bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of Inpatient Versus Ambulatory Lumbar Surgical Care Utilization Among Minority Patients
Authors: Tiao Justin , Alasadi Husni , Herrera Michael M. , Zubizarreta Nicole , Huang Jonathan , Poeran Jashvant , Chaudhary Saad
Published: February 2025

Study Design:

Retrospective cohort study.

Objectives:

Identify and compare racial/ethnic disparities in ambulatory versus inpatient surgical care utilization for single-level lumbar spine surgery.

Summary of Background Data:

The proportion of spine surgeries performed in the ambulatory setting has dramatically increased over the past 2 decades. However, few studies have investigated whether this shift has resulted in racial/ethnic disparities in surgical care utilization, particularly for outpatient lumbar spine surgery, compared with the inpatient setting.

Materials and Methods:

Utilizing the 2019 National Inpatient Sample and Nationwide Ambulatory Surgical Sample discharge, we included patients who had undergone a single-level lumbar discectomy, laminectomy, and/or fusion, were of Black, White, or Hispanic race/ethnicity, were covered under Medicare, Medicaid, or private insurance, and were aged 18 years or above. The primary outcome was the rate ratio (RR) of patients from the aforementioned 3 racial/ethnic groups undergoing lumbar surgical care, in the ambulatory and inpatient settings. US Bureau of Labor Statistics data were utilized to offset the model for population-based variations in sociodemographic factors utilizing nested coefficients.

Results:

Among 397,173 cases, 220,250 (55.5%) were inpatient, and 176,923 (44.5%) were ambulatory. Compared with White patients, Black (RR: 0.54, 95% CI: 0.53–0.55) and Hispanic (RR: 0.61, 95% CI: 0.60–0.62) patients had lower utilization rates of ambulatory surgical care. More pronounced patterns were observed for Black (RR: 0.44 95% CI: 0.44–0.45) and Hispanic (RR: 0.55, 95% CI: 0.54–0.56) inpatient surgical utilization; all P < 0.001.

Conclusions:

Racial/ethic disparities in single-level lumbar surgical care utilization exist in both the ambulatory and the inpatient setting.

Level of Evidence:

Level 3.
The Relationship Between Anxiety and Readiness Levels Regarding Artificial Intelligence in Midwives
Authors: Yilmaz Ayşe Nur , Altiparmak Sümeyye , Sökmen Remziye
Published: February 2025

This study aimed to compare Generations X, Y, and Z in terms of anxiety and readiness levels regarding artificial intelligence and investigate the relationship between anxiety and readiness levels regarding artificial intelligence in midwives across generations. This study is cross-sectional and comparative with a study sample of 218 midwives working in a province in the east of Turkey. Data were collected with the “Personal Information Form,” “Artificial Intelligence Anxiety Scale,” and “Medical Artificial Intelligence Readiness Scale.” The evaluation of the data was carried out using the IBM SPSS Statistics version 22.0 (IBM Inc., Armonk, NY, USA) package program. Descriptive statistics, a one-way analysis of variance test, Pearson correlation, and regression analysis were used to analyze the data. The total mean score of midwives from the Artificial Intelligence Anxiety Scale was 47.07 ± 12.10 in Generation X, 43.91 ± 12.63 in Generation Y, and 36.16 ± 12.61 in Generation Z (P < .05), and the difference between the groups was significant. Generation X had a higher level of artificial intelligence anxiety than Generation Y, and Generation Y had higher levels of artificial intelligence than Generation Z. The total mean score of midwives from the Medical Artificial Intelligence Readiness Scale was 67.43 ± 14.28 in Generation X, 66.78 ± 17.83 in Generation Y, and 74.73 ± 16.15 in Generation Z (P < .05), and the difference between the groups was significant. Generation Z is more ready for medical artificial intelligence than Generation X, and Generation X is more ready for medical artificial intelligence than Generation Y. In addition, in the regression analysis, there was a weakly negative and significant relationship between the mean scores of Artificial Intelligence Anxiety Scale and Medical Artificial Intelligence Readiness Scale in Generation Z midwives, and as artificial intelligence anxiety levels increased, medical artificial intelligence readiness levels decreased. The artificial intelligence anxiety levels of midwives differed by generation, being highest in Generation X and lowest in Generation Z, and the level of medical artificial intelligence readiness was highest in Generation Z and lowest in Generation Y. As artificial intelligence anxiety increased in Generation Z midwives, the level of medical artificial intelligence readiness decreased.
A Meta-analysis on Effects of Chimeric Antigen Receptor T-cell Therapy in Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia
Authors: Jamil Abdur , Qureshi Zaheer , Siddique Rimsha , Altaf Faryal , Jamil Rohma , Wali Neehal
Published: February 2025

Objectives:

This review evaluates the long-term outcomes and adverse events associated with chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL).

Methods:

We conducted the search in relevant databases up to June 2024. We included clinical trials on CAR T-cell therapy for patients with r/r B-ALL. Meta-analyses were conducted using Comprehensive Meta-Analysis V3 and Review Manager 5.4.

Results:

Out of 2659 identified studies, 10 were included in this review. The pooled analysis demonstrated a high minimal residual disease-negative complete remission, with an overall event rate (ER) of 70% (95% CI: 61%-78%, I
2 =8 8.35%). Anti-CD19 CAR T-cell therapy showed the highest efficacy with an ER of 74.75% (95% CI: 61%-80%, I
2 = 89.84%). Combination therapies targeting CD19 and CD22 had an ER of 69% (95% CI: 53%-83%, I
2 = 82.56%). Significant adverse effects included cytokine release syndrome with a mean incidence of 81.8% (95% CI: 76.7%-86.9%), neurotoxicity at 33.2% (95% CI: 28.1%-38.3%), and hematologic toxicities at 71.9% (95% CI: 66.4%-77.4%).

