bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter, Randomized, Placebo-controlled Crossover Trial Evaluating Topical Lidocaine for Mechanical Cervical Pain
Authors: Cohen Steven P. , Larkin Thomas M. , Weitzner Aidan S. , Dolomisiewicz Edward , Wang Eric J. , Hsu Annie , Anderson-White Mirinda , Smith Marin S. , Zhao Zirong 
Published: December 2023

Background
There are few efficacious treatments for mechanical neck pain, with controlled trials suggesting efficacy for muscle relaxants and topical nonsteroidal anti-inflammatory drugs. Although studies evaluating topical lidocaine for back pain have been disappointing, the more superficial location of the cervical musculature suggests a possible role for topical local anesthetics.

Methods
This study was a randomized, double-blind, placebo-controlled crossover trial performed at four U.S. military, Veterans Administration, academic, and private practice sites, in which 76 patients were randomized to receive either placebo followed by lidocaine patch for 4-week intervals (group 1) or a lidocaine-then-placebo patch sequence. The primary outcome measure was mean reduction in average neck pain, with a positive categorical outcome designated as a reduction of at least 2 points in average neck pain coupled with at least a 5-point score of 7 points on the Patient Global Impression of Change scale at the 4-week endpoint.

Results
For the primary outcome, the median reduction in average neck pain score was −1.0 (interquartile range, −2.0, 0.0) for the lidocaine phase versus −0.5 (interquartile range, −2.0, 0.0) for placebo treatment (P = 0.17). During lidocaine treatment, 27.7% of patients experienced a positive outcome versus 14.9% during the placebo phase (P = 0.073). There were no significant differences between treatments for secondary outcomes, although a carryover effect on pain pressure threshold was observed for the lidocaine phase (P = 0.015). A total of 27.5% of patients in the lidocaine group and 20.5% in the placebo group experienced minor reactions, the most common of which was pruritis (P = 0.36).

Conclusions
The differences favoring lidocaine were small and nonsignificant, but the trend toward superiority of lidocaine suggests more aggressive phenotyping and applying formulations with greater penetrance may provide clinically meaningful benefit.

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Astrocyte PERK and IRE1 Signaling Contributes to Morphine Tolerance and Hyperalgesia through Upregulation of Lipocalin-2 and NLRP3 Inflammasome in the Rodent Spinal Cord
Authors: Wang Bing , Wang Li-Na , Wu Bin , Guo Ran , Zhang Li , Zhang Jiang-Tao , Wang Zhi-Hong , Wu Feng , Feng Yu , Liu Hong , Jin Xiao-Hong , Miao Xiu-Hua , Liu Tong 
Published: December 2023

Background
Endoplasmic reticulum stress plays a crucial role in the pathogenesis of neuroinflammation and chronic pain. This study hypothesized that PRKR-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme type 1 (IRE1) regulate lipocalin-2 (LCN2) and Nod-like receptor family pyrin domain containing 3 (NLRP3) expression in astrocytes, thereby contributing to morphine tolerance and hyperalgesia.

Methods
The study was performed in Sprague–Dawley rats and C57/Bl6 mice of both sexes. The expression of LCN2 and NLRP3 was assessed by Western blotting. The tail-flick, von Frey, and Hargreaves tests were used to evaluate nociceptive behaviors. Chromatin immunoprecipitation was conducted to analyze the binding of activating transcription factor 4 (ATF4) to the promoters of LCN2 and TXNIP. Whole-cell patch-clamp recordings were used to evaluate neuronal excitability.

Results
Pharmacologic inhibition of PERK and IRE1 attenuated the development of morphine tolerance and hyperalgesia in male (tail latency on day 7, 8.0 ± 1.13 s in the morphine + GSK2656157 [10 μg] group vs. 5.8 ± 0.65 s in the morphine group; P = 0.04; n = 6 rats/group) and female (tail latency on day 7, 6.0 ± 0.84 s in the morphine + GSK2656157 [10 μg] group vs. 3.1 ± 1.09 s in the morphine group; P = 0.0005; n = 6 rats/group) rats. Activation of PERK and IRE1 upregulated expression of LCN2 and NLRP3 in vivo and in vitro. Chromatin immunoprecipitation analysis showed that ATF4 directly bound to the promoters of the LCN2 and TXNIP. Lipocalin-2 induced neuronal hyperexcitability in the spinal cord and dorsal root ganglia via melanocortin-4 receptor.

Conclusions
Astrocyte endoplasmic reticulum stress sensors PERK and IRE1 facilitated morphine tolerance and hyperalgesia through upregulation of LCN2 and NLRP3 in the spinal cord.

