bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials
Authors: Delaunois Annie , Cardenas Alvaro , de Haro Teresa , Gerets Helga H J , Gryshkova Vitalina , Hebeisen Simon , Korlowski Chloé , Laleu Benoit , Lowe Martin A , Valentin Jean-Pierre 
Published: July 2024

Abstract
Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration–response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.
Parent Perspectives on Communication Quality in the Neonatal Intensive Care Unit
Authors: Guttmann Katherine F. , Raviv Gabriella N. , Fortney Christine A. , Ramirez Mildred , Smith Cardinale B. 
Published: July 2024

Background:
Though prior literature has demonstrated that communication in the Neonatal Intensive Care Unit (NICU) needs to be improved, in-depth descriptions of parents’ views of NICU communication are lacking.

Purpose:
We sought (1) to explore parent perceptions of communication in the NICU and (2) to understand parents’ communication needs and preferences.

Methods:
We conducted in-depth semi-structured cognitive interviews utilizing concurrent probes with parents of 10 patients in our urban level IV Neonatal Intensive Care Unit over a period of 4 months (July 2021-October 2021). Interview questions were derived from the Quality of Communication scale. We conducted thematic analysis of interview transcripts modeled after work by Braun and Clarke.

Results:
Four overarching themes were identified: Strengths, Challenges, People, and Coping Strategies. Parents reported a range of communication quality in the NICU. Results revealed that the first 48 hours of NICU hospitalization represent a period of vulnerability and uncertainty for parents. Parents value clear yet hopeful communication about a baby’s clinical status and expected course.

Implications for Practice and Research:
We hope that the concrete findings from this study can both inform practice in the NICU now and influence practice guidelines to include such components as emphasis on the first 48 hours, desire for proactive information sharing, and the importance of including hope.
Novel Predictive Scoring System for Bone Union Rate After Conservative Management of Lumbar Spondylolysis
Authors: Gamada Hisanori , Tatsumura Masaki , Asada Tomoyuki , Okuwaki Shun , Nagashima Katsuya , Yosuke Takeuchi , Funayama Toru , Yamazaki Masashi 
Published: July 2024

Study Design.
A single-center retrospective cohort study.

Objectives.
To develop a predictive scoring system for bone union after conservative treatment of lumbar spondylolysis and assess its internal validity.

Summary of Background Data.
Lumbar spondylolysis, a common stress fracture in young athletes, is typically treated conservatively. Predicting bone union rates remains a challenge.

Methods.
This study included patients aged ≤18 years with lumbar spondylolysis undergoing conservative treatment. A multivariable logistic regression analysis was used to develop a scoring system containing six factors: sex, age, lesion level, main side stage of the lesion, contralateral side stage of the lesion, and spina bifida occulta. The predictive scoring system was internally validated from the receiver operating characteristic (ROC) curve using bootstrap methods.

Results.
The final analysis included 301 patients with 416 lesions, with an overall bone union rate of 80%. On multivariable analysis, the main and contralateral stages were identified as factors associated with bone union. The predictive scoring system was developed from the main side stage score (prelysis, early=0, progressive stage=1) and the contralateral side stage score (none=0, prelysis, early, progressive stage=1, terminal stage=3). The area under the curve was 0.855 (95% confidence interval: 0.811–0.896) for the ROC curve, showing good internal validity. The predicted bone union rates were generally consistent with the actual rates.

Conclusions.
A simple predictive scoring system was developed for bone union after conservative treatment of lumbar spondylolysis, based on the stage of the lesion on the main and contralateral sides. The predicted bone union rate was approximately 90% for a total score of 0–1 and ≤30% for a score of 3–4. This system demonstrated good internal validity, suggesting its potential as a useful tool in clinical decision making for the management of spondylolysis.
Provision of Inpatient Rehabilitation to Individuals with Lower-Limb Amputation in Canada: An Epidemiological Analysis
Authors: Imam Bita , Miller William C. , Tregobov Noah 
Published: July 2024

ABSTRACT

Objective
The aim of this study was to determine the proportion of individuals with major lower-limb amputation (LLA) who received inpatient rehabilitation in Canadian provinces, their rehabilitation length, and their functional independence level at admission and discharge.