Conclusions:

CAR T-cell therapy is a groundbreaking advancement in treating r/r B-ALL, offering high rates of durable remissions.
TCF7L2 as a target of peripheral artery disease in patients with type 2 diabetes: A 2-sample Mendelian randomization and bioinformatics study
Authors: Liu Jie , Liu XingDe , Rao Rui , Li Wen
Published: February 2025

This study examines the causal relationship between type 2 diabetes (T2D) and peripheral artery disease (PAD) and their potential mechanisms based on the analysis of the Gene Expression Omnibus database and 2-sample Mendelian randomization (MR). The first part involved a 2-sample MR study and a comprehensive meta-analysis. Differences in the results were assessed using inverse-variance weighting. Heterogeneity was examined using the Cochrane Q statistical test. The leave-one-out method was applied for sensitivity analysis. The potential horizontal pleiotropic effect was assessed using the MR-Egger intercept technique. The second part involved differential gene analysis and weighted gene coexpression network analysis. Subsequently, we overlapped and consolidated the results from the 2 parts to identify the key genes between them. MR analysis results suggested a statistically significant correlation between the incidence of PAD and T2D (odds ratio: 1.22, 95% confidence interval: 1.13–1.32, P = 3.74e−07). We anticipated a pivotal role for TCF7L2 in PAD and T2D. T2D was significantly associated with PAD risk. Simultaneously, the study deepened our understanding of the underlying mechanisms of both diseases, proposing TCF7L2 as a promising target.
Significance of CD8+T cells related gene ITGB2 in prognosis and tumor microenvironment of small cell lung cancer
Authors: Wang Nana , Tian Wen , Zhao Jinhui , Wang Wenzhong , Mi Fu
Published: February 2025

The CD8 + T cells could enhance response of antitumor immune in cancers. Therefore, we aimed to analyze the CD8 + T cells related genes in small cell lung cancer (SCLC) patients. The data of SCLC samples were collected from the Gene Expression Omnibus database. The hub genes were screened by weighted gene co-expression network analysis, protein–protein interaction network and survival analyses. Moreover, the relative proportions of the 22 immune cells in the samples were calculated using CIBERSORT software. The relationship between target gene and immunotherapy was analyzed in IMvigor210 cohort. We identified 10 genes (PTPRC, RPS27A, UBA52, CD8A, ITGB2, GNB2L1, TYROBP, CD86, TLR4, and FCGR3A) that were correlated with CD8 + T cells in SCLC. Among them, ITGB2 was positively correlated with CD8 + T cells in SCLC. ITGB2 was down-regulated in SCLC. SCLC patients with low ITGB2 expression exhibited a poor prognosis, and ITGB2 was an independent prognostic factor for survival rate of SCLC patients. The differentially expressed genes between ITGB2
high and ITGB2
low groups were significantly enriched in 143 signaling pathways. We also discovered that the ImmuneScore, StromalScore, and the expression of immune checkpoints (PD-1 (PDCD1), CTLA4, PDL-1 (CD274), TIGIT, IFNG, GZMA, TBX2, and IDO1) were significantly increased in ITGB2
high group. Moreover, SCLC patients with high ITGB2 expression had lower tumor immune dysfunction and exclusion scores, and the proportion of urothelial cancer patients with complete response/partial response was observably decreased in ITGB2
high group. Finally, we found that ITGB2 was correlated with IC50 of cancer drugs. In conclusion, SCLC patients with low ITGB2 expression exhibited worse prognosis. ITGB2 might be correlated with immunotherapy response of SCLC patients.
The effect of preoperative laboratory values on prognostic factors following cytoreduction surgery in ovarian cancer: Neutrophil lymphocyte ratio, platelet lymphocyte ratio, and lymphocyte monocyte ratio
Authors: Akyol Duygu , Özcan Funda Gümüş
Published: February 2025

In cancer patients, prognostic markers are needed to improve the management and clinical course of both the cancer itself and surgery therefor. Elevated systemic inflammatory markers are associated with morbidity and mortality in most cancer types. In this study, we aimed to determine the prognostic value of inflammatory markers such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) in patients undergoing cytoreductive surgery for ovarian cancer. The data of 188 patients who underwent surgery for ovarian cancer between December 2022 and December 2023 were retrospectively analyzed. Receiver operating characteristic (ROC) curves were constructed to evaluate the correlation between complications and the inflammatory prognostic factors NLR, PLR, and LMR. Optimal cutoff values were determined as the points where the Youden index (sensitivity + specificity − 1) was maximal. Patients were compared according to the presence of complications. As a result of the ROC curve analysis, patients were divided as high and low NLR and PLR groups. The difference of preoperative and postoperative inflammatory prognostic factors was compared according to the presence of complications. In this study in which a total of 90 patients were evaluated, the cutoff value for NLR was 2.04 (areas under the ROC curve: 0.655; P < .05) and the cutoff value for PLR was 145.3 (areas under the ROC curve: 0.740; P < .05) according to the presence of complications. In the group with complications, lymphopenia and thrombocytosis were more common preoperatively, while patients were more anemic postoperatively (P < .05). Patients in the high NLR group were younger and received less neoadjuvant chemotherapy. In the high PLR group, the number of patients receiving neoadjuvant chemotherapy was lower, and although the patients were more anemic and lymphopenic, higher rates of neutrophilia and thrombocytosis were observed. The analysis of preoperative and postoperative NLR, PLR, and LMR differences revealed an increase in NLR and PLR values and a decrease in LMR values (P < .05). The preoperative systemic inflammatory biomarkers NLR and PLR may be considered as prognostic predictors of poor postoperative outcomes. Therefore, consideration of these biomarkers may have an important role in clinical course management.
Determination of intraoperative complication rate and risk factors in patients undergoing surgery for tubo-ovarian abscess: A retrospective cohort study
Authors: Tas Emre Erdem
Published: February 2025

This study aimed to assess intraoperative complication rates and risk factors in patients who underwent surgery for tubo-ovarian abscess. A retrospective review of the medical records of 170 patients who underwent tubo-ovarian abscess surgery between January 2014 and December 2023 was conducted. Four patients were excluded due to a histopathologic diagnosis of cancer, and 166 patients were included in the final analysis. Intraoperative complications were observed in 10 (6.0%) patients, including 8 (4.8%) and 2 (1.2%) patients with bowel and bladder injuries, respectively. The included patients were categorized into complication-positive (n = 10, 6.0%) and complication-negative (n = 156, 94.0%) groups, with between groups comparisons based on demographic, clinical, and surgical characteristics. The complication-positive group had significantly higher mean age and serum c-reactive protein (CRP) levels than the complication-negative group (46.6 ± 7.4 years vs 40.6 ± 8.5 years; P = .03, and 199.2 ± 89.4 mg/L vs 112.2 ± 84.2 mg/L; P ≤ .01, respectively). Extensive surgery, such as hysterectomy with bilateral adnexectomy, was more commonly performed in the complication-positive group than in the complication-negative group (8/10 [80.0%] vs 43/156 [27.5%], P < .01). Receiver operating characteristic curve analysis identified a serum CRP level of 186.5 mg/L as the optimal cutoff for predicting intraoperative complications. Binary logistic regression analysis showed that elevated serum CRP levels (≥186.5 mg/L) (odds ratio: 7.9; P < .01) and extensive surgery (odds ratio: 11.0, P = .01) were independently associated with intraoperative complications. Our findings indicate that elevated serum CRP levels and extensive surgery are associated with increased intraoperative complication risks, which may have important implications in clinical practice, potentially informing preoperative assessments, and surgical planning. This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement.
Cellular and soluble plasma immune markers at presentation in multisystem inflammatory syndrome in children and Kawasaki disease in South Africa: An observational study
Authors: Abraham Deepthi R. , van Coller Ansia , Tattersall Megan M. , Mohlake Edwin , Yunis Nurea A. , Webb Kate , Zunza Moleen , van der Zalm Marieke M. , Rabie Helena , Glashoff Richard H.
Published: February 2025

Immune and inflammatory alterations in multisystem inflammatory syndrome in children (MIS-C) as compared to Kawasaki disease (KD) were investigated in South Africa, a region of unique genetic background and high infectious disease burden. The observational study included MIS-C and KD patients during 4 severe acute respiratory syndrome coronavirus 2 waves (June 1, 2020–March 31, 2023) plus 12 healthy controls. Clinical features, routine inflammatory markers, hematological parameters, lymphocyte subsets and plasma inflammatory cytokines/chemokines were compared between groups. We enrolled 68 MIS-C, 18 KD, and 12 healthy controls. MIS-C patients had higher rates of Intensive Care Unit admission compared to KD (46% vs 17%; P = .03) and longer hospital stay (8.5 vs 6 days; P < .001). 8 MIS-C but no KD patients had an ejection fraction of < 40% (P = .07). Median lymphocyte counts were decreased in MIS-C, 1.2 cells/μL (interquartile range 0.7–2.3) versus KD 2.5 cells/μL (interquartile range 1.2–3.7), P = .02. Median CD3 + T-cell counts were lower in MIS-C (P = .04). Children with MIS-C had a higher median N-terminal pro-B-type natriuretic peptide of 5836 ng/L (1784–25,698) versus 7 ng/L (88–3262), P < .001 and Troponin T 25 ng/L (9–73) versus 7 ng/L (4–24), P = .01. Majority of cytokines/chemokines were elevated in both MIS-C and KD. When MIS-C was stratified by severity, significant differences in C-reactive protein (P < .001), total lymphocytes (P = .01), and N-terminal pro-B-type natriuretic peptide (P = .01) were observed. Inflammatory cytokine and chemokine levels were markedly raised in both KD and MIS-C. 3 markers were highlighted as indicators of MIS-C severity. There is a strong overlap in inflammatory marker alterations between MIS-C and KD at presentation in the African setting.
Analysis of factors affecting hospitalization costs in Parkinson disease patients: A retrospective study based on 848 cases
Authors: Li Yatan , Ma Xiaoqiang , Zhang Shanquan , Jia Yingying , Yang Fan , Jia Wei
Published: February 2025

