bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients
Authors: Kurtz Pedro , Elias Anna Beatriz Ribeiro , Suarez-Kurtz Guilherme 
Published: October 2024

Aims
To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System.

Methods
Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH].

Results
Wide (22-fold) interindividual variation in [PTH] was observed (2.2–47.5 mg/l). [PTH] associated significantly (Kruskal–Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere–Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10–20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér’s V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211).

Conclusion
Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline ‘strong’ recommendation for phenytoin dosing adjustments in PMs.
The role of advanced physiological guidance in contemporary coronary artery disease management
Authors: Munhoz Daniel , Ikeda Kazumasa , Bouisset Frederic , Sakai Koshiro , Tajima Atomu , Mizukami Takuya , Sonck Jeroen , Johnson Nils P. , Collet Carlos 
Published: October 2024

Purpose of review
This review evaluates the emerging role of the pullback pressure gradient (PPG) as a standardized metric for assessing coronary artery disease (CAD) patterns and its implications for clinical decision-making when managing patients undergoing percutaneous coronary interventions (PCIs). By integrating PPG with existing physiological assessments, this review highlights the potential benefits of PPG in predicting treatment outcomes and refining therapeutic strategies for CAD.

Recent findings
Recent studies, particularly the PPG Global study have demonstrated a strong correlation between PPG values and post-PCI outcomes, revealing that focal disease is associated with improved fractional flow reserve (FFR) and lower rates of adverse events than vessels with diffuse disease (low PPG). Additionally, PPG has been linked to specific atherosclerotic plaque characteristics, indicating its utility in identifying high-risk plaques. The integration of PPG with advanced imaging techniques further enhances the understanding of CAD patterns and their implications for treatment planning.

Summary
The PPG represents a significant advancement in the management of CAD, providing a reproducible and objective assessment of coronary artery disease patterns that can inform clinical decision-making. As research continues to explore the relationship among PPG, atherosclerotic characteristics, and patient outcomes, its integration into routine practice is expected to improve the effectiveness of PCI and optimize patient management strategies. Future studies are warranted to establish specific PPG thresholds and further investigate its potential in identifying vulnerable plaques and guiding treatment decisions.
CARTp/GPR160 mediates behavioral hypersensitivities in mice through NOD2
Authors: Schafer Rachel M. , Giancotti Luigino A. , Chrivia John C. , Li Ying , Mufti Fatma , Kufer Thomas A. , Zhang Jinsong , Doyle Timothy M. , Salvemini Daniela 
Published: October 2024

Abstract
Neuropathic pain is a debilitating chronic condition that remains difficult to treat. More efficacious and safer therapeutics are needed. A potential target for therapeutic intervention recently identified by our group is the G-protein coupled receptor 160 (GPR160) and the cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand for GPR160. Intrathecal administration of CARTp in rodents causes GPR160-dependent behavioral hypersensitivities. However, the molecular and biochemical mechanisms underpinning GPR160/CARTp-induced behavioral hypersensitivities in the spinal cord remain poorly understood. Therefore, we performed an unbiased RNA transcriptomics screen of dorsal horn spinal cord (DH-SC) tissues harvested at the time of peak CARTp-induced hypersensitivities and identified nucleotide-binding oligomerization domain-containing protein 2 (Nod2) as a gene that is significantly upregulated. Nucleotide-binding oligomerization domain-containing protein 2 is a cytosolic pattern-recognition receptor involved in activating the immune system in response to bacterial pathogens. While NOD2 is well studied under pathogenic conditions, the role of NOD2-mediated responses in nonpathogenic settings is still not well characterized. Genetic and pharmacological approaches reveal that CARTp-induced behavioral hypersensitivities are driven by NOD2, with co-immunoprecipitation studies indicating an interaction between GPR160 and NOD2. Cocaine- and amphetamine-regulated transcript peptide–induced behavioral hypersensitivities are independent of receptor-interacting protein kinase 2 (RIPK2), a common adaptor protein to NOD2. Immunofluorescence studies found NOD2 co-expressed with endothelial cells rather than glial cells, implicating potential roles for CARTp/NOD2 signaling in these cells. While these findings are based only on studies with male mice, our results identify a novel pathway by which CARTp causes behavioral hypersensitivities in the DH-SC through NOD2 and highlights the importance of NOD2-mediated responses in nonpathogenic settings.
Elucidation of neuronal activity in mouse models of temporomandibular joint injury and inflammation by in vivo GCaMP Ca2+ imaging of intact trigeminal ganglion neurons
Authors: Son Hyeonwi , Shannonhouse John , Zhang Yan , Gomez Ruben , Amarista Felix , Perez Daniel , Ellis Edward , Chung Man-Kyo , Kim Yu Shin 
Published: October 2024

