SAT and VAT in overweight subjects. Multiple regression analysis revealed PPL n‐6 PUFA were positively correlated with SAT instead of VAT in healthy subjects, but positively associated with VAT instead of SAT in overweight subjects after adjustment for age, sex, BMI, smoking, drinking and education level. PPL n‐3 PUFA did not significantly correlate with both SAT and VAT after adjustments. Logistic regression results showed that PPL n‐6 PUFA levels could be used to estimate the obese state.ConclusionsPPL phospholipid n‐6 PUFA instead of n‐3 PUFA and SFA as important predictors positively correlate with fat distribution from SAT to VAT. Consequently, PPL n‐6 PUFA levels could be used to estimate the obese state.
Discovery of novel Pneumococcal surface adhesin A (PsaA) inhibitors using fragment‐based drug design
Authors: Bajaj Megha , Mamidyala Sreeman , Zuegg Johannes , Begg Stephanie , Ween Miranda , Huang Johnny , Kobe Bostjan , Paton James , McDevitt Christopher , Cooper Matthew 
Published: June 2021

Streptococcus pneumoniae is a leading cause of pneumococcal infections, especially in young children in developing countries. Treatment relies heavily on β‐lactam antibiotics, however, rapid emergence of multidrug‐resistant strains of S. pneumoniae over the past two decades has shifted the focus towards identification of novel drug targets. Pneumococcal surface adhesin A (PsaA) is one such drug target, found on the cell surface of S. pneumoniae. It functions as surface adhesin, as well as substrate binding protein, facilitating acquisition of Mn2+, an essential cation that plays an important role in protecting S. pneumoniae from reactive oxygen species produced during oxidative stress. PsaA is essential for bacterial survival and is an important virulence factor, rendering it a promising target for antibiotic development.To design novel PsaA inhibitors, we used a combination of de novo fragment‐based drug discovery (FBDD) and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo‐PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve their potency while maintaining their ligand‐efficiency and physicochemical properties. The optimized hits were validated using cell‐based assay and molecular dynamics simulations. We found that virtual screening substantially augmented FBDD approaches, leading to the identification of novel PsaA inhibitors.
Exercise Response in a New Porcine Model of Chronic Embolic Pulmonary Hypertension
Authors: Stam Kelly , de Wijs‐ Meijler Daphne , Verzijl Annemarie , van Duin Richard , Reiss Irwin , Duncker Dirk , Merkus Daphne 
Published: June 2021

Chronic Thromboembolic Pulmonary hypertension (CTEPH) is a deadly disease initiated by thrombo‐embolisms persisting in the pulmonary vasculature, followed by remodelling of the pulmonary vascular bed, resulting in a sustained increase in afterload of the right ventricle (RV). Although the response of the pulmonary vasculature to the initiating thromboembolic events as well as the response of the RV to the increased afterload are known to be the most important determinants of patient outcome, the factors that underlie these processes are incompletely understood. In the present study, we developed a novel chronically instrumented swine model of CTEPH. CTEPH was induced by up to 5 weekly injections of polyethylene beads of 700 μm in combination with induction of endothelial dysfunction by eNOS‐inhibition. Swine were followed up to one month after the last embolization. Changes in mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were used as indices of RV afterload and pulmonary vascular remodeling. and assessed at rest and during treadmill exercise (EX) . Repeated embolization resulted in increases in PAP and PVR.

Control

After first embolization

Prior to sacrifice

rest
EX
rest
Ex
Rest
Ex

PAP (mmHg)
16±1
33±3*
29±3†
61±7*†
47±15†
72±16*†

PVR (mmHg.min.kg.L‐1)
86±13
98±16
160±42†
197±23†
510±237†
633±344†

* P<0.05 vs Rest,
† P< 0.05 vs Control

The increase in PAP was exaggerated during exercise, and in two animals, limited the increase in cardiac output during exercise. The increase in PVR induced by repeated embolization correlated well with RV weight (r2=0.78), indicating that swine developed RV hypertrophy. Moreover, histology revealed increased muscularization of pulmonary arterioles.In conclusion, our new swine model of CTEPH mimics critical features of patients with CTEPH in that pulmonary vascular remodeling is present and exercise capacity is reduced.Supported by CVON‐ PHAEDRA2012‐08
Isolation and Preliminary Characterization of Mitochondrial Spherules Involved in Flock House Virus RNA Replication
Authors: Short James , Gopal Radhika , Speir Jeff , Schneemann Anette 
Published: June 2021