This retrospective study aimed to examine hospitalization costs and associated factors for Parkinson disease (PD) patients. A total of 848 PD patients were extracted from the National Neurological and Brain Center in Xinjiang, and basic demographic information, medical insurance payment, and hospital expenses were collected. SPSS 26.0 was used and univariate analysis was performed on the number of days of hospitalization, times of hospitalizations, gender, payment method, and total hospitalization costs. Correlation analysis was performed using multiple linear regression to explore the influencing factors of hospitalization expenses. The average hospitalization cost of PD patients was 15,515.78 ± 29,667.49 yuan. Diagnosis fees accounted for the highest proportion (29.50%), followed by material costs (25.50%) and drug costs (21.20%). PD patients with less than 5 hospitalizations were the main source of disease, but 2.83% of them had more than 10 hospitalizations (P = .025). Female patients were significantly more than male patients, but the total hospitalization costs of male patients were much higher than those of female patients (P < .001). The number of PD patients increased significantly when they were over 60 years old, but the hospitalization costs were much lower than those of patients under 60 years old (P = .007). The effect of the payment method on total hospitalization cost did not show a statistical difference (P = .213). There was a positive correlation between hospitalization days and total hospitalization cost (P < .001). In conclusion, the results of the regression model suggested that age, length of hospital stay, gender, and number of hospitalizations could be used as predictive variables for hospitalization costs in PD patients.
Detection and classification of glomerular lesions in kidney graft biopsies using 2-stage deep learning approach
Authors: Fogaing Irène Mappé , Abdo Ammar , Ballis-Berthiot Pavlina , Adrian-Felix Sophie , Olagne Jérôme , Merieux Rudy , Vuiblet Vincent
Published: February 2025

Acute allograft rejection in patients undergoing renal transplantation is diagnosed through histopathological analysis of renal graft biopsies, which can be used to quantify elementary lesions. However, quantification of elementary lesions requires considerable expertise, time, and effort. Using a 2-stage classification strategy, we sought to examine the effectiveness of deep learning in detecting and classifying glomeruli into 4 groups, namely normal, abnormal, sclerotic, and glomerulitis, as a potential biopsy triage system focused on transplant rejection. We used the U-Net model to build a glomeruli detection model using 137 kidney biopsy slides obtained from 80 kidney transplant patients. The median age of the patients was 52 (19–74) years, with 65% being men and 35% women. MobileNetV2 and VGG16 models were compared using a 2-stage classification strategy. In the first classification step, the models classified glomeruli into sclerotic and nonsclerotic glomeruli. In the second classification step, the nonsclerotic glomeruli from the first step were classified as normal, abnormal, or glomerulitis. The U-Net model achieved satisfactory detection (Dice coefficient = 0.90), and the MobileNetV2 model was the best for the 2 classification steps, with F1 scores of 0.85, 0.91, 0.98, and 0.92 for normal, abnormal, sclerotic, and glomerulitis, respectively. The 2-stage classification strategy identifies sclerotic glomeruli and abnormal glomeruli relative to permeable glomeruli and quantifies glomerulitis with significant accuracy while avoiding bias from abnormal glomeruli that do not have glomerulitis, providing valuable diagnostic information.
Current status of healthcare financial literacy among medical trainees and junior hospitalists: An observational survey study
Authors: Ekeh Odera , Simmons Amonte , Farmer Alka , Hunter Krystal , Zheng Lin
Published: February 2025

The absence of comprehensive education on hospital value-based purchasing during undergraduate medical education may lead to inadequate comprehension of healthcare finance during Graduate Medical Education and subsequent medical practice. Medicine residents and junior hospitalists (defined as those who completed their residency in the last 5 years) may lack essential healthcare financial skills to address the needs of their patients and the healthcare system effectively. To assess healthcare financial literacy among medical students, medicine residents, and junior hospitalists, we conducted a survey at an academic Internal Medicine residency affiliated with a US Medical School. Participants completed a 40-item questionnaire sourced from federal government healthcare system websites, providing demographic data and indicating prior formal healthcare finance education. Of the 126 respondents, only 15.6% reported receiving formal healthcare financial education, with merely 4 out of 34 junior hospitalists having prior education. Notably, there were no significant differences in correct answer percentages between 3rd and 4th-year medical students, medicine residents, and junior hospitalists across 3 domains: Medicaid/Medicare insurance, US healthcare systems & insurance, and healthcare access, quality and value-based purchasing. However, participants performed better in the domain of Medicaid/Medicare insurance compared to the other domains. This study underscores the potential deficiency in financial skills among junior healthcare providers, highlighting the importance of addressing this gap to ensure effective patient care.
Consecutive 5-year outcomes of chorionic villus sampling at a tertiary center
Authors: Kuyucu Melda , Erdogan Kadri Murat , Adiyaman Duygu , Konuralp Atakul Bahar , Golbasi Hakan , Kutbay Yasar Bekir , Gokmen Karasu Ayse Filiz , Ozeren Mehmet
Published: February 2025