Abstract
Patients with temporomandibular disorders (TMDs) typically experience facial pain and discomfort or tenderness in the temporomandibular joint (TMJ), causing disability in daily life. Unfortunately, existing treatments for TMD are not always effective, creating a need for more advanced, mechanism-based therapies. In this study, we used in vivo GCaMP3 Ca2+ imaging of intact trigeminal ganglia (TG) to characterize functional activity of the TG neurons in vivo, specifically in mouse models of TMJ injury and inflammation. This system allows us to observe neuronal activity in intact anatomical, physiological, and clinical conditions and to assess neuronal function and response to various stimuli. We observed a significant increase in spontaneously and transiently activated neurons responding to mechanical, thermal, and chemical stimuli in the TG of mice with TMJ injection of complete Freund adjuvant or with forced mouth opening (FMO). An inhibitor of the calcitonin gene–related peptide receptor significantly attenuated FMO-induced facial hypersensitivity. In addition, we confirmed the attenuating effect of calcitonin gene–related peptide antagonist on FMO-induced sensitization by in vivo GCaMP3 Ca2+ imaging of intact TG. Our results contribute to unraveling the role and activity of TG neurons in the TMJ pain, bringing us closer to understanding the pathophysiological processes underlying TMJ pain after TMJ injury. Our study also illustrates the utility of in vivo GCaMP3 Ca2+ imaging of intact TG for studies aimed at developing more targeted and effective treatments for TMJ pain.
Differences in Attentional Bias Toward e-Cigarette Cues Between e-Cigarette Users and Nonusers
Authors: Gwon Seok Hyun , Cho Youngjoo , Kim Yourim , Paek Suna , Lee Han-Joo 
Published: October 2024

Abstract
The use of electronic nicotine delivery systems (ENDS) has increased rapidly in recent years, particularly among young adults. There is a dearth of research on the cognitive factors that contribute to ENDS use. One of the possible cognitive mechanisms involved with addictive behavior is attentional bias (AB). AB can manifest as either facilitated attention engagement toward or delayed attention disengagement from a relevant stimulus. The purpose of this study was to examine the difference in AB toward ENDS-related cues between ENDS users and non-ENDS users. ENDS users (n = 29) and nonusers (n = 24) between the ages of 18 and 29 years participated in the dot-probe and eye-tracking picture-viewing tasks. The results showed that there was a significant difference in the variance of AB between the two groups. In the eye-tracking task, ENDS users displayed significantly greater net dwell time and fixation time at time frames of 6–9, 9–12, and 12–15 seconds, compared to nonusers. It is noteworthy that ENDS users exhibited attentional fluctuation toward ENDS cues as well as difficulties disengaging attention from ENDS cues. The current findings offer insight into the nature of attentional processes associated with ENDS cues and provide useful data to guide the development of a nurse-led cognitive intervention focusing on biased attentional processing related to ENDS cues.
The Role of Hopelessness in Patients With Borderline Personality Disorder
Authors: Aguglia Andrea , Cioci Daniele , Meinero Matteo , Placenti Valeria , Verrina Edoardo , Bianchi Davide , Fusar-Poli Laura , Costanza Alessandra , Schiavetti Irene , Amerio Andrea , Amore Mario , Serafini Gianluca 
Published: October 2024

Background:
The goal of this study was to evaluate specific characteristics associated with hopelessness, potentially correlated with coping strategies, sensory profile, and alexithymia in patients with borderline personality disorder (BPD).

Materials and Methods:
Two hundred twenty-four (N=224) inpatients completed a clinical interview with administration of the Beck Hopelessness Scale (BHS), the Adolescent/Adult Sensory Profile (AASP), the Coping Orientation to Problems Experienced Inventory (COPE), and the Toronto Alexithymia Scale (TAS).

Results:
Hopelessness was significantly associated with female gender, more hospitalizations, current suicidal ideation, number of suicide attempts, current and lifetime medication abuse, and alcohol misuse. Furthermore, patients with BHS ≥ 9 had higher scores in low registration, sensory sensitivity and sensation avoiding in AASP, higher rate of alexithymia, and the use of maladaptive coping strategies.

