bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatic encephalopathy is not a contraindication to pre-emptive TIPS in high-risk patients with cirrhosis with variceal bleeding
Authors: Rudler Marika , Hernández-Gea Virginia , Procopet Bogdan Dumitru , Giráldez Alvaro , Amitrano Lucio , Villanueva Càndid , Ibañez Luis , Silva-Junior Gilberto , Genesca Joan , Bureau Christophe , Trebicka Jonel , Bañares Rafael , Krag Aleksander , Llop Elba , Laleman Wim , Palazon Jose Maria , Castellote Jose , Rodrigues Susana , Gluud Lise Lotte , Noronha Ferreira Carlos , Canete Nouria , Rodríguez Manuel , Ferlitsch Arnulf , Mundi Jose Luis , Gronbaek Henning , Hernandez-Guerra Manuel , Sassatelli Romano , Dell’era Alessandra , Senzolo Marco , Abraldes Juan G , Romero-Gómez Manuel , Zipprich Alexander , Casas Meritxell , Masnou Helena , Larrue Hélène , Primignani Massimo , Nevens Frederik , Calleja Jose Luis , Schwarzer Remy , Jansen Christian , Robic Marie-Angèle , Conejo Irene , Martínez Gonzalez Javier , Catalina Maria Vega , Albillos Agustín , Alvarado Edilmar , Guardascione Maria Anna , Mallet Maxime , Tripon Simona , Casanovas Georgina , Bosch Jaume , Garcia-Pagan Juan-Carlos , Thabut Dominique 
Published: September 2022

BackgroundA pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown. We aimed to (1) assess the prevalence of HE in patients with AVB; (2) evaluate the outcome of patients presenting HE at admission after pTIPS; and (3) determine if HE at admission is a risk factor for death and post-TIPS HE.Patients and methodsThis is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation.Results671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p<0.001). In high-risk patients with HE at admission, pTIPS was associated with a lower 1-year mortality than endoscopic+drug (HR 0.374, 95% CI 0.166 to 0.845, p=0.0181). The incidence of HE was not different between patients treated with pTIPS and endoscopic+drug (38.2% vs 38.7%, p=0.9721), even in patients with HE at admission (56.4% vs 58.7%, p=0.4594). Age >56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients.ConclusionpTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission.
Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis
Authors: Loomba Rohit , Huang Daniel Q. , Sanyal Arun J , Anstee Quentin Mark , Trauner Michael , Lawitz Eric J , Ding Dora , Ma Lily , Jia Catherine , Billin Andrew , Huss Ryan S , Chung Chuhan , Goodman Zachary , Wong Vincent Wai-Sun , Okanoue Takeshi , Romero-Gómez Manuel , Abdelmalek Manal F , Muir Andrew , Afdhal Nezam , Bosch Jaime , Harrison Stephen , Younossi Zobair M , Myers Robert P 
Published: September 2022

ObjectiveIn retrospective studies, liver stiffness (LS) by vibration-controlled transient elastography (VCTE) is associated with the risk of liver decompensation in patients with non-alcoholic steatohepatitis (NASH), but prospective data in biopsy-confirmed cohorts with advanced fibrosis are limited. We aimed to establish thresholds for LS by VCTE that predict progression to cirrhosis among patients with bridging fibrosis and hepatic decompensation among patients with cirrhosis due to NASH.DesignWe used data from four randomised placebo-controlled trials of selonsertib and simtuzumab in participants with advanced fibrosis (F3–F4). The trials were discontinued due to lack of efficacy. Liver fibrosis was staged centrally at baseline and week 48 (selonsertib study) or week 96 (simtuzumab study). Associations between LS by VCTE with disease progression were determined using Cox proportional hazards regression analysis.ResultsProgression to cirrhosis occurred in 16% (103/664) of participants with bridging fibrosis and adjudicated liver-related events occurred in 4% (27/734) of participants with baseline cirrhosis. The optimal baseline LS thresholds were ≥16.6 kPa for predicting progression to cirrhosis, and ≥30.7 kPa for predicting liver-related events. Baseline LS ≥16.6 kPa (adjusted HR 3.99; 95% CI 2.66 to 5.98, p<0.0001) and a ≥5 kPa (and ≥20%) increase (adjusted HR 1.98; 95% CI 1.20 to 3.26, p=0.008) were independent predictors of progression to cirrhosis in participants with bridging fibrosis, while baseline LS ≥30.7 kPa (adjusted HR 10.13, 95% CI 4.38 to 23.41, p<0.0001) predicted liver-related events in participants with cirrhosis.ConclusionThe LS thresholds identified in this study may be useful for risk stratification of NASH patients with advanced fibrosis.
Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD): a randomised clinical trial
Authors: Zoller Heinz , Wolf Myles , Blumenstein Irina , Primas Christian , Lindgren Stefan , Thomsen Lars L , Reinisch Walter , Iqbal Tariq 
Published: September 2022

ObjectiveIntravenