bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of obesity on clinical outcomes and treatment continuation in rheumatoid arthritis patients receiving non-TNF-targeted therapies
Authors: Park Dong-Jin , Jeong Hyemin , Choi Sung-Eun , Kang Ji-Hyoun , Lee Shin-Seok 
Published: December 2024

Background: Recent studies have shown the impact of obesity on achieving low disease activity or remission in rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors. However, there is limited research on the effects of obesity on clinical responses to non-TNF-targeted treatments. Objectives: This study investigated the influence of body mass index (BMI) on clinical response to non-TNF-targeted treatments in RA patients. Design: We used data from the KOrean nationwide BIOlogics & targeted therapy (KOBIO) registry, a multicenter, prospective, observational cohort that included RA patients in South Korea. Methods: Patients who received at least one prescription for non-TNF-targeted treatments, including abatacept, tocilizumab, and Janus kinase inhibitors, were included. They were categorized into three BMI groups: under 25 kg/m2 (434 patients), between 25 and 30 kg/m2 (146 patients), and over 30 kg/m2 (22 patients). After 1 year of treatment, treatment continuation rates and clinical responses among these BMI groups were compared. Time on treatment for each category was analyzed using Kaplan–Meier curves and Cox regression, adjusting for confounders. Results: The 1-year continuation rate of the targeted treatment was significantly lower in the obese group (81.8%) compared to the normal BMI (93.8%) and overweight (89.0%) groups ( p = 0.033). Disease Activity Score of 28 joints-erythrocyte sedimentation rate score improvement was less in the obese group (2.06 ± 2.14) than in the normal BMI group (2.76 ± 1.55) ( p = 0.045). Multivariable Cox proportional hazard analysis showed a higher discontinuation rate in the obese group (hazard ratio: 3.407, 95% confidence interval: 1.157–10.211; p = 0.029). Conclusion: Higher BMI in RA patients was associated with poorer clinical response and higher discontinuation rates for non-TNF-targeted treatments.
The role of checkpoint inhibitor rechallenge in patients with metastatic renal cell carcinoma: A systematic review
Authors: Patel Kanishka , Gulati Shuchi , Mitsiades Nicholas , Lara Primo N , Parikh Mamta 
Published: December 2024

Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and combination regimens with targeted therapy are the current standard of care. Given their success in the first-line setting, re-use or continuation of ICIs in subsequent line settings has been a growing area of research interest. Objective This systematic review assesses the safety and efficacy of ICI re-challenge in patients with refractory mRCC. Methods Scopus, Embase, Cochrane, Ovid MEDLINE, and TRIP databases as well as clinicaltrials.gov were searched systematically for published prospective and upcoming clinical trials from inception to August 15, 2023. Inclusion criteria included patients with clear cell histology who had received at least one prior line of systemic therapy including an ICI. Trials with ICI as an intervention either in second-line or beyond were included and did not require a control arm. Safety and efficacy outcomes including overall response rates, overall survival, progression free survival, median duration of response, and grade 3 or higher adverse events (AEs) were extracted. Results Seven prospective studies and 49 upcoming clinical trials were identified. mPFS ranged from 3.7 to 12.2 months, with longer PFS rates being associated with ICI/VEGF combination re-challenge. However, data from the only phase III randomized controlled trial (CONTACT-03) did not support rechallenge of ICI with tyrosine kinase inhibitor (TKI) versus TKI alone. Rates of grade 3 or higher AEs ranged from 28–65%. Conclusions Given the paucity of current data regarding efficacy as well as high toxicity rates, patients with mRCC should not receive ICI-rechallenge unless as part of a prospective clinical trial.
Exploring Infection in Primary Total Ankle Arthroplasty
Authors: Anastasio Albert T. , Wu Kevin , O'Neill Conor N. , Luo Emily Joan , Kim Billy I. , Nunley James A. , DeOrio James K. , Easley Mark E. , Adams Samuel B. 
Published: December 2024

