bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics
Authors: Sussman Jonathan H , Xu Jason , Amankulor Nduka , Tan Kai 
Published: August 2023

Abstract
Malignant gliomas are incurable brain neoplasms with dismal prognoses and near-universal fatality, with minimal therapeutic progress despite billions of dollars invested in research and clinical trials over the last 2 decades. Many glioma studies have utilized disparate histologic and genomic platforms to characterize the stunning genomic, transcriptomic, and immunologic heterogeneity found in gliomas. Single-cell and spatial omics technologies enable unprecedented characterization of heterogeneity in solid malignancies and provide a granular annotation of transcriptional, epigenetic, and microenvironmental states with limited resected tissue. Heterogeneity in gliomas may be defined, at the broadest levels, by tumors ostensibly driven by epigenetic alterations (IDH- and histone-mutant) versus non-epigenetic tumors (IDH-wild type). Epigenetically driven tumors are defined by remarkable transcriptional programs, immunologically distinct microenvironments, and incompletely understood topography (unique cellular neighborhoods and cell–cell interactions). Thus, these tumors are the ideal substrate for single-cell multiomic technologies to disentangle the complex intra-tumoral features, including differentiation trajectories, tumor-immune cell interactions, and chromatin dysregulation. The current review summarizes the applications of single-cell multiomics to existing datasets of epigenetically driven glioma. More importantly, we discuss future capabilities and applications of novel multiomic strategies to answer outstanding questions, enable the development of potent therapeutic strategies, and improve personalized diagnostics and treatment via digital pathology.
Sociopragmatics
Authors: Terkourafi Marina , Delbar Natasja 
Published: August 2023

As the composite nature of the term itself suggests, “sociopragmatics” focuses on actual language use in real-life settings and across cultures. These aspects of language use had been neglected in early pragmatic work by philosophers such as H. P. Grice, J. L. Austin and J. Searle, which focused primarily on individual speakers’ intentions and language-internal, structural (in the Saussurean sense) explanations for differences in meaning across (putative) circumstances of use. Conversely, empirical and cross-cultural aspects of language use were given center stage in the development of politeness theories, which can be considered early precursors of sociopragmatics from the 1970s onward. Unlike its antecedent fields, sociolinguistics and pragmatics, which grew out of the Anglo-American (analytical) tradition in the late 1950s and 1960s, sociopragmatics reflects a functionalist focus usually found in continental work of the time. Early mentions of the term can be found in the work of Marcel Dascal and Ludger Hoffman, although the term itself was made popular through the work of two British scholars, Jenny Thomas and Geoffrey Leech, who famously distinguished between “pragmalinguistics” as knowledge of the non-truth conditional/interpersonal meanings linguistic forms can express, and “sociopragmatics” as the distribution of these form/meaning pairs in different contexts and the social parameters that regulate that. In terms of its subject matter, sociopragmatics focuses on how language expressions are used, by whom, and to what effect. In this sense, it can be contrasted to formal pragmatics, which focuses on the expressions’ meaning potential more abstractly conceived. Another major difference between sociopragmatics and formal pragmatics concerns where explanations are sought, with formal pragmatics seeking explanations in linguistic structure, while sociopragmatics does so in societal reasons. More specifically, sociopragmatics considers differences in meaning stemming from language users’ social (cultural, ethnic, ideological, interpersonal relationship, and so on) background and how this background shapes and is in turn shaped by their use (production and comprehension) of language. Sociopragmatics, in other words, fully acknowledges and tries to do justice to the performative potential of language, that is, its potential to bring the social world into existence. It thus bears links to more analytical fields, such as the philosophy of language, but also to more applied ones, such as discourse analysis, while at the same time differing from both, in terms of the questions it poses, as well as the tools it uses to address them. Major themes in sociopragmatics include identity, face and relational work, cultural conventions and norms, and (increasingly) emotions. To analyze these themes, sociopragmatics uses theoretical tools from pragmatics, most prominently implicatures and speech acts, and methodological ones from sociolinguistics (ethnographic observation, corpora, interviews, and questionnaires) and sociology (conversation analysis).
Immune-Related Diarrhea and Colitis in Non-small Cell Lung Cancers: Impact of Multidisciplinary Management in a Real-World Setting
Authors: Bonanno Laura , Lorenzi Martina , Massa Davide , De Nuzzo Mattia , Angerilli Valentina , Zingone Fabiana , Barberio Brigida , Russi Alberto , Girardi Fabio , Ferro Alessandra , Dal Maso Alessandro , Frega Stefano , Pasello Giulia , Dei Tos Angelo Paolo , Coppola Marina , Fassan Matteo , Savarino Edoardo Vincenzo , Guarneri Valentina 
Published: August 2023

Abstract

Introduction
Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management.

Methods
We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators.

Results
Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P &lt; .001) and overall survival (28.3 vs 9.5, P &lt; .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P &lt; .001), colonoscopy (P &lt; .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns).

Conclusion
These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned.
Real-world evidence for secukinumab in UK patients with psoriatic arthritis or radiographic axial spondyloarthritis: interim 2-year analysis from SERENA
Authors: Gaffney Karl , Gullick Nicola , MacKay Kirsten , Patel Yusuf , Sengupta Raj , Sheeran Tom , Hemmings Louise , Pamies Paula 
Published: August 2023

Abstract

Objectives
The aim was to evaluate retention rates for secukinumab in patients with active PsA or radiographic axial spondyloarthritis (r-axSpA) treated in routine UK clinical practice.

Methods
SERENA (CAIN457A3403) is an ongoing, non-interventional, international study of patients with moderate-to-severe chronic plaque psoriasis, active PsA or active r-axSpA, who had received secukinumab for ≥16 weeks before enrolment. The primary objective of this interim analysis was to assess treatment retention rates in patients with PsA or r-axSpA who were enrolled and followed for ≥2 years at centres in the UK. The safety analysis set includes all patients who received at least one dose of secukinumab. The target population set includes all patients who fulfilled the patient selection criteria.

Results
The safety set comprised 189 patients (PsA, n = 81; r-axSpA, n = 108), and the target population set comprised 183 patients (PsA, n = 78; r-axSpA, n = 105). In the safety set, 107 patients (45 of 81 with PsA and 62 of 108 with r-axSpA) had previously received a biologic agent. Retention rates were similar between patients with PsA and r-axSpA after 1 year (PsA 91.0%, 95% CI: 84.0, 98.0; r-axSpA 89.2%, 95% CI: 82.7, 95.7) and 2 years (PsA 77.6%, 95% CI: 67.6, 87.7; r-axSpA 76.2%, 95% CI: 67.4, 85.0) of observation. Overall, 17.5% of patients (33 of 189) experienced at least one treatment-related adverse event, and 12.7% of patients (24 of 189) discontinued secukinumab because of adverse events.

Conclusion
This analysis of real-world data from the UK demonstrates high retention rates for secukinumab over 2 years in patients with PsA or r-axSpA, with a favourable safety profile.
Unilateral optogenetic stimulation of Lhx6 neurons in the zona incerta increases REM sleep
Authors: Vidal-Ortiz Aurelio , Blanco-Centurion Carlos , Shiromani Priyattam J 
Published: August 2023