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Cryptococcal Infection Presenting as a Pleural Effusion in a Liver Transplant Recipient
Authors: Al-Kaabneh Basil , Alpizar-Rivas Rodolfo , Chuang Sally , Gupta Purba 
Published: December 2023

Abstract
We report a rare case of a liver transplant recipient who experienced acute respiratory failure early posttransplantation because of cryptococcal pleural effusion. Although cryptococcal disease presenting solely as pleural effusion has been reported in the literature, it is not widely described in liver transplant recipients. Cryptococcal disease usually manifests late in the posttransplant period, whereas our patient was diagnosed with the infection early posttransplant. Diagnosis was made by pleural fluid culture. The initial serum cryptococcal antigen testing was negative. This case demonstrates the potential of subclinical or latent infections in patients with cirrhosis and liver transplant recipients and the importance of considering pleural fluid culture in the diagnostic evaluation of pleural effusions in cirrhotic patients.
Empyema Necessitans Following Bacille Calmette-Guérin Administration for Urothelial Carcinoma
Authors: Amar Maisam , Weber Gabriel , Yassin Rabah , Salah Ola , Mishan Pninit Shaked , Brudenski Maya , Shehade Shereen , Najjar-Debbiny Ronza 
Published: December 2023

Background
Bacille Calmette-Guérin wash for urothelial carcinoma is a very common adjuvant treatment with a low potential for serious systemic adverse events. We present a case of a rare serious complication, empyema necessitans, following treatment with BCG.

Case Presentation
A 77-year-old patient with urothelial cancer treated with adjuvant BCG wash developed empyema due to Mycobacterium bovis related to his previous BCG exposure, which progressed to empyema necessitans treated with antituberculosis medications in conjugant with multiple thoracic drainages. Despite treatment, the patient's condition deteriorated slowly leading to death.

Conclusion
Rare adverse events of common treatments should be considered when evaluating a patient, as BCG wash could potentially lead to empyema necessitans.
Gallbladder perforation in acute acalculous vs. calculous cholecystitis: a retrospective comparative cohort study with 10-year single-center experience
Authors: Lee Kyong Joo , Park Se Woo , Park Da Hae , Cha Hye Won , Choi Ana , Koh Dong Hee , Lee Jin , Lee Jung Min , Park Chan Hyuk 
Published: December 2023

Background:
Gallstones are a well-known risk factor for acute cholecystitis. However, their role as a risk factor for gallbladder perforation (GBP) remains unclear. Therefore, this study aimed to determine the effect of gallstones on the development of GBP.

Materials and methods:
This large-scale retrospective cohort study enroled consecutive patients who underwent cholecystectomy for acute cholecystitis. The primary endpoint was the role of gallstones as a risk factor for developing GBP. Secondary endpoints included the clinical characteristics of GBP, other risk factors for GBP, differences in clinical outcomes between patients with acalculous cholecystitis (AC) and calculous cholecystitis (CC), and the influence of cholecystectomy timing.

Results:
A total of 4497 patients were included in this study. The incidence of GBP was significantly higher in the AC group compared to the CC group (5.6% vs. 1.0%, P<0.001). However, there were no differences in ICU admission and hospital stay durations. The incidence of overall complications was significantly higher in the AC group than in the CC group (2.2% vs. 1.0%, P<0.001). Patients with AC had a higher risk of developing GBP than those with CC (odds ratio, 5.00; 95% CI, 2.94–8.33). In addition, older age (≥60 years), male sex, comorbidities, poor performance status, and concomitant acute cholangitis were associated with the development of GBP. Furthermore, the incidence of GBP was significantly higher in the delayed cholecystectomy group than in the early cholecystectomy group (2.0% vs. 0.9%, P<0.001).

Conclusions:
AC is a significant risk factor for GBP. Furthermore, early cholecystectomy can significantly reduce GBP-related morbidity and mortality.
Portal venous blood flow velocity is a factor associated with portal venous thrombosis after partial splenic artery embolization in hepatic cirrhosis patients
Authors: Huang Jiaming , Liu Haifeng 
Published: December 2023

Objective:
To investigate risk factors for portal venous thrombosis (PVT) after partial splenic artery embolization (PSE) in hepatic cirrhosis patients.

Methods:
The authors retrospectively analyzed 151 hepatic cirrhosis patients with hypersplenism who underwent partial splenic artery embolization between January 2020 and December 2021. The patients were divided into a PVT group and a non-PVT group according to whether they had PVT after PSE. Univariate analyses were performed to select risk factors for PVT after PSE, and multivariate analysis was used to analyze variates with a value of P less than 0.1 in univariate analysis.