Methods
Major LLA records from April 1, 2006, to March 31, 2012, were obtained from the Canadian Institute for Health Information and linked to National Rehabilitation Reporting System data (Quebec data were unavailable). The proportions of individuals who received inpatient rehabilitation, mean length of stay, and Functional Independence Measure (FIM) scores (admission and discharge) were calculated.

Results
A total of 16,114 new individuals had major LLAs in nine Canadian provinces over the study period; 18% received inpatient rehabilitation. The mean (SD) length of stay was 37.3 (25.2) days. Nova Scotia and Ontario had the highest provision of inpatient rehabilitation (n = 235, 28.6% and n = 1779, 23.4%, respectively). Newfoundland and Labrador had the longest mean (SD) inpatient rehabilitation stay, 62.6 (36.6) days. Prince Edward Island had the highest FIM scores at admission and discharge (mean = 105.3, SD = 12.8; mean = 111.3, SD = 12.9 days, respectively).

Conclusions
We found that 18% of individuals with major LLA received inpatient rehabilitation across nine Canadian provinces. Costs and resource demands may prevent inpatient rehabilitation provision. Novel, cost-effective strategies may facilitate the provision of rehabilitation services.

Clinical Relevance
Despite the benefits of rehabilitation for individuals with major LLA, especially those whose amputations resulted from a traumatic incident, only 18% of patients with major LLA received inpatient rehabilitation across nine provinces between 2006 and 2012. Provinces with longer durations of inpatient rehabilitation reported higher levels of functional independence when patients with LLA were discharged.
Crystalloid volume versus catecholamines for management of hemorrhagic shock during esophagectomy: assessment of microcirculatory tissue oxygenation of the gastric conduit in a porcine model using hyperspectral imaging – an experimental study
Authors: Studier-Fischer Alexander , Özdemir Berkin , Rees Maike , Ayala Leonardo , Seidlitz Silvia , Sellner Jan , Kowalewski Karl-Friedrich , Haney Caelan Max , Odenthal Jan , Knödler Samuel , Dietrich Maximilian , Gruneberg Daniel , Brenner Thorsten , Schmidt Karsten , Schmitt Felix C. F. , Weigand Markus Alexander , Salg Gabriel Alexander , Dupree Anna , Nienhüser Henrik , Mehrabi Arianeb , Hackert Thilo , Müller Beat Peter , Maier-Hein Lena , Nickel Felix 
Published: July 2024

Introduction:
Oncologic esophagectomy is a two-cavity procedure with considerable morbidity and mortality. Complex anatomy and the proximity to major vessels constitute a risk for massive intraoperative hemorrhage. Currently, there is no conclusive consensus on the ideal anesthesiologic countermeasure in case of such immense blood loss. The objective of this work was to identify the most promising anesthesiologic management in case of intraoperative hemorrhage with regards to tissue perfusion of the gastric conduit during esophagectomy using hyperspectral imaging.

Material and methods:
An established live porcine model (n=32) for esophagectomy was used with gastric conduit formation and simulation of a linear stapled side-to-side esophagogastrostomy. After a standardized procedure of controlled blood loss of about 1 l per pig, the four experimental groups (n=8 each) differed in anesthesiologic intervention, that is, (I) permissive hypotension, (II) catecholamine therapy using noradrenaline, (III) crystalloid volume supplementation, and (IV) combined crystalloid volume supplementation with noradrenaline therapy. Hyperspectral imaging tissue oxygenation (StO2) of the gastric conduit was evaluated and correlated with systemic perfusion parameters. Measurements were conducted before (T0) and after (T1) laparotomy, after hemorrhage (T2), and 60 min (T3) and 120 min (T4) after anesthesiologic intervention.

Results:
StO2 values of the gastric conduit showed significantly different results between the four experimental groups, with 63.3% (±7.6%) after permissive hypotension (I), 45.9% (±6.4%) after catecholamine therapy (II), 70.5% (±6.1%) after crystalloid volume supplementation (III), and 69.0% (±3.7%) after combined therapy (IV). StO2 values correlated strongly with systemic lactate values (r=−0.67; CI −0.77 to −0.54), which is an established prognostic factor.

Conclusion:
Crystalloid volume supplementation (III) yields the highest StO2 values and lowest systemic lactate values and therefore appears to be the superior primary treatment strategy after hemorrhage during esophagectomy with regards to microcirculatory tissue oxygenation of the gastric conduit.
Exploring potential plasma drug targets for cholelithiasis through multiancestry Mendelian randomization
Authors: Liu Xiaoduo , Shi Lubo , Zhang Shutian , Zhou Anni 
Published: July 2024

Background:
Cholelithiasis poses significant health and economic burdens, necessitating novel pharmacological targets to enhance treatment efficacy.

Method:
Based on genome-wide association analysis studies, the authors performed a two-sample Mendelian randomization (MR) analysis based on plasma proteomics to explore potential drug targets in European (nCase=40 191 and nControl=361 641) and Asian (nCase=9305 and nControl=168 253) populations. The authors confirmed the directionality and robust correlation of the drug targets with the results through reverse MR analysis, Steiger filtering, Bayesian colocalization, phenotype scanning, and replication in multiple databases. Further exploration of the safety and possible mechanisms of action of phenome-wide MR analysis and protein–protein interactions (PPIs) as individual drug targets was performed.

Results:
Our proteomics-based MR analyses suggested that FUT3 (OR=0.87; 95% CI: 0.84–0.89; P=4.70×10−32), NOE1 (OR=0.58; 95% CI: 0.52–0.66; P=4.21×10−23), UGT1A6 (OR=0.68; 95% CI: 0.64–0.73; P=9.58×10−30), and FKBP52 (OR=1.75; 95% CI: 1.37–2.24; P=8.61×10−6) were potential drug targets in Europeans, whereas KLB (OR=1.11; 95% CI: 1.07–1.16; P=7.59×10−7) and FGFR4 (OR=0.94; 95% CI: 0.91–0.96; P=4.07×10−6) were valid targets in East Asians. There was no reverse causality for these drug targets. Evidence from Bayesian colocalization analyses supported that exposure and outcome shared consistent genetic variables. Phenome-wide MR analysis suggested the potential deleterious effects of NOE1 and FGFR4. PPI analysis confirmed the pathways associated with the potential targets involved in bile acid metabolism.

Conclusions:
Genetically predicted levels of the plasma proteins FUT3, NOE1, UGT1A6, and FKBP52 have the potential as prospective targets in Europeans. Moreover, the plasma levels of KLB and FGFR4 may serve as potential targets for the treatment of cholelithiasis in East Asians.
Perioperative intravenous lidocaine infusion improves postoperative analgesia after hysterectomy: a systematic review and meta-analysis of randomized controlled trials
Authors: Tang Peng , Sun Qingxia , Li Zhihao , Tong Xiangyi , Chen Fengshou 
Published: July 2024

Background:
The effectiveness of intravenous lidocaine in reducing acute pain after hysterectomy remains uncertain. The authors conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of intravenous lidocaine on posthysterectomy recovery.

Methods:
This study was completed based on the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. A systematic search was conducted in PubMed/MEDLINE, the Cochrane Controlled Trials Register (CENTRAL), and Embase up to 27 July 2023. The authors identified RCTs involving hysterectomy patients comparing lidocaine to a placebo. Outcome measures included postoperative pain scores at rest and during movement, opioid consumption, postoperative nausea and vomiting (PONV), improvements in functional gastrointestinal recovery, and Quality of Recovery scores.