Abstract
To determine how a waking brain falls asleep researchers have monitored and manipulated activity of neurons and glia in various brain regions. While imaging Gamma-Aminobutyric Acid (GABA) neurons in the zona incerta (ZI) we found a subgroup that anticipates onset of NREM sleep (Blanco-Centurion C, Luo S, Vidal-Ortiz A, Swank C, Shiromani PJ. Activity of a subset of vesicular GABA-transporter neurons in the ventral ZI anticipates sleep onset. Sleep. 2021;44(6):zsaa268. doi:10.1093/sleep/zsaa268.). To differentiate the GABA subtype we now image and optogenetically manipulate the ZI neurons containing the transcription factor, Lhx6. In the first study, Lhx6-cre mice (n = 5; female = 4) were given rAAV-DJ-EF1a-DIO-GCaMP6M into the ZI (isofluorane anesthesia), a GRIN lens implanted, and 21days later sleep and fluorescence in individual Lhx6 neurons were recorded for 4 hours. Calcium fluorescence was detected in 132 neurons. 45.5% of the Lhx6 neurons were REM-max; 30.3% were wake-max; 11.4% were wake + REM max; 9% were NREM-max; and 3.8% had no change. The NREM-max group of neurons fluoresced 30 seconds ahead of sleep onset. The second study tested the effects of unilateral optogenetic stimulation of the ZI Lhx6 neurons (n = 14 mice) (AAV5-Syn-FLEX-rc[ChrimsonR-tdTomato]. Stimulation at 1 and 5 Hz (1 minute on- 4 minutes off) significantly increased percent REM sleep during the 4 hours stimulation period (last half of day cycle). The typical experimental approach is to stimulate neurons in both hemispheres, but here we found that low-frequency stimulation of ZI Lhx6 neurons in one hemisphere is sufficient to shift states of consciousness. Detailed mapping combined with mechanistic testing is necessary to identify local nodes that can shift the brain between wake–sleep states.
Allogeneic Cell Therapy Applications in Neonates: A Systematic Review
Authors: Razak Abdul , Lei Donna , McDonald Courtney A , Hunt Rod W , Miller Suzanne L , Malhotra Atul 
Published: August 2023

Abstract

Background
Neonatal cell therapy applications are increasing; however, data on allogeneic cell therapy are limited.

Objective
To summarize evidence on allogeneic cell therapy in term and preterm neonates.

Methods
Cochrane Central Register of Controlled Trials, Embase, Ovid Medline, and various registries were searched for studies investigating the safety, feasibility, and efficacy of allogeneic cell therapy in neonates. Two authors independently selected the articles, extracted data, and assessed the risk of bias.

Results
Twelve published (153 infants) and 21 ongoing studies were included. These studies predominantly sourced allogeneic cells from umbilical cord blood (UCB). Mesenchymal stromal cells (MSCs) were the main cell type used (134 of 153 infants); others included UCB-derived total nucleated cells (TNCs) and human amnion epithelial cells (hAECs). Applications included bronchopulmonary dysplasia (BPD; 113 infants), Krabbe disease (13 infants), intraventricular haemorrhage (10 infants), perinatal arterial ischemic stroke (10 infants), hypoxic-ischaemic encephalopathy (6 infants), and necrotizing enterocolitis (1 infant). Nine out of 12 studies did not report any serious adverse events (SAEs) related to cell administration. Three studies reported SAEs, such as graft versus host disease (GVHD) in 5 infants (UCB-derived TNCs for Krabbe disease); and transient cardiorespiratory compromise in 1 infant (hAECs for BPD). Data on efficacy outcomes were limited.

Conclusion
The safety and feasibility of allogeneic cell therapy applications in neonates are available, mainly from the use of MSCs. Further safety data for other cell types are required, and the risk of GVHD in different settings needs to be determined. Efficacy studies are largely lacking for all cell types.

Protocol Registration
The protocol was registered with PROSPERO (registration number CRD42023397876), the international prospective register for systematic reviews (https://www.crd.york.ac.uk/PROSPERO).
The Direct Effects of Norepinephrine Administration on Pressure Injuries in Intensive Care Patients: A Retrospective Cohort Study
Authors: Argenti Graziela , Ishikawa Gerson , Fadel Cristina Berger 
Published: August 2023

ABSTRACT

OBJECTIVE
To estimate the direct effects of norepinephrine administration on pressure injury (PI) incidence in intensive care patients.

METHODS
This is a secondary and exploratory analysis of a retrospective cohort study of intensive care patients discharged in 2017 to 2018. Observational cases only included patients who received primary PI preventive care during intensive care (N = 479). As a first-choice vasopressor drug, norepinephrine administration was approximated with days of norepinephrine. Linear path models were examined from norepinephrine administration to PI development. The identification of confounding variables and instrumental variables was grounded on directed acyclic graph theory. Direct effects were estimated with instrumental variables to overcome bias from unobserved variables. As models were re-specified with data analysis, the robustness of path identification was improved by requiring graph invariance with sample split.