Conclusions:
Hopelessness in BPD was associated with higher severity of illness, alternative process sensory input from the environment, reduced ability to cope with stressful events, and alexithymia. Therefore, a routine assessment of hopelessness in patients with BPD could lead to better and more specific therapeutic strategies.
SeqFirst: Building equity access to a precise genetic diagnosis in critically ill newborns
Authors: Wenger Tara L. , Scott Abbey , Kruidenier Lukas , Sikes Megan , Keefe Alexandra , Buckingham Kati J. , Marvin Colby T. , Shively Kathryn M. , Bacus Tamara , Sommerland Olivia M. , Anderson Kailyn , Gildersleeve Heidi , Davis Chayna J. , Love-Nichols Jamie , MacDuffie Katherine E. , Miller Danny E. , Yu Joon-Ho , Snook Amy , Johnson Britt , Veenstra David L. , Parish-Morris Julia , McWalter Kirsty , Retterer Kyle , Copenheaver Deborah , Friedman Bethany , Juusola Jane , Ryan Erin , Varga Renee , Doherty Dan , Dipple Katrina , Chong Jessica X. , Kruszka Paul , Bamshad Michael J. 
Published: October 2024

SummaryAccess to a precise genetic diagnosis (PrGD) in critically ill newborns is limited and inequitable because complex inclusion criteria used to prioritize testing eligibility omits many patients at high risk for a genetic condition. SeqFirst-neo is a program to test whether a genotype-driven workflow using simple, broad exclusion criteria to assess eligibility for rapid whole genome sequencing (rWGS) increases access to a PrGD in critically ill newborns. All 408 newborns admitted to a neonatal intensive care unit between January 2021 and February 2022 were assessed and of 240 eligible infants, 126 were offered rWGS (i.e., intervention group [IG]) and compared to 114 infants who received conventional care in parallel (i.e., conventional care group [CCG]). A PrGD was made in 62/126 (49.2%) IG neonates compared to 11/114 (9.7%) CCG infants. The odds of receiving a PrGD was ∼9 times greater in the IG vs. the CCG, and this difference was maintained at 12 months follow up. Access to a PrGD in the IG versus CCG differed significantly between infants identified as non-white (34/74, 45.9% vs. 6/29, 20.7%; p=0.024) and Black (8/10, 80.0% vs. 0/4; p=0.015). Neonatologists were significantly less successful at predicting a PrGD in non-white than non-Hispanic white patients. Use of a standard workflow in the IG with a PrGD revealed that a PrGD would have been missed in 26/62 (42%) of infants. Use of simple, broad exclusion criteria that increases access to genetic testing significantly increases access to a PrGD, improves access equity and results in fewer missed diagnoses.
Anthocyanin-rich extract mitigates the contribution of the pathobiont genusHaemophilusin mild-to-moderate ulcerative colitis patients
Authors: Zobrist Yannik , Doulberis Michael , Biedermann Luc , Leventhal Gabriel E , Rogler Gerhard 
Published: October 2024

AbstractObjectiveAnthocyanins (AC) have been shown to elicit anti-inflammatory and antioxidant effects in several animal models of colitis. Furthermore, AC lowered biochemical disease activity in our double-blind randomized trial in patients with ulcerative colitis. Here, we report on the changes in the faecal microbiome composition in the patient upon AC exposure in this trial.MethodsUlcerative colitis patients received a 3g daily dose of an AC-rich bilberry extract (ACRE) for eight weeks. We determined the microbiome composition in longitudinal stool samples from 24 patients and quantified the degree of change over time. We also correlated the relative abundances of individual microbial taxa at different time points to faecal concentration measurements of calprotectin.ResultsMicrobiome compositions did not change over time as a result of the intervention, both in terms of alpha and beta diversity. Before the intervention, Haemophilus parainfluenzae was positively correlated with faecal calprotectin concentrations, and this correlation persisted in placebo-treated subjects throughout the study. In contrast, the correlation between H. parainfluenzae and the concentration of faecal calprotectin vanished in ACRE-treated subjects, while the relative abundance of H. parainfluenzaae did not change. Conclusion: Our results suggest that ACRE treatment mitigates the contribution of H. parainfluenzae to inflammation. Further research is warranted to better comprehend the role of microbial composition in response to medical therapy including AC-rich extract in ulcerative colitis patients.Key messages1. What is already known on this topicAnthocyanins are a promising therapeutic alternative for ulcerative colitis patients given their effect on faecal calprotectin, excellent safety profile, and low costs.2. What this study addsThe administration of anthocyanin-rich extract to ulcerative colitis patients in a Phase 2a study reduced faecal calprotectin concentrations by mitigating the contribution from the pathobiont genus Haemophilus but did not affect the overall microbiome composition.3. How this study might affect research, practice or policyOur results could aid in targeted treatment of ulcerative colitis patients with anthocyanins, according to individual microbial composition.
Biomedical Text Normalization through Generative Modeling
Authors: Berkowitz Jacob S. , Fatapour Yasaman , Srinivasan Apoorva , Cortina Jose Miguel Acitores , Tatonetti Nicholas P 
Published: October 2024