Results:
There were 151 patients enroled in the study, with 22 patients in the PVT group and 129 patients in the non-PVT group. There was no significant difference in terms of age, sex, smoking, hypertension, diabetes, Child–Pugh between two groups. White blood cell (WBC) and platelet counts after PSE were significantly higher than those before PSE in both the PVT group and non-PVT group. Univariate analysis showed that portal venous blood flow velocity, ligation of oesophageal varices and WBC after PSE were found to have a P value less than 0.1. Multivariate analysis showed that portal venous blood flow velocity was a factor associated with PVT after PSE.

Conclusion:
Portal venous blood flow velocity was a factor associated with PVT after PSE. Portal venous blood flow velocity should be considered before patients undergo PSE.
Experiences and Unmet Needs of Adolescent and Young Adult Survivors of a Brain Tumor (Aged 15–39 Years)
Authors: Law Kate , Salam Iram , McCabe Martin G. , van der Veer Sabine N. , Gibson Faith , Yorke Janelle 
Published: December 2023

Background
Brain tumors account for 15% of all adolescent and young adult cancers, and survivors are at risk of ongoing late effects that can severely impact their ability to reach independence. Despite follow-up initiatives advocating a personalized approach, survivors continue to experience ongoing sequelae. A better understanding of the survivorship experience is required to ensure services are able to deliver personalized support.

Objective
The aim of this systematic search and meta-ethnography was to identify and synthesize qualitative studies to better understand the experiences, perspectives, and needs of adolescent and young adult brain tumor survivors.

Methods
Five databases were searched using predefined criteria, studies were independently screened by two researchers, and those meeting inclusion criteria were synthesized.

Results
Twenty-seven studies were synthesized, generating 2 main themes, each with subthemes: (1) individual factors impacting resilience, namely, positive coping styles, managing emotions, and family functioning, and (2) cancer-related factors that challenge the individual, namely, living with societal expectations and barriers to coping.

Conclusion
The conceptual framework illustrates the challenges and resilience of survivors along the continuum from adolescence to adulthood, reflecting the needs of this age group in 1 model, despite it being a time of rapid growth. The lack of awareness of potential physical and emotional late effects challenges individual resilience, which is further challenged when significant milestones cannot be reached.

Implications for Practice
There is a role for follow-up services to identify and address unmet needs, provide better information to equip survivors to manage late effects, and support families, particularly those who underwent more intensive treatment.
Retinal Photograph-based Deep Learning System for Detection of Thyroid-Associated Ophthalmopathy
Authors: Jiang Xue , Dong Li , Luo Lihua , Zhang Kai , Li Dongmei 
Published: December 2023

Background:
The diagnosis of thyroid-associated ophthalmopathy (TAO) usually requires a comprehensive examination, including clinical symptoms, radiological examinations, and blood tests. Therefore, cost-effective and noninvasive methods for the detection of TAO are needed. This study aimed to establish a deep learning-based system to detect TAO based on retinal photographs.

Materials and methods:
The multicenter observational study included retinal photographs taken from TAO patients and normal participants in 2 hospitals in China. Forty-five-degree retinal photographs, centered on the midpoint between the optic disc and the macula, were captured by trained ophthalmologists. The authors first trained a convolutional neural network model to identify TAO using data collected from one hospital. After internal validation, the model was further evaluated in another hospital as an external validation data set.

Results:
The study included 1182 retinal photographs of 708 participants for model development, and 365 retinal photographs (189 participants) were obtained as the external validation data set. In the internal validation, the area under the receiver operator curve was 0.900 (95% CI: 0.889–0.910) and the accuracy was 0.860 (95% CI: 0.849–0.869). In the external data set, the model reached an area under the curve of 0.747 (95% CI: 0.728–0.763) and achieved an accuracy of 0.709 (95% CI: 0.690–0.724).

Conclusions:
Deep learning-based systems may be promising for identifying TAO in normal subjects using retinal fundus photographs. It may serve as a cost-effective and noninvasive method to detect TAO in the future.
Associated Risk Factors for Extended Operative Time Following Cranial Vault Remodeling for Craniosynostosis: Analysis of the 2012 to 2021 NSQIP-Pediatric Database
Authors: Serrato Paul , Hengartner Astrid C. , Sayeed Sumaiya , Prassinos Alexandre J. , Alperovich Michael , DiLuna Michael , Elsamadicy Aladine A. 
Published: December 2023

Study Design:
Retrospective cohort study.

Objectives:
The aim of this study was to identify the factors associated with extended operative time (EOT) for pediatric patients with craniosynostosis undergoing cranial vault remodeling (CVR).

Methods:
A retrospective cohort study was performed using the 2012 to 2021 American College of Surgeons National Surgical Quality Improvement Program Pediatric–-Pediatric database. Pediatric patients below 2 years old with craniosynostosis who underwent CVR were identified using Current Procedural Terminology and International Classification of Diseases-9/10 codes. Patients were dichotomized according to whether they encountered an EOT, which was defined as operative time greater than the 75th percentile for the entire cohort (246 min). Patient demographics, comorbidities, intraoperative variables, postoperative adverse events, and health care resource utilization were assessed. Multivariate logistic regression analysis was utilized to identify predictors of EOT and length of stay.

Results:
In the cohort of 9817 patients undergoing CVR, 24.3% experienced EOT. The EOT cohort was significantly older and less likely to be non-Hispanic White. Patient comorbidities and surgical adverse events were more frequent among the EOT cohort, including proportions of postoperative surgical site infections. Independent predictors for EOT included age, racial identity, weight, and a higher American Society of Anesthesiologists classification. EOT was found to be an independent predictor for prolonged hospitalization EOT [adjusted odds ratios: 0.78 (0.44–1.13), P<0.001].

Conclusions:
This study demonstrates that age, race, and comorbidities contribute to EOT after CVR for craniosynostosis. EOT is independently associated with a longer length of stay. Additional investigations to further understand the risk factors and impacts of extended EOT are warranted to improve patient outcomes.
SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma
Authors: Daley Brianna R , Sealover Nancy E , Sheffels Erin , Hughes Jacob M. , Gerlach Daniel , Hofmann Marco H , Kostyrko Kaja , Mair Barbara , Linke Amanda , Beckley Zaria , Frank Andrew , Dalgard Clifton , Kortum Robert L 
Published: December 2023

SummaryClinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressorKEAP1limits the clinical effectiveness of G12Cis, andKEAP1andSTK11deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ciin situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless ofKEAP1andSTK11mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.SignificanceThe SOS1 inhibitor BI-3406 both inhibits intrinsic/adaptive resistance and targets drug tolerant persister cells to limit the development of acquired resistance to clinical KRASG12Cinhibitors in lung adenocarcinoma cells.
Multi-parameter phenotyping of platelets and characterisation of the effects of agonists using machine learning
Authors: Vadgama Ami , Boot James , Allan Harriet E. , Mein Charles A. , Armstrong Paul C. , Warner Timothy D. 
Published: December 2023

AbstractBackgroundPlatelets are crucial for thrombosis and haemostasis, with their function driven by the expression of specialised surface markers. The concept of distinct circulating sub-populations of platelets has emerged in recent years, but their exact nature remains debatable. We reasoned that a more comprehensive characterisation of surface marker changes at rest and upon activation would be valuable in determining this.ObjectiveTo use a full spectrum flow cytometry-based panel, together with parameters of physical properties, to describe surface marker changes in healthy platelets at rest and on activation, and to observe how these responses differ according to platelet age.MethodsA 14-marker flow cytometry panel was developed and applied to vehicle- or agonist-stimulated platelet-rich plasma samples obtained from healthy volunteers, or to platelets sorted according to SYTO-13 staining intensity as an indicator of platelet age. Data were analysed using both user-led and independent approaches incorporating novel machine learning-based algorithms.ResultsThe assay detected changes in marker expression in healthy platelets, at rest and on agonist activation, that are consistent with the literature. Machine learning identified stimulated populations of platelets with high accuracy (>80%). Similarly, differentiation between young and old platelet populations achieved 76% accuracy, primarily weighted by FSC-A, CD41, SSC-A, GPVI, CD61, and CD42b expression patterns.ConclusionsOur findings provide a novel assay to phenotype platelets coupled with a robust bioinformatics and machine learning workflow for deep analysis of the data. This could be valuable in characterising platelets in disease.(240 words)EssentialsPlatelet function is directed by the expression of specialised surface markersCirculating platelet sub-populations are incompletely characterisedMulti-parameter spectral flow cytometry allows robust and comprehensive phenotyping of plateletsCoupling multi-parameter spectral flow cytometry with machine learning offers a powerful method to determine platelet sub-populations
Non Parametric Differential Network Analysis for Biological Data
Authors: Guzzi Pietro Hiram , Roy Arkaprava , Veltri Pierangelo 
Published: December 2023

AbstractRewiring of molecular interactions under different conditions causes different phenotypic responses. Differential Network Analysis (also indicated as DNA) aims to investigate the rewiring of gene and protein networks. DNA algorithms combine statistical learning and graph theory to explore the changes in the interaction patterns starting from experimental observation. Despite there exist many methods to model rewiring in networks, we propose to use age and gender factors to guide rewiring algorithms. We present a novel differential network analysis method that consider the differential expression of genes by means of sex and gender attributes. We hypothesise that the expression of genes may be represented by using a non-gaussian process. We quantify changes in nonparametric correlations between gene pairs and changes in expression levels for individual genes. We apply our method to identify the differential networks between males and females in public expression datasets related to mellitus diabetes in liver tissue. Results show that this method can find biologically relevant differential networks.