RESULTS
Norepinephrine caused PI development from one stage to another after 4.0 to 6.3 days of administration in this cohort as a total effect (90% CI). The direct effect was estimated to advance the stage of PI at a rate of 0.140 per day of norepinephrine administered (standard error, 0.029; P < .001). The direct effect accounted for about 70% of the total effect on PI development.

CONCLUSIONS
Estimations with instrumental variables and structural equation modeling showed that norepinephrine administration directly and substantially affected hospital-acquired PI incidence in intensive care patients in this cohort.
Frequency and Trends of Pre-Pandemic Surge Periods in U.S. Emergency Departments, 2006–2019
Authors: Anesi George L. , Xiong Ruiying (Aria) , Delgado M. Kit 
Published: August 2023

OBJECTIVES:
To quantify the frequency, outside of the pandemic setting, with which individual healthcare facilities faced surge periods due to severe increases in demand for emergency department (ED) care.

DESIGN:
Retrospective cohort study.

SETTING:
U.S. EDs.

PATIENTS:
All ED encounters in the all-payer, nationally representative Nationwide Emergency Department Sample from the Healthcare Cost and Utilization Project, 2006–2019.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
Frequency of surge periods defined as ED months in which an individual facility ED saw a greater than 50% increase in ED visits per month above facility-/calendar month-specific medians. During 2006–2019, 3,317 U.S. EDs reported 354,534,229 ED visits across 142,035 ED months. Fifty-seven thousand four hundred ninety-five ED months (40.5%) during the study period had a 0% to 50% increase in ED visits that month above facility-specific medians and 1,952 ED months (1.4%) qualified as surge periods and had a greater than 50% increase in ED visits that month above facility-specific medians. These surge months were experienced by 397 unique facility EDs (12.0%). Compared with 2006, the most proximal pre-pandemic period of 2016–2019 had a notably elevated likelihood of ED-month surge periods (odds ratios [ORs], 2.36–2.84; all p < 0.0005). Compared with the calendar month of January, the winter ED months in December through March have similar likelihood of an ED-month qualifying as a surge period (ORs, 0.84–1.03; all p > 0.05), while the nonwinter ED months in April through November have a lower likelihood of an ED-month qualifying as a surge period (ORs, 0.65–0.81; all p < 0.05).

CONCLUSIONS:
Understanding the frequency of surges in demand for ED care—which appear to have increased in frequency even before the COVID-19 pandemic and are concentrated in winter months—is necessary to better understand the burden of potential and realized acute surge events and to inform cost-effectiveness preparedness strategies.
Comparison of Five-Year Graft Survival After Keratoplasty in the Veteran Population
Authors: Wendt Sydney , Gordon Abigail , Bhatnagar Anshul , Orengo-Nania Silvia , Biggerstaff Kristin , Khandelwal Sumitra 
Published: August 2023

Purpose:
We investigated the corneal graft survival rate after penetrating keratoplasty (PK) and Descemet stripping endothelial keratoplasty (DSEK) in a veteran population.

Methods:
A retrospective review was conducted on patients undergoing a primary PK or DSEK at a large Veterans Affairs Medical Center between January 2005 and August 2019. Exclusion criteria included patients with a postoperative follow-up less than 5 years and patients undergoing additional ocular procedures during surgery. Patients were classified into 3 groups depending on their glaucoma status before corneal transplant: no pre-existing glaucoma, medically managed glaucoma, or surgically managed glaucoma. Graft survival was calculated using the Kaplan–Meier survival analysis.

Results:
A total of 30 eyes underwent PK, and 28 eyes underwent DSEK. There was no significant difference in graft survival rates between PK and DSEK at 1 year (83% vs. 79%, P = 0.555), 3 years (53% vs. 64%, P = 0.536), and 5 years (40% vs. 54%, P = 0.399). When combining PK and DSEK groups, Kaplan–Meier analysis showed a highly significant difference in 5-year graft survival between patients without pre-existing glaucoma (58%) and patients with either medically (50%) or surgically managed glaucoma (0%).