The replication of genomic RNA by positive‐sense RNA viruses occurs in association with host membranes. Flock House virus (FHV) is an ideal system for studying these unique interactions since much of the molecular basis for the replication of its RNA is already understood. Protein A, the viral RNA‐dependent RNA polymerase protein, is targeted to the outer mitochondrial membrane (OMM) where it is responsible for viral RNA synthesis. OMM invaginations (or spherules) containing Protein A are formed and are known to be the site of viral RNA replication. Kopek and colleagues previously generated a three‐dimensional reconstruction of these spherules using EM tomography of thin‐sectioned FHV‐infected Drosophila cells. However, these structures have not been studied in the absence of chemical fixation and staining, nor have optimal RNA replication conditions been established for the wild‐type protein in the presence of host membranes.As part of a larger study directed at understanding the structural basis of spherule formation, we aimed to develop techniques for the robust production of replication‐induced OMM invaginations in isolated mitochondrial membranes for imaging by cryo‐electron microscopy (EM). We are now able to consistently isolate replication‐competent mitochondrial fragments and have optimized several reaction conditions enabling the imaging of spherules by cryo‐EM. Our results reveal a number of important initial insights, including the transient nature of the spherules as well as the possibility of visualizing replicated viral RNA.
A Novel Method for Expression and Purification of the C‐Terminal Domain of Apolipoprotein A‐I
Authors: Sallee Daniel , Horn James , Weers Paul 
Published: June 2021

Apolipoprotein A‐I (apoA‐I) is the most abundant protein in high‐density lipoprotein, an anti‐antherogenic complex responsible for reverse cholesterol transport. Human apoA‐I is a 243 amino acid protein comprised of two domains, a helix bundle N‐terminal domain, and an unstructured C‐terminal (CT) domain comprising residues 179‐243 which adopts a helical conformation when lipid bound. To better understand the function of the CT apoA‐I, a novel strategy was employed to produce large quantities of this small fragment using a recombinant expression system. The strategy required the introduction of a methionine residue in front of the CT domain to be able to cleave with cyanogen bromide and isolate the desired fragment. However, apoA‐I contains three methionine residues making it difficult to cleave and isolate the correct fragment. Therefore, a new construct was engineered by combining CT apoA‐I with apolipophorin III (apoLp‐III), an insect apolipoprotein that lacks methionine. A unique methionine was then introduced by site‐directed mutagenesis between apoLp‐III and CT apoA‐I. The chimeric protein was expressed in E. coli BL21 cells, purified by nickel affinity chromatography, and cleaved by cyanogen bromide. SDS‐PAGE revealed the presence of three distinct bands at 7 kDa (CT apoA‐I), 18 kDa (apoLp‐III), and a minor band at 26 kDa of uncleaved protein. Then, reversed‐phase HPLC was employed to isolate the 7 kDa fragment. SDS‐PAGE of the first peak eluted from the C8 column confirmed isolation of CT apoA‐I. This novel expression system allows for production of significant quantities of CT apoA‐I needed for the analysis to understand how this important part of apoA‐I functions.This project was supported by NIH/NIGMS GM089564 and GM008074.
Use of an Observer Tool to Enhance Observers' Learning of Anesthesia Residents During High-Fidelity Simulation
Authors: Suet Guillaume , Blanie Antonia , De Montblanc Jacques , Benhamou Dan 
Published: June 2021

Introduction
The growing number of learners implies that all of them cannot play an active role during high-fidelity scenarios. Studies suggest a positive educational value when learners are observers only, but it remains uncertain whether learning outcomes might be improved by using an observer tool (OT).

Methods
Eighty-nine anesthesia residents were randomized to use an OT (n = 44, OT+; based on a cognitive aid) or not (n = 45, OT−) when not role-playing. The main outcome parameter was the learning outcomes assessed by comparing the change (before-after) in the response score to a questionnaire dedicated to medical knowledge obtained in the OT+ and OT− groups. The impact of using the OT was also assessed by measuring the perceived stress level and the change of the Anesthetists' Non-Technical Skill items values.

Results
At the end of the session, the mean medical knowledge score (mean ± SD) was higher in the OT+ group than in the OT− group (11.4 ± 2.7 vs. 9.6 ± 2.4, respectively, P = 0.0008). The mean Anesthetists' Non-Technical Skill score and level of stress perceived did not differ between groups. Trainees rated similarly the learning value and satisfaction related to the simulation course.

Conclusions
This study suggests that observing high-fidelity simulation scenarios using an OT based on a cognitive aid increases the medical knowledge gain when compared with that seen in passive observers. This study suggests that the use of an OT improves the educational value of simulation.
Association of Simulation Participation With Diagnostic Reasoning Scores in Preclinical Students
Authors: Hayden Emily M. , Petrusa Emil , Sherman Alexander , Feinstein David M. , Khoury Kimberly , Krupat Edward , Pawlowski John , Oriol Nancy E. , Smithedajkul Patrick Y. , Venkatan Suresh K. , Gordon James A. 
Published: June 2021

Purpose
The aim of the study was to evaluate for an association between the number of voluntary mannequin simulation sessions completed during the school year with scores on a year-end diagnostic reasoning assessment among second-year medical students.