ABSTRACTObjectiveAround 80% of electronic health record (EHR) data consists of unstructured medical language text. By its nature, this text is flexible and inconsistent, making it challenging to use for clinical trial matching, decision support, and predictive modeling. In this study, we develop and assess text normalization pipelines built using large-language models.Materials and MethodsHere, we evaluated four LLM-based normalization strategies: Zero-Shot Recall, Prompt Recall, Semantic Search, and Retrieval-Augmented Generation (RAG) and one baseline, TF-IDF based String Matching. We compared normalization performance across two datasets of condition terms mapped to SNOMED, one tailored to oncology, and one covering a wide range of medical conditions. Additionally, we benchmarked our models against the TAC 2017 drug label annotations, which normalizes terms to the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms.ResultsRAG, which effectively combines Prompt Recall and Semantic Search, was the most effective, accurately identifying the correct term 88.31% of the time for the domain-specific dataset and 79.97% for the broader dataset. Our model achieved a micro F1 score of 88.01 on task 4 of the TAC2017 conference, surpassing all other models without relying on the provided training data.DiscussionThese findings demonstrate the potential of LLMs in medical text normalization. We find that retrieval-focused approaches overcome traditional LLM limitations for this task.ConclusionLarge language models combined with retrieval-augmented generation should be explored for text normalization of biomedical free text.
Real-time prediction of drug-induced proarrhythmic risk with sex-specific cardiac emulators
Authors: Dominguez-Gomez Paula , Zingaro Alberto , Baldo-Canut Laura , Balzotti Caterina , Darpo Borje , Morton Christopher , Vázquez Mariano , Aguado-Sierra Jazmin 
Published: October 2024

AbstractIn silicotrials for drug safety assessment require a large number of high-fidelity 3D cardiac electrophysiological simulations to predict drug-induced QT interval prolongation, making the process computationally expensive and time-consuming. These simulations, while necessary to accurately model the complex physiological conditions of the human heart, are often cost-prohibitive when scaled to large populations or diverse conditions. To overcome this challenge, we develop sex-specific emulators for the real-time prediction of QT interval prolongation, with separate models for each sex. Building an extensive dataset from 900 simulations allows us to show the superior sensitivity of 3D models over 0D single-cell models in detecting abnormal electrical propagation in response to drug effects as the risk level increases. The resulting emulators trained on this dataset showed high accuracy level, with an average relative error of 4% compared to simulation results. This enables global sensitivity analysis and the replication ofin silicocardiac safety clinical trials with accuracy comparable to that of simulations when validated againstin vivodata. With our emulators, we carry outin silicoclinical trials in seconds on a standard laptop, drastically reducing computational time compared to traditional high-performance computing methods. This efficiency enables the rapid testing of drugs across multiple concentration ranges without additional computational cost. This approach directly addresses several key challenges faced by the biopharmaceutical industry: optimizing trial designs, accounting for variability in biological assays, and enabling rapid, cost-effective drug safety evaluations. By integrating these emulators into the drug development process, we can enhance the reliability of preclinical assessments, streamline regulatory submissions, and advance the practical application of digital twins in biomedicine. This work represents a significant step toward more efficient and personalized drug development, ultimately benefiting patient safety and accelerating the path to market.
Human bioaccumulation of micro- and nanoplastics is primarily determined by the organs’ vascular volume
Authors: Gañán-Calvo Alfonso M. 
Published: October 2024

AbstractRecent studies have demonstrated the accumulation of micro- and nanoplastics (MNPs) in human organs, particularly in the brain, at an alarming rate (Campen et al., 2024, doi.org/10.21203/rs.3.rs-4345687/v1). This study examines the phenomenon of bioaccumulation in relation to up to six distinct biological and biomedical parameters pertaining to vascular structure and composition in seven organ tissues: the brain cortex, kidney, liver, testis, and three arteries (coronary, carotid and aorta). As anticipated based on fundamental mechanistic considerations of bioaccumulation (washing rate), the MNP content appears to be proportional to the inverse of the capillary volume fraction (Vc), exhibiting no correlation with any other geometric variable, such as capillary diameter or capillary segment length. This finding is consistent with the small size spectra of MNPs in comparison to these dimensions. However, contrary to expectations, no correlation was observed between MNP content and biological composition (lipid, water, or carbohydrate content), while a likely non-causal correlation was observed between MNP content and protein content, which may be simply attributed to the non-linear correlation between protein content andVc. The conclusions that point to a possibly exceedingly large number of MNP particles currently in our brains call for urgent further investigation and the revision of the published data.
Yearly trends in cause-specific age-adjusted mortality from 1999-2020 in Black and White Non-Hispanic Americans
Authors: Arun Adith S. , Krumholz Harlan M. 
Published: October 2024

AbstractFrom 1999 to 2020, disparities in all-cause age-adjusted mortality rates between Black and White Non-Hispanic Americans decreased then stagnated and increased. Consistent improvement in racial disparities were made for cancer, HIV, and sepsis regardless of all-cause trends. In contrast, conditions like heart disease and external causes of death mirrored the overall trends.