Conclusions:
We find approximate parity in 1-year, 3-year, and 5-year survival rates after PK and DSEK within the veteran population. However, survival rates for both procedures are lower than those previously reported within other populations. Additional studies to understand these differences in larger cohorts are warranted. Ophthalmologists must understand the increased risk of graft failure in the veteran population to provide appropriate counseling.
Diagnostic Patterns of Age-Related Macular Degeneration among Asian Medicare Beneficiaries Macular Degeneration in Asians
Authors: Hussain Zain S. , Wu Gloria , Loya Asad , Ding Kai , Sambhav Kumar , Riaz Kamran M. , Shah Vinay A. 
Published: August 2023

Abstract

Purpose:
To characterize prevalence estimates by race, age, gender, and comorbidity (diabetes, hypertension) within the Medicare beneficiary demographic.

Methods:
In this US population-based retrospective cohort analysis, the Vision and Eye Health Surveillance System was analyzed for a 100% sample of Medicare Fee-For-Service beneficiary populations of Asians and non-Hispanic Whites between 2014 and 2018. Exclusionary criteria included beneficiaries less than 40 years of age. Prevalence rate ratios (PRRs), defined as prevalence rate for Asians divided by prevalence rate for non-Hispanic Whites, were calculated utilizing multivariate negative binomial regression or Pearson-scaled Poisson regression, stratified by age, gender, and comorbidity.

Results:
A total of 21,892,200 Medicare beneficiaries fulfilled the inclusionary criteria in 2018. Of the entire cohort, 3.2%(N=714,500) were Asian. For beneficiaries aged 40-64 years, Asian males (PRR 1.73,95% CI 1.64 – 1.83,p<0.0001) and females (PRR 1.34,95% CI 1.28 – 1.41,p<0.0001) had increased prevalence rate of all AMD relative to non-Hispanic Whites. Significant time-wise increases in PRR were observed within several age groups, genders, and comorbidities (race-time interaction coefficients p<0.05).

Conclusions:
This analysis highlights increased AMD prevalence estimates within the Asian American demographic relative to non-Hispanic Whites. Furthermore, specific Asian subpopulations are experiencing accelerated prevalence rates over time.
Efficacy of surgical treatment and conservative treatment for cervical spinal cord injury without fracture and dislocation in adults: A meta-analysis
Authors: Chen Deyuan , Chen Huajian , Huang Fuli 
Published: August 2023

Background:
The aim of this study was to investigate the efficacy of surgical treatment and conservative treatment for cervical spinal cord injury without fracture and dislocation (CSCIWFD) in adults by meta-analysis.

Methods:
With a time span from 2010 to 2022, PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for all clinical randomized controlled trials on the comparison of surgical treatment and conservative treatment for CSCIWFD in adults. The Cochrane quality assessment tool was used as the standard. Stata 16.0 statistical software was used for meta-analysis.

Results:
A total of 870 articles were retrieved, and 12 studies were finally included for meta-analysis. Among them, there were 451 patients in the observation group (surgical treatment) and 346 patients in the control group (conservative treatment). The results of meta-analysis showed that the observation group was superior to the control group in the effective rate (OR = 4.737, 95% CI [2.613, 8.586], P < .001), Japanese Orthopedic Association (JOA) score at 3 months after treatment (SMD = 1.038, 95% CI [0.417, 1.659], P = .001), 6 months after treatment (SMD = 3.135, 95% CI [2.120, 4.151], P < .001) and 12 months after treatment (SMD = 2.808, 95% CI [1.880, 3.737], P < .001). In addition, the JOA scores of patients at 12 months after surgical treatment (SMD = 6.397, 95% CI [4.654, 8.14], P < .001) and conservative treatment (SMD = 3.197, 95% CI [2.144, 4.24], P < .001) were significantly higher than those before treatment.

Conclusions:
Surgical treatment can improve the effective rate and JOA score of adult patients with CSCIWFD compared to conservative treatment. This suggests that surgical treatment can significantly improve the patient’s spinal cord function.