Category: Ankle; Ankle Arthritis Introduction/Purpose: Infection is a serious complication of primary total ankle arthroplasty (TAA) and can lead to implant failure and revision surgery. While various patient demographics, comorbidities, and surgical factors have been associated with an increased risk of infection, evidence is limited, and further research is required to better understand infection in TAA. This study aims to analyze risk factors of infection and explore outcomes following infected TAA. Methods: A retrospective cohort study was conducted using data from a single institution from 2002 to 2022. Patients who underwent primary TAA and had subsequent infection were identified and matched using propensity-score matching (PSM) based on various demographic, comorbidity, and surgical factors. Demographics were compared between the matched groups using Mann-Whitney U test and Fisher's exact test. The outcomes following infection were identified and summarized using descriptive statistics. Results: A total of 1,863 patients who underwent primary TAA were identified, and 19 (1%) were diagnosed with an infection. After PSM, there were no significant differences in age, gender, BMI, and smoking status between the cohorts. There was a statistically significant increase in the rate of diabetes in the infected cohort (26.3 vs. 15.3; p =0.01). Subsequent surgical intervention resulted in limb salvage in 18 (94.7%) cases. Two-stage revision to total ankle replacement was performed in 7 cases (36.8%), while revision to arthrodesis and isolated polyethylene exchange were each carried out in 4 cases (21.1%). One patient had to undergo amputation, however, at the time of the most recent follow-up (5.3%). All patients were found to be free of infection. Conclusion: This study demonstrated significantly increased rates of smoking and diabetes in the infected TAA cohort. Two-stage revision to TAR and revision to arthrodesis with isolated polyethylene exchange were successful in eradicating infection. Overall, a high rate of limb salvage was reported.
One Third of Alcohol Use Disorder Diagnoses are Missed by ICD Coding
Authors: Mercurio Laura , Garcia Augusto , Ruest Stephanie , Duffy Susan J. , Eickhoff Carsten 
Published: December 2024

Background/Significance: Alcohol use carries significant morbidity and mortality, yet accurate identification of alcohol use disorder (AUD) remains a multi-layered problem for both researchers and clinicians. Objective: To fine-tune a language model to AUD in the clinical narrative and to detect AUDs not accounted for by ICD-9 coding in the MIMIC-III database. Materials and Methods: We applied clinicalBERT to unique patient discharge summaries. For classification, patients were divided into nonoverlapping groups stratified by the presence/absence of AUD ICD diagnosis for model training (80%), validation (10%), and testing (10%). For detection, the model was trained (80%) and validated (20%) on 1:1 positive/negative patients, then applied to remaining negative patient population. Physicians adjudicated 600 samples from the full model confidence spectrum to confirm AUD by Diagnostic and Statistical Manual of Mental Disorders-V criteria. Results: The model exhibited the following characteristics (mean, standard deviation): precision (0.9, 0.02), recall (0.65, 0.03), F-1 (0.75, 0.02), area under the receiver operating curve (0.97, 0.01), and area under the precision-recall curve (0.86, 0.01). Adjudication produced an estimated 4% under-documentation rate for the total study population. As model confidence increased, AUD under-documentation rate rose to 30% of the number of patients identified as positive by ICD-9 coding. Conclusion: Our model improves the identification of patients meeting AUD criteria, outperforming ICD codes in detecting cases of AUD. Detection discrepancy between ICD and free-text highlights clinician under documentation, not under recognition. Adjudication revealed model over-sensitivity to language around substance use, withdrawal, and chronic liver disease; future study requires application to a broader set of patient age and acuity. This model has the potential to improve rapid identification of patients with AUD and enhance treatment allocation.
Aerobic exercise inhibits GSDME-dependent myocardial cell pyroptosis to protect ischemia-reperfusion injury
Authors: Li Yi , Wang Xiang , Meng Xuyang , Xia Chenxi , Yang Chenguang , Wang Jun , Yang Jiefu , Wang Fang 
Published: December 2024

Abstract
Background
Acute myocardial infarction (AMI) remains a significant cause of global mortality, exacerbated by ischemia-reperfusion (IR) injury. Myocardial cell pyroptosis has emerged as a critical pathway influencing IR injury severity.