This study shares our 5-year experience with chorionic villus sampling (CVS) and analyzes the indications, results, and complications of this procedure. We conducted a retrospective analysis of data from singleton pregnancies that underwent CVS between 2015 and 2020 at the Maternal-Fetal Medicine Unit of Health Science University, Izmir Tepecik Research, and Training Hospital. Maternal demographics, indications, karyotype results, and pregnancy outcomes were recorded. We retrospectively analyzed data from 468 CVS procedures, conducted between 2015 and 2020. The most common indications for CVS were positive screening test results in the first trimester, fetal structural abnormalities, and increased nuchal translucency (NT) observed during ultrasound. Fetal structural abnormalities had the highest detection rate, at 34.5% for chromosomal abnormalities, followed by increased NT and first-trimester screen-positive test results (26.9% and 11.3%), respectively. The culture success rate was 96.3% (451 out of 468). The most prevalent chromosomal abnormalities were numerical, including Trisomy 21 (10.9%), Trisomy 18 (4.2%), and Trisomy 13 (1.9%). Results could not be obtained in 17 patients (3.6%); 12 (2.5%) were due to insufficient samples and culture failure, while 5 (1.06%) were due to maternal contamination. Amniocentesis was required as a secondary sampling in 24 cases (5.1%) and performed in 17 cases (3.6%). This study emphasizes the significance of CVS in prenatal diagnosis and the management of high-risk pregnancies. However, we must be aware of the associated risks and limitations, which include culture success rates, inconclusive results, and the occasional need for secondary sampling.
Advancements in conventional cancer therapy combined with immunotherapy
Authors: Li Hongxia , Han Songyan , Dong Chunbo , Liu Zhida
Published: February 2025

Conventional therapies are primary cancer treatments that directly eliminate or inhibit the growth of tumor cells, reducing the overall tumor burden. Increasing evidence suggests that conventional therapies possess significant immunomodulatory properties in addition to their established direct tumoricidal effects. Emerging immunotherapies have revolutionized the clinical management of various cancer types. Conventional therapy and immunotherapy have demonstrated remarkable clinical efficacy, leading to numerous ongoing clinical investigations exploring their potential synergistic effects. However, trials investigating the combination of conventional therapy and immunotherapy have shown limited synergistic therapeutic efficacy. This unsatisfactory clinical outcome may be attributed to the suboptimal design of the combination approach and the inadequate understanding of the mechanisms and impacts of radiotherapy, chemotherapy, targeted therapy regimens (including dosing, timing, and administration route), and surgery on both cancer cells and the host immune system. Here, we comprehensively review preclinical and clinical investigations exploring the therapeutic effects and mechanisms of conventional therapy alone or in combination with immunotherapy. We proposed that optimizing the dosing, timing, and route of administration of conventional therapies can enhance the synergistic efficacy of combination therapies, thus offering significant clinical advantages.
Video Grading of Bile Duct Anastomoses During Robotic Pancreatoduodenectomy Predicts Bile Leak and Identifies the Learning Curve
Authors: Zwart Maurice J.W. , van den Broek Bram L.J. , Zwetsloot Sabrina L.M. , Busch Olivier R. , Tran T.C.Khé , Luyer Misha D. , Schreinemakers Jennifer , Wijsman Jan H. , van der Schelling George P. , de Hingh Ignace H.J.T. , Mieog J. Sven D. , Bonsing Bert A. , Takagi Kosei , de Wilde Roeland F. , Zeh Herbert J. , Zureikat Amer H. , Hogg Melissa E. , Groot Koerkamp Bas , Besselink Marc G. ,   for the Dutch Pancreatic Cancer Group
Published: February 2025

Objective:

To determine if video grading using Objective Structured Assessment of Technical Skills (OSATS) could estimate the risk of postoperative bile leak (BL) after robotic pancreatoduodenectomy (RPD) and to identify a learning curve effect.

Summary Background Data:

The hepaticojejunostomy (HJ) bile leak rate after RPD is rather high with 10% and may be improved by structured training and skills. Robotic HJ therefore requires confirmation of adequate performance. Grading of surgical performance during HJ could be used in competency-based surgical training.

Methods:

Post-hoc analysis of patients included the Dutch LAELAPS-3 RPD training program in 6 centers. Technical performance during robotic HJ was graded by two blinded graders using OSATS (attainable scores 6-30). Primary outcome was grade B/C bile leak according to the ISGLS. Logistic regression determined the performance cut-off and CUSUM analysis identified the learning curve.

Results:

Videos from robotic HJ in 259 patients were included with a 6.9% rate of grade B/C bile leak (n=18/259). The median OSATS for the HJ was 25.0 [22–27], with an OSATS score>21 associated with a reduced risk of BL. The rate of BL was 5.1% in patients for OSATS>21 and 12.5% for OSATS ≤21, amounting to a relative reduction of 59.2% and an absolute reduction of 7.4% (8/64 vs. 10/195, OR 0.378, P=0.013). These findings remained similar when only including grade C BL: OR 0.076, P=0.004. On multivariable analysis for grade B/C BL, the only significant predictive factor was OSATS>21: OR 0.273, P=0.025. Stabilization of the CUSUM learning curve for grade B/C BL was reached at 19 RPD procedures, and after 44 procedures the learning curve showed a continuous downward trend. The rate of grade B/C BL was significantly lower beyond 19 RPD: 5.6% versus 8.6% (8/143 vs. 10/116, OR 0.710, P=0.040).

Conclusions:

The risk of postoperative BL after RPD is strongly associated with surgical performance during robotic HJ as objectified using OSATS. This approach can be used for rapid assessment of the learning curve and competency-based surgical training, aiming for a safe implementation RPD.
Integration of functional genomics and statistical fine-mapping systematically characterizes adult-onset and childhood-onset asthma genetic associations
Authors: Zhong Xiaoyuan , Mitchell Robert , Billstrand Christine , Thompson Emma , Sakabe Noboru J. , Aneas Ivy , Salamone Isabella M. , Gu Jing , Sperling Anne I. , Schoettler Nathan , Nóbrega Marcelo A. , He Xin , Ober Carole
Published: February 2025

Background

Genome-wide association studies (GWAS) have identified hundreds of loci underlying adult-onset asthma (AOA) and childhood-onset asthma (COA). However, the causal variants, regulatory elements, and effector genes at these loci are largely unknown.

Methods

We performed heritability enrichment analysis to determine relevant cell types for AOA and COA, respectively. Next, we fine-mapped putative causal variants at AOA and COA loci. To improve the resolution of fine-mapping, we integrated ATAC-seq data in blood and lung cell types to annotate variants in candidatecis-regulatory elements (CREs).

We then computationally prioritized candidate CREs underlying asthma risk, experimentally assessed their enhancer activity by massively parallel reporter assay (MPRA) in bronchial epithelial cells (BECs) and further validated a subset by luciferase assays. Combining chromatin interaction data and expression quantitative trait loci, we nominated genes targeted by candidate CREs and prioritized effector genes for AOA and COA.

Results

Heritability enrichment analysis suggested a shared role of immune cells in the development of both AOA and COA while highlighting the distinct contribution of lung structural cells in COA. Functional fine-mapping uncovered 21 and 67 credible sets for AOA and COA, respectively, with only 16% shared between the two. Notably, one-third of the loci contained multiple credible sets. Our CRE prioritization strategy nominated 62 and 169 candidate CREs for AOA and COA, respectively. Over 60% of these candidate CREs showed open chromatin in multiple cell lineages, suggesting their potential pleiotropic effects in different cell types. Furthermore, COA candidate CREs were enriched for enhancers experimentally validated by MPRA in BECs. The prioritized effector genes included many genes involved in immune and inflammatory responses. Notably, multiple genes, includingTNFSF4, a drug target undergoing clinical trials, were supported by two independent GWAS signals, indicating widespread allelic heterogeneity. Four out of six selected candidate CREs demonstrated allele-specific regulatory properties in luciferase assays in BECs.

Conclusions

We present a comprehensive characterization of causal variants, regulatory elements, and effector genes underlying AOA and COA genetics. Our results supported a distinct genetic basis between AOA and COA and highlighted regulatory complexity at many GWAS loci marked by both extensive pleiotropy and allelic heterogeneity.
Serum IL-6, IL-10, TNF-α and IFN-γ bio-signature for neonatal sepsis diagnosis and treatment outcome
Authors: T Suraj , Ahmed Riya , Debata Pradeep , Gaind Rajni , Kaushal GP , Gur Renu , Nirmal Kirti , Kaur Ravinder , Nangia Sushma , Kumar Vivek , Ghosh Dipankar , Chandele Anmol , Atmakuri Krishnamohan , Sankar M Jeeva , Nanda Ranjan Kumar
Published: February 2025

Background

Diagnosing sepsis in preterm neonates is a significant challenge, underscoring the urgent need for timely and accurate methods. Serum inflammatory protein signatures show promising potential for early and precise disease diagnosis.

Methods

In this study, a cohort of preterm neonates (n=50, 25-35 weeks gestation, female 40%) at the time of suspicion and follow-up were enrolled along with healthy neonates. Based on clinical presentation and blood culture or MALDI results, the sepsis suspicion cases were categorized into culture-positive (CP)/culture-negative (CN) sepsis (n=13 each) or no-sepsis (NS, n=12) and compared with healthy controls (HC, n=12) from similar settings. These sub-groups (CP, CN, and NS) were followed up till completion of antibiotic therapy. Serum inflammatory proteins and trace elementals (57Fe,66Zn,63Cu,77Se,44Ca,24Mg) were profiled using the Olink® Target 96 inflammation panel and inductively coupled plasma mass spectrometry (ICP-MS), respectively. Serum proteins with log2fold changes>±1.3 and p<0.05 were identified as differentially expressed proteins (DEPs) and monitored in the follow-up samples receiving treatment. Elements showing significant differences (p<0.05) between the study groups were also identified for correlation analysis.

Results

Serum inflammatory protein levels showed group-specific trends. Significantly higher serum IL-6, IL-10, TNF-α and LIF levels with low IFN-γ and CCL28 were observed in the CP sepsis group compared to HC. CN group also showed reduced serum IFN-γ along with CXCL10 and CCL11 levels when compared to HC. Also, the serum IL-6 level in CP cases was positively correlated with IFN-γ and IL-10 levels (r<0.77, p<0.05), and an increased IL6:IFN-γ was observed in the CP, CN and NS groups compared to the HC. Serum of NS patients showed higher FGF-23 levels with lower IFN-γ and CCL11 than HC. Upon recovery, the serum IL-6 levels reached normal levels in CP, whereas the CN group showed IFN-γ, CXCL10, and CCL11 levels returned to normal. Serum iron levels were significantly reduced in both the CP and CN groups, while serum selenium was low in the CP group and serum copper was lower in the CN group, with all levels returning to normal upon recovery.

Conclusions

Absolute levels of IL-6, IL-10, IFN-γ, and TNF-α in serum can be used as biosignatures for neonatal sepsis, offering the potential for early disease diagnosis and monitoring therapeutic response. Additionally, these markers implicated in disease resolution mechanisms might serve as therapeutic targets in sepsis treatment.
Systematic Bias in Clinical Decision Instrument Development: A Quantitative Meta-Analysis
Authors: Obra Jed Keenan , Singh Chandan , Watkins Kenshata , Feng Jean , Obermeyer Ziad , Kornblith Aaron
Published: February 2025

Clinical decision instruments (CDIs) face an equity dilemma. On the one hand, they often reduce disparities in patient care through data-driven standardization of best practices. On the other hand, this standardization may itself inadvertently perpetuate bias and inequality within healthcare systems. Here, we quantify different measures of potential for implicit bias present in CDI development that can inform future CDI development. We find evidence for systematic bias in the development of 690 CDIs that underwent validation through various analyses: self-reported participant demographics are skewed—e.g. 73% of participants are White, 55% are male; investigator teams are geographically skewed—e.g. 52% in North America, 31% in Europe; CDIs use predictor variables that may be prone to bias—e.g. 13 CDIs explicitly useRace and Ethnicity; outcome definitions may further introduce bias—e.g. 28% of CDIs involve follow-up, which may disproportionately skew outcome representation based on socioeconomic status. As CDIs become increasingly prominent in medicine, we recommend that these factors are considered during development and clearly conveyed to clinicians using CDIs.
Tumor suppressor collateral damage screens reveal mRNA homeostasis protein HBS1L as a novel vulnerability in ch9p21 driven FOCAD deleted cancer
Authors: Zhang Hongxiang , Tonini Matthew R. , Martires Lauren Catherine M. , Pratt Charlotte B. , Jenkins Helena N. , Gordon Eden N. , Zhao Shanchuan , Choi Ashley H. , Meier Samuel R. , Khendu Tenzing , Liu Shangtao , Shen Binzhang , Stowe Hannah , Pashiardis Katerina , Pan Xuewen , Bandi Madhavi , Zhang Minjie , Yu Yi , Min Chengyin , Huang Alan , Andersen Jannik N. , Nicholson Hilary E. , Teng Teng
Published: February 2025

Chromosomal deletion of tumor suppressor genes often occurs in an imprecise manner, leading to co-deletion of neighboring genes. This collateral damage can create novel dependencies specific to the co-deleted context. One notable example is the dependency on PRMT5 activity in tumors withMTAPdeletion, which co-occurs withCDKN2A/Bloss, leading to the development of MTA-cooperative PRMT5 inhibitors. To identify additional collateral damage context/target pairs for chromosome 9p and other common loci of chromosomal deletions, we conducted a combinatorial CRISPR screen knocking out frequently co-deleted genes in combination with a focused target library. We identified the gene encoding the ribosome rescue factor PELO as synthetic lethal with the SKI complex interacting exonuclease FOCAD, which is frequently co-deleted alongsideMTAPandCDKN2A/Bon chromosome 9p. A genome-wide screen inFOCADisogenic cells further identified the ribosome rescue GTPase and PELO binding partner HBS1L as the top synthetic lethal target forFOCADloss. Analysis of publicly available data and genetic manipulation ofHBS1Lusing orthogonal modalities validated this interaction. HBS1L dependency inFOCAD-deleted cells was rescued byFOCADre-expression, andFOCADintact cells could be rendered HBS1L-dependent byFOCADknockout, demonstrating the context specificity of this interaction. Mechanistically,HBS1Lloss led to translational arrest and activated the unfolded protein response inFOCAD-deleted cells.In vivo,HBS1Ldeletion eliminated growth ofFOCAD-deleted tumors. Here we propose a model where the FOCAD/SKI complex and HBS1L/PELO work together to resolve aberrant mRNA-induced ribosomal stalling, making the HBS1L/PELO complex an intriguing novel target for treatingFOCAD-deleted tumors.
A positive feedback loop of ‘MPK3-PIN1A trafficking-auxin flux’ trio governs dual gravitropic and wounding response in rice
Authors: Manna Mrinalini , Rengasamy Balakrishnan , Jonwal Sarvesh , Pal Uttam , Banerjee Gopal , Sinha Alok Krishna
Published: February 2025

The auxin flow in plants plays a pivotal role in gravitropic organ movement and tissue regeneration following injury. However, the regulatory aspects of these phenomena are not entirely understood. In this study, we found that hyperactivity of MAP Kinase 3 (MPK3) led to downregulation ofPINsand reduction in tissue auxin content, impairing gravitropic response of rice and accelerating tissue senescence following mechanical wounding. The MPK3 was found to phosphorylate PIN1A majorly at its Ser351residue, mutation of which into its phospho-mimic variant enhanced latter’s endosomal trafficking and consequently improved auxin flux. Further, overexpression of the phospho-null variant ofPIN1Alowered gravitropic response of rice, thus causing wider tiller angle similar to thepin1aknockout lines. Additionally, upon wounding, their tissue senescence was faster in comparison to the overexpression lines of wild-type and phospho-mimic variants ofPIN1A, which also displayed improved resistance to wounding byBipolaris oryzae. The PIN1A trafficking-mediated auxin flux also regulated MPK3 activity via a positive feedback loop. Together, these results uncover a novel feedback loop encompassing “MPK3-PIN1A trafficking-auxin flux” trio that regulates dual gravitropic and wounding response in rice.
Estrogen Receptors/E2F1/CDKN3 Axis Protects from UV-induced Skin Cancers in Females
Authors: Lukowicz Celine , Winkler Carine , Roger Catherine , Fowler Joanna C , Tsai Yi-Chien , Meuli Joachim , Claudinot Stephanie , Chang Yun-Tsan , Iselin Christoph , Jones Philip , Guenova Emmanuella , Jafari Paris , Michalik Liliane
Published: February 2025

Men have a significantly higher risk of developing cutaneous squamous cell carcinoma (SCC) compared to women, but models and comprehensive analysis of signaling pathways highlighting this sexual dimorphism are missing. In this study, we display a UV-induced SCC model in hairless mice recapitulating this sex difference, with enhanced SCC development in males. While UV-induced DNA damage is similar between sexes, we uncovered sex-specific responses in epidermal cell proliferation and differentiation. Using global transcriptional profile analyses, we identified E2F transcription factors as key sex-specific markers involved in the proliferative response to UV. Notably, E2F1/2, along with their target gene CDKN3, were selectively downregulated in female mice and human epidermis following UV exposure. Mechanistically, UV-induced and sex-specific modulation of E2F1 and CDKN3 expression is mediated by Estrogen Receptors. Lastly, low levels of CDKN3 in head and neck SCC are observed exclusively in female patients correlating with better prognosis. These findings shed new light on fundamental mechanisms protecting women from cancer after carcinogen exposure and could lead to better sex-targeted preventive and therapeutic strategies in SCC and other malignancies.
Application of a human lectin array to rapidin vitroscreening of sugars used as targeting tags for therapeutics
Authors: Benjamin Stefi V. , Taylor Maureen E. , Drickamer Kurt
Published: February 2025

An increasing number of clinical applications employ oligosaccharides as tags to direct therapeutic proteins and RNA molecules to specific target cells. Current applications are focused on endocytic receptors that result in cellular uptake, but additional applications of sugar-based targeting in signaling and protein degradation are emerging. These approaches all require development of ligands that bind selectively to specific sugar-binding receptors, known as lectins. In the work reported here, a human lectin array has been employed as a predictor of targeting specificity of different oligosaccharide ligands and as a rapidin vitroscreen to identify candidate targeting ligands. The approach has been validated with existing targeting ligands, such as a GalNAc cluster ligand that targets siRNA molecules to hepatocytes through the asialoglycoprotein receptor. Additional small oligosaccharides that can selectively target other classes of cells have also been identified and the potential of larger glycans derived from glycoproteins has been investigated. In initial screens, ligands for targeting either vascular or sinusoidal endothelial cells and plasmacytoid dendritic cells have been identified. Lectin array screening has also been used to characterize the specificity of glycolipid-containing liposomes that are used as carriers for targeted delivery. The availability of a rapidin vitroscreening approach to characterizing natural oligosaccharides and glycomimetic compounds has the potential to facilitate selection of appropriate targeting tags before undertaking more complexin vivostudies.
Ultrasensitive fitness costs arise from membrane proteome displacement under protein overexpression
Authors: Mueller Janina , Angermayr S. Andreas , Ansmann Gerrit , Bollenbach Tobias
Published: February 2025

Protein overexpression is crucial in many diseases and can lead to antibiotic resistance by increasing the expression of drug targets or resistance genes, such as membrane-localized efflux pumps. Using a high-throughput colony-imaging technique, we performed a quantitative genome-wide study of protein overexpression in Escherichia coli. Our results show that most membrane proteins impose steep overexpression costs, leading to an abrupt growth collapse beyond a critical expression threshold. By manipulating synthetic membrane proteins to target different translocation pathways, we ruled out saturation of these pathways as the cause of these fitness costs. Instead, we found that the growth collapse is driven by the displacement of endogenous membrane proteins, which we show directly using single-cell time-lapse imaging with fluorescently tagged membrane proteins in a microfluidic device. Displacement of as little as 10% of the membrane proteome trapped most bacteria in a non-growing state. Our findings enhance the quantitative understanding of expression costs, with implications for antibiotic resistance and the biotechnological production of membrane proteins.
Inhibiting fibronectin assembly in the breast tumor microenvironment increases cell death and improves response to doxorubicin
Authors: Gari Metti K. , Lee Hye Jin , Inman David R. , Burkel Brian M. , Highland Margaret A. , Kwon Glen S. , Gupta Nikesh , Ponik Suzanne M.
Published: February 2025

Purpose

Effective therapies for solid tumors, including breast cancers, are hindered by several roadblocks that can be largely attributed to the fibrotic extracellular matrix (ECM). Fibronectin (FN) is a highly upregulated ECM component in the fibrotic tumor stroma and is associated with poor patient prognosis. This study aimed to investigate the therapeutic potential of an anti-fibrotic peptide that specifically targets FN and blocks the fibrillar assembly of FN.

Methods

To target FN, we used PEGylated Functional Upstream Domain (PEG-FUD), which binds to the 70 kDa N-terminal region of FN with high affinity, localizes to mammary tumors, and potently inhibits FN assembly in vitro and in vivo. Here, we used the 4T1 tumor model to investigate the efficacy and mechanisms of PEG-FUD to inhibit tumor growth.

Results

Our data demonstrates that PEG-FUD monotherapy reduces tumor growth without systemic toxicity. Analysis of the tumor microenvironment revealed that PEG-FUD effectively inhibited FN matrix assembly within tumors and reduced adhesion-mediated signaling through α5 integrin and FAK leading to enhanced tumor cell death. Notably, signaling through FAK has been associated with resistance mechanisms to doxorubicin (DOX). Therefore, we tested the combination of PEG-FUD and Dox, which significantly reduced tumor growth by 60% compared to vehicle control and 30% compared to Dox monotherapy.

Conclusions

Our findings demonstrate that PEG-FUD significantly modifies the peritumoral ECM of breast cancer, leading to increased tumor cell death, and potentiates the efficacy of conventional breast cancer therapy.