Method
This is retrospective analysis of participation in 0 to 8 extracurricular mannequin simulation sessions on diagnostic reasoning assessed among 129 second-year medical students in an end-of-year evaluation. For the final skills assessment, 2 physicians measured students' ability to reason through a standardized case encounter using the Diagnostic Justification (DXJ) instrument (4 categories each scored 0–3 by raters reviewing students' postencounter written summaries). Rater scores were averaged for a total DXJ score (0–12). To provide additional baseline comparison, zero participation students were divided into 2 groups based on intent to participate: those who signed up for extracurricular sessions but never attended versus those who never expressed interest. Scores across the attendance groups were compared with an analysis of variance and trend analysis.

Results
The class DXJ mean equaled 7.56, with a standard deviation of 2.78 and range of 0 to 12. Post hoc analysis after a significant analysis of variance (F = 4.91, df = 8, 128, P < 0.001) showed those participating in 1 or more extracurricular sessions had significantly higher DXJ scores than those not participating. Students doing 7 extracurricular sessions had significantly higher DXJ scores than those doing 0 and 2 (P < 0.05). Zero attendance groups were not different. A significant linear trend (R = 0.48, F = 38.0, df = 1, 127, P < 0.001) was found with 9 groups. A significant quadratic effect, like a dose-response pattern, was found (F = 18.1, df = 2, 125, P < 0.001) in an analysis including both zero attendance groups, a low (1–4 extracurricular sessions) group and a high (5–8) group.

Conclusions
Higher year-end diagnostic reasoning scores were associated with increased voluntary participation in extracurricular mannequin-based simulation exercises in an approximate dose-response pattern.
Antibody Responses after SARS-CoV-2 Vaccination in Lymphoma
Authors: Lim Sean Hua , Campbell Nicola , Johnson Marina , Joseph-Pietras Debora , Collins Graham P , O’Callaghan Ann , Fox Christopher P , Ahearne Matthew , Johnson Peter WM , Goldblatt David , Davies Andrew J 
Published: June 2021

AbstractIndividuals with lymphoid malignancies have an increased mortality risk from COVID-19. Paradoxically, this population is least likely to be protected by SARS-CoV-2 vaccination as a result of disease- or treatment-related immunosuppression. Current data on vaccine responses in persons with lymphoid malignancies is limited.PROSECO is a UK multi-centre prospective observational study evaluating COVID-19 vaccine immune responses in individuals with lymphoma. This early interim analysis details the antibody responses to first- and second-SARS-CoV-2 vaccination with either BNT162b2 (Pfizer-BioNTech) and ChAdOx1 (AstraZeneca), in 129 participants. Responses are compared to those obtained in healthy volunteers.The key findings of this interim analysis are first, 61% of participants who are vaccinated during or within 6 months of receiving systemic anti-lymphoma treatment, do not have detectable antibodies despite two doses of vaccine. Second, individuals with curable disease such has Hodgkin (6/6) and aggressive B-cell non-Hodgkin lymphoma (13/16) develop robust antibody levels to either first or second doses, when vaccinated > 6 months after treatment completion. Third, participants incurable, indolent lymphomas have reduced antibody levels to first and second vaccine doses, irrespective of treatment history. Finally, whilst there was no difference in antibody responses between BNT162b2 and ChAdOx1 in lymphoma participants, BNT162b2 induces 11-fold higher antibody responses than ChAdOx1 after the second dose in healthy donors.These findings serve to reassure the community that individuals with treated Hodgkin and aggressive B-NHL can develop antibody responses to SARS-CoV-2 vaccine. Simultaneously it also highlights the critical need to identify an alternative strategy against COVID-19 for those undergoing systemic anti-lymphoma treatment, and for individuals with indolent lymphomas.
Data-driven identification of health conditions associated with incident Alzheimer’s disease dementia risk: a 15 years follow-up cohort from electronic health records in France and the United Kingdom
Authors: Nedelec Thomas , Couvy-Duchesne Baptiste , Monnet Fleur , Daly Timothy , Ansart Manon , Gantzer Laurène , Lekens Béranger , Epelbaum Stéphane , Dufouil Carole , Durrleman Stanley 
Published: June 2021

AbstractImportanceThe identification of modifiable risk factors for Alzheimer’s disease (AD) is paramount for early prevention and the targeting of new interventions.ObjectiveTo assess the associations between health conditions diagnosed in primary care and the risk of incident AD over time.Design, Setting, and ParticipantsData for 20,214 AD patients from the United Kingdom and 19,458 AD patients from France were extracted from The Health Improvement Network (THIN) database. For each AD case, a control was randomly assigned after matching for sex and age at dementia diagnosis. We agnostically tested the associations between 123 different ICD10 diagnoses extracted from health records and AD dementia, by conditional logistic regression. We focused on two time periods: 2 to 10 years vs. 0 to 2 years before the diagnosis of AD, to separate risk factors from early symptoms/comorbidities.ExposuresWe considered all health conditions that had been recorded in more than 0.1% of visits per 1000 person-years in both cohorts, corresponding to 123 potential types of exposure.Main Outcomes and MeasuresOdds ratios (ORs) for the association of AD with the various health conditions were calculated after Bonferroni correction for multiple comparisons.ResultsTen health conditions were significantly associated with high odds ratios for AD when diagnosed 2 to 10 years before AD, in the British and French samples: major depressive disorder (OR 95% confidence interval (UK):1.23-1.46)), anxiety (1.25-1.47), reaction to severe stress (1.24-1.59), hearing loss (1.11-1.28), constipation (1.22-1.41), spondylosis (1.14-1.39), abnormal weight loss (1.33-1.63), malaise and fatigue (1.14-1.32), memory loss (6.65-8.76) and syncope and collapse (1.1-1.37). Depression was the first comorbid condition associated with AD, appearing at least nine years before the first clinical diagnosis of AD, followed by, anxiety, constipation and abnormal weight loss.Conclusions and RelevanceThese results from two independent primary care databases provide new evidence on the temporality of risk factors and early signs of Alzheimer’s disease. These results could guide new dementia prevention strategies.
Risk factors for hospitalization, disease severity and mortality in children and adolescents with COVID-19: Results from a nationwide German registry
Authors: Armann J , Doenhardt M , Hufnagel M , Diffloth N , Reichert F , Haas W , Schilling J , Haller S , Hübner J , Simon A , Schneider DT , Brunner J , Trotter A , Roessler M , Schmitt J , Berner R 
Published: June 2021

AbstractObjectiveTo characterize the clinical features of children and adolescents hospitalized with SARS-CoV-2 infections and to explore predictors for disease severity.DesignNationwide prospective observational cohort study.SettingData collected from 169 out of 351 children’s hospitals in Germany between March 18, 2020 and April 30, 2021 and comparison with the Statutory Notification System.Participants1,501 children and adolescents up to 19 years of age with laboratory confirmed SARS-CoV-2 infections who were admitted to children’s hospitals and subsequently reported to the COVID-19 registry of the German Pediatric Infectious Disease Society (DGPI).Main outcome measuresAdmission to intensive care, in-hospital.ResultsAs compared to the information in the statutory notification system, up to 30% of all children and adolescents hospitalized in Germany during the study period were reported to the DGPI registry. Median age was three years (IQR, 0-12), with 36% of reported cases being infants. Although roughly half of patients in the registry were not admitted to the hospital due to their SARS-CoV-2 infection, 72% showed infection-related symptoms during hospitalization. Preexisting comorbidities were present in 28%, most commonly respiratory disorders, followed by neurological, neuromuscular, and cardiovascular diseases. Median length of hospitalization was five days (IQR 3-10). Only 20% of patients received a SARS-CoV-2-related therapy. Infants were less likely to require therapy as compared to older children. Overall, 111 children and adolescents were admitted to intensive care units (ICU). In a fully adjusted model, patient age, trisomy 21, coinfections and primary immunodeficiencies (PID) were significantly associated with intensive care treatment. In a bivariate analysis, pulmonary hypertension, cyanotic heart disease, status post (s/p) cardiac surgery, fatty liver disease, epilepsy and neuromuscular impairment were statistically significant risk factors for ICU admission.ConclusionOverall, a small proportion of children and adolescents was hospitalized in Germany during the first year of the pandemic. The majority of patients within our registry was not admitted due to COVID-19 suggesting an overestimation of the disease burden even in hospitalized children. Nevertheless, a large proportion of children and adolescents with confirmed COVID-19 reported in Germany could be captured. This allowed for detailed assessment of overall disease severity and underlying risk factors in our cohort. The main risk factors for COVID-19 disease associated intensive care treatment were older patient age, trisomy 21, PIDs and coinfection at the time of hospitalization.Trial registrationRegistry of hospitalized pediatric patients with SARS-CoV-2 infection (COVID-19), DRKS00021506