Methods
We aimed to investigate the cardioprotective effects of aerobic exercise on IR injury by examining the modulation of IGFBP2 and its impact on GSDME-dependent myocardial cell pyroptosis. Mechanistic pathways were explored using western blot analysis, ELISA, immunofluorescence, and echocardiography.

Results
Our findings demonstrate that aerobic exercise leads to increased circulating levels of IGFBP2, which effectively suppresses GSDME-dependent myocardial cell pyroptosis. This regulation occurs via the AKT-GSK3β signaling pathway, involving VDAC1 phosphorylation, thereby enhancing mitochondrial function and reducing oxidative stress.

Conclusion
In conclusion, our study highlights the role of IGFBP2 in mitigating GSDME-dependent pyroptosis as a mechanism through which aerobic exercise exerts cardioprotective effects against IR injury. These insights suggest potential therapeutic targets for managing acute myocardial infarction.
Meta-assembly of genomic associations to identify cattle fat depot candidate genes and pleiotropic effects
Authors: Yao Junpeng , Bottema Cynthia D.K. , Khatkar Mehar Singh 
Published: December 2024

Abstract
Background
Fat traits in cattle are considered important due to their contribution to beef eating quality and carcass economic value. Discovering the genes controlling fat traits in cattle will enable better selection of these traits, but identifying these genes in individual experiments has proven difficult. Compared to individual experiments, meta-analyses allow greater statistical power for detecting quantitative trait loci and identifying genes that influence single and multiple economically important fat traits.

Results
This meta-analysis study focussed on fat traits related to the major adipose depots in cattle (namely, carcass fat, intramuscular fat, internal fat, intermuscular fat, and subcutaneous fat) and was conducted using data from the Animal Quantitative Trait Loci (QTL) database. There were more Meta-QTL regions for intramuscular fat and subcutaneous fat (n = 158 and n = 55 regions, respectively) and far fewer for carcass fat and internal fat (n = 2 regions each). There were no Meta-QTL regions found for intermuscular fat. Of these 216 Meta-QTL regions, only 16 regions overlapped and affected two or more fat depots. The number of genes found for the fat depots was reflected in the size and number of the Meta-QTL regions (n = 20, 84, 1336 and 3853 genes for the carcass, internal, subcutaneous and intramuscular fat, respectively). The identification of these QTL allowed a more refined search for candidate genes. For example, the 232 genes in the Meta-QTL regions for carcass fat on BTA2, for intramuscular fat on BTA12, and the overlapping Meta-QTL regions on BTA2, BTA5, and BTA6 were readily screened, and 26 candidate genes were nominated based on their physiological roles using the GeneCards and DAVID databases.

Conclusions
The number of Meta-QTL regions for the various fat depots was relative to the number of associations in the database. However, the scarcity of overlapping Meta-QTL regions suggests that pleiotropic gene variants, which control multiple fat depots in cattle, are rare. The identification of candidate genes in the Meta-QTL regions will improve our knowledge of the genes with regulatory functions in adipose metabolism affecting meat quality and carcass economic value.
Generalizing from qualitative data: a case example using critical realist thematic analysis and mechanism mapping to evaluate a community health worker-led screening program in India
Authors: Broderick Kathryn , Vaidyanathan Arthi , Ponticiello Matthew , Hooda Misha , Kulkarni Vaishali , Chalem Andrea , Chebrolu Puja , Onawale Ashlesha , Baumann Ana , Mathad Jyoti , Sundararajan Radhika 
Published: December 2024