Results:
Nine RCTs were included in the meta-analysis, comprising 352 patients who received intravenous lidocaine and 354 controls. The analysis revealed that intravenous lidocaine significantly reduced postoperative pain scores at rest at 2, 6, 8, and 24 h following hysterectomy, as well as postoperative opioid consumption within 24 h and PONV rates. Furthermore, no observed benefit was noted in shortening the time to first flatus with intravenous lidocaine administration posthysterectomy.

Conclusion:
Intravenous lidocaine administration effectively reduces acute postoperative pain, opioid consumption, and PONV rates following hysterectomy. Lidocaine serves as an opioid-sparing agent, reducing the morphine equivalent dose while maintaining a similar degree of postoperative pain.
Results From the Big Ten COVID-19 Cardiac Registry: Impact of SARS-COV-2 on Myocardial Involvement
Authors: Albrecht Jennifer S. , Greenshields Joel T. , Smart Suzanne , Law Ian H. , Rink Larry R. , Daniels Curt J. , Rajpal Saurabh , Chung Eugene H. , Jeudy Jean , Kovacs Richard , Womack Jason , Esopenko Carrie , Bosha Philip , Terrin Michael , Rosenthal Geoffrey L. , Peterson Andrew R. 
Published: July 2024

Objective:
COVID-19 has been associated with myocardial involvement in collegiate athletes. The first report from the Big Ten COVID-19 Cardiac Registry (Registry) was an ecological study that reported myocarditis in 37 of 1597 athletes (2.3%) based on local clinical diagnosis. Our objective was to assess the relationship between athlete and clinical characteristics and myocardial involvement.

Design:
Cross-sectional study.

Setting:
We analyzed data from 1218 COVID-19 positive Big Ten collegiate athletes who provided informed consent to participate in the Registry.

Participants:
1218 athletes with a COVID-19–positive PCR test before June 1, 2021.

Assessment of Independent Variables:
Demographic and clinical characteristics of athletes were obtained from the medical record.

Main Outcome Measures:
Myocardial involvement was diagnosed based on local clinical, cardiac magnetic resonance (CMR), electrocardiography, troponin assay, and echocardiography. We assessed the association of clinical factors with myocardial involvement using logistic regression and estimated the area under the receiver operating characteristic (ROC) curve.

Results:
25 of 1218 (2.0%) athletes met criteria for myocardial involvement. The logistic regression model used to predict myocardial involvement contained indicator variables for chest pain, new exercise intolerance, abnormal echocardiogram (echo), and abnormal troponin. The area under the ROC curve for these indicators was 0.714. The presence of any of these 4 factors in a collegiate athlete who tested positive for COVID-19 would capture 55.6% of cases. Among noncases without missing data, 86.9% would not be flagged for possible myocardial involvement.

Conclusion:
Myocardial involvement was infrequent. We predicted case status with good specificity but deficient sensitivity. A diagnostic approach for myocardial involvement based exclusively on symptoms would be less sensitive than one based on symptoms, echo, and troponin level evaluations. Abnormality of any of these evaluations would be an indication for CMR.
COVID-19 Infection in Ultramarathon Runners: Findings of the Ultrarunners Longitudinal TRAcking Study
Authors: Jastifer James R. , Jastifer Ethan J. , Hoffman Martin D. 
Published: July 2024

Objective:
Ultramarathon runners are a unique patient population who have been shown to have a lower rate of severe chronic medical conditions. This study aimed to determine the effect that COVID-19 infection has had on this population and their running behavior.

Design:
The Ultrarunners Longitudinal TRAcking (ULTRA) Study is a large longitudinal study of ultramarathon runners. Questions on health status, running behavior, and COVID-19 infection were included in the most recent survey.

Setting:
Community survey.

Participants:
Seven hundred thirty-four ultramarathon runners participated in the study.

Interventions:
None.

Main Outcome Measures:
Personal, exercise, and COVID-19 infection history.