Abstract
Background
A central goal of implementation science is to generate insights that allow evidence-based practices to be successfully applied across diverse settings. However, challenges often arise in preserving programs’ effectiveness outside the context of their intervention development. We propose that qualitative data can inform generalizability via elucidating mechanisms of an intervention. Critical realist thematic analysis provides a framework for applying qualitative data to identify causal relationships. This approach can be used to develop mechanism maps, a tool rooted in policy that has been used in health systems interventions, to explain how and why interventions work. We illustrate use of these approaches through a case example of a community health worker (CHW)-delivered gestational diabetes (GDM) screening intervention in Pune, India. CHWs successfully improved uptake of oral glucose tolerance tests (OGTT) among pregnant women, however clinical management of GDM was suboptimal.

Methods
Qualitative interviews were conducted with 53 purposively sampled participants (pregnant women, CHWs, maternal health clinicians). Interview transcripts were reviewed using a critical realist thematic analysis approach to develop a coding scheme pertinent to our research questions: “What caused high uptake of GDM screening?” and “Why did most women with GDM referred to clinics did not receive evidence-based management?”. Mechanism maps were retrospectively generated using short- and long-term outcomes as fenceposts to illustrate causal pathways of the CHW–delivered program and subsequent clinical GDM management.

Results
Critical realist thematic analysis generated mechanism maps showed that CHWs facilitated GDM screening uptake through affective, cognitive and logistic pathways of influence. Lack of evidence-based treatment of GDM at clinics was caused by 1) clinicians lacking time or initiative to provide GDM counseling and 2) low perceived pre-test probability of GDM in this population of women without traditional risk factors. Mechanism mapping identified areas for adaptation to improve the intervention for future iterations.

Conclusions
Mechanism maps created by repeated engagement following the critical realist thematic analysis method can provide a retrospective framework to understand causal relationships between factors driving intervention successes or failures. This process, in turn, can inform the generalizability of health programs by identifying constituent factors and their interrelationships that are central to implementation.
Electroacupuncture ameliorates inflammatory pain through CB2 receptor-dependent activation of the AMPK signaling pathway
Authors: Lan Yuye , Jing Xianghong , Zhou Ziyu , Rao Yiqing , Wang Kaichen , Qin Renjie , Wu Yisong , Sun Jingjing , Zhang Ke , Liu Xinyue , Wang Zixiao , Xu Jiahao , zhao Minzhen , Yuan Xiao Cui , Liu Yongmin , Zhang Hong , Hu Xuefei , Pan Huilin , Hou Tengfei , Li Man 
Published: December 2024

Abstract
Background
Chronic inflammatory pain is a pervasive condition, and electroacupuncture (EA) is an effective treatment, but its mechanisms are not fully understood. AMP-activated protein kinase (AMPK), a key energy sensor, is involved in pain relief and EA’s effects. EA may work by increasing endocannabinoids, upregulating CB2 receptors (CB2R), and stimulating β-endorphin (β-END). This study tests if EA activates AMPK via CB2R to modulate β-END and reduce pain.

Methods
The inflammatory pain model was established with Complete Freund’s adjuvant (CFA), and EA was administered daily for six consecutive days, targeting the acupoints “Zusanli” (ST36) and “Shangjuxu” (ST37). Pain sensitivity was evaluated using Von Frey filaments for mechanical thresholds and a hot plate for thermal thresholds. Ultra-high Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS) was used to quantitatively determine the levels of endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA). The expression levels of the CB2R and β-END were measured by Western blotting, along with the activation of AMPK. Immunofluorescence double-labeling was applied to visualize AMPK activation and β-END expression within CD68-positive macrophages. The study encompassed both wild-type and CB2R gene knockout mice, elucidating the role of CB2R in EA-induced AMPK activation.

Results
CFA-induced inflammatory pain model mice exhibited mechanical allodynia and thermal hyperalgesia. EA activated AMPK in the inflamed skin tissue when it exerted analgesic effect on the inflammatory pain. Pre-administration of the AMPK inhibitor Compound C significantly inhibited the effect of EA on pain relief. EA elevated β-END expression in inflamed skin tissue, which was reversed by Compound C, indicating that AMPK has a regulatory role in EA inducing β-END expression. In addition, EA significantly upregulated the levels of 2-AG, AEA and the expression of CB2Rs in the inflamed skin tissue compared with the CFA group. In wild-type mice, EA activates AMPK in macrophages, while CB2 knockout reduced EA's ability to activate AMPK in these cells.

Conclusion
EA activates AMPK through CB2R, enhancing β-END expression in inflamed skin to alleviate inflammatory pain. This study reveals a new link between endocannabinoids, endorphins, and AMPK in analgesic effects of EA, highlighting the CB2R-AMPK-β-END pathway.
Multiomic molecular patterns of lipid dysregulation in a subphenotype of sepsis with higher shock incidence and mortality
Authors: Augustin Beulah , Wu Dongyuan , Black Lauren Page , Bertrand Andrew , Sulaiman Dawoud , Hopson Charlotte , Jacob Vinitha , Shavit Jordan A. , Hofmaenner Daniel A. , Labilloy Guillaume , Smith Leslie , Cagmat Emilio , Graim Kiley , Datta Susmita , Reddy Srinivasa T. , Guirgis Faheem W. 
Published: December 2024

Abstract
Background
Lipids play a critical role in defense against sepsis. We sought to investigate gene expression and lipidomic patterns of lipid dysregulation in sepsis.

Methods
Data from four adult sepsis studies were analyzed and findings were investigated in two external datasets. Previously characterized lipid dysregulation subphenotypes of hypolipoprotein (HYPO; low lipoproteins, increased mortality) and normolipoprotein (NORMO; higher lipoproteins, lower mortality) were studied. Leukocytes collected within 24 h of sepsis underwent RNA sequencing (RNAseq) and shotgun plasma lipidomics was performed.

Results
Of 288 included patients, 43% were HYPO and 57% were NORMO. HYPO patients exhibited higher median SOFA scores (9 vs 5, p = < 0.001), vasopressor use (67% vs 34%, p = < 0.001), and 28-day mortality (30% vs 16%, p = 0.004). Leukocyte RNAseq identified seven upregulated lipid metabolism genes in HYPO (PCSK9, DHCR7, LDLR, ALOX5, PLTP, FDFT1, and MSMO1) vs. NORMO patients. Lipidomics revealed lower cholesterol esters (CE, adjusted p = < 0.001), lysophosphatidylcholines (LPC, adjusted p = 0.001), and sphingomyelins (SM, adjusted p = < 0.001) in HYPO patients. In HYPO patients, DHCR7 expression strongly correlated with reductions in CE, LPC, and SM (p < 0.01), while PCSK9, MSMO1, DHCR7, PLTP, and LDLR upregulation were correlated with low LPC (p < 0.05). DHCR7, ALOX5, and LDLR correlated with reductions in SM (p < 0.05). Mortality and phenotype comparisons in two external datasets (N = 824 combined patients) corroborated six of the seven upregulated lipid genes (PCSK9, DHCR7, ALOX5, PLTP, LDLR, and MSMO1).

Conclusion
We identified a genetic lipid dysregulation signature characterized by seven lipid metabolism genes. Five genes in HYPO sepsis patients most strongly correlated with low CE, LPC, and SMs that mediate cholesterol storage and innate immunity.
Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness
Authors: Kelani Khadiga M. , Hegazy Maha A. , Hassan Amal M. , Nadim Ahmed H. 
Published: December 2024

AbstractA simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0–9.0 µg mL−1 for ANT, 1.0–5.0 µg mL−1 for BEN, 0.5–2.5 µg mL−1 for ANT imp-A, and 0.25–1.25 µg mL−1 for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL−1 for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL−1 for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL−1 for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.