Results:
52.7% of study participants reported having been symptomatic from a COVID-19 infection, with 6.7% testing positive multiple times. Participants required a total of 4 days of hospitalization. The most common symptoms included fever (73.6%), fatigue (68.5%), sore throat (68.2%), runny nose (67.7%), and cough (67.4%). Cardiovascular symptoms, which are of particular interest in the running population, included shortness of breath (46.3%), tachycardia (44.7%), chest pain (36.2%), and wheezing (33.3%). A total of 50 subjects (6.8%) reported long COVID (symptoms lasting more than 12 weeks).

Conclusions:
Severe COVID-19 infection has been rare in this population of ultramarathon runners, although symptomatic infection that affects running is common. To support the well-being of this group of highly active athletes, clinicians should appreciate that cardiovascular symptoms are common and the long-term significance of these symptoms in runners is unknown.

Level of Evidence:
Level 2 prospective study.
Is Access to Optimal Concussion Care for Pediatric Athletes Limited by Geography?
Authors: Powers Ryan , Trevino Robert , Erpenbach Holly , Thomas Danny 
Published: July 2024

Objective:
To evaluate access to optimal concussion care based on a pediatric patients' geography; the hypothesis is that differential access across the Unites States exists.

Design:
Employed a novel strategy using internet searches to find local care, mimicking what families might do in different parts of the country.

Setting:
Virtual internet searches.

Participants:
Not applicable.

Independent Variable:
Various metropolitan and rural geographic regions within each state in the United States.

Main Outcome Measures:
Evaluate access (defined as distance to clinic and ability to see pediatric patients) and optimal care (defined as self-referral process and presence of multidisciplinary care).

Results:
Search strategy yielded 490 results. Overall ∼60% were within 50 miles of searched locations with significant differences in access based on rural versus metropolitan areas (P < 0.0001); in rural areas, only ∼22% of results were within 50 miles. Only about one-third of the results (n = 157) saw pediatric patient with no differences between regions. There was significant regional and geographic variation for optimal care regarding both self-referral processes and access to multidisciplinary care. A diverse group of specialists was represented in search results for concussion care.

Conclusions:
Nationwide, there is an overall lack of access to multidisciplinary concussion care for pediatric patients. Additionally, those in rural communities face more limitations related to access to facilities with increased distances from closest clinic sites.
Incidence of Adverse Events Using Flumazenil in Patients With Iatrogenic Benzodiazepine Delirium: A Retrospective Study
Authors: Hieger Michelle A. , Moore Philip W. , Maskell Kevin F. 
Published: July 2024

Background:
Flumazenil is a competitive benzodiazepine (BZD) antagonist most used for treating delirium in BZD overdoses. Since its introduction, many have expressed concerns about its safety secondary to the risk of inducing BZD withdrawal and refractory seizures.

Study Question:
What is the incidence of adverse drug events after the administration of flumazenil in patients with suspected iatrogenic BZD delirium?

Study Design:
This is a retrospective cross-sectional study of patients from a single center from 2010 to 2013. Patients experiencing delirium after receiving BZDs in the hospital were included if they had a bedside toxicology consult and were administered flumazenil. Patients were excluded if they were given BZDs for ethanol withdrawal or if they did not have mental status documentation before and after flumazenil administration. Descriptive statistics were calculated.

Measures and Outcomes:
The primary outcome was the incidence of adverse drug events after flumazenil administration. The secondary outcome was the efficacy of flumazenil determined by the patient's mental status.

Results:
A total of 501 patient records were reviewed, and 206 patients were included in the final analysis. Of those patients, 172 (83.5%) experienced an objective improvement in their mental status within 1 hour after flumazenil administration. A total of 5 patients experienced adverse events (2.4%), 95% confidence interval (0.78, 5.54). Of these, 3 patients experienced minor agitation or restlessness without pharmacologic intervention. Two patients experienced moderate agitation or restlessness that resolved with haloperidol or physostigmine administration. No patients had a reported seizure, 95% confidence interval (0.0, 1.77).

Conclusions:
Flumazenil seems to be a safe and effective intervention for the reversal of delirium secondary to iatrogenic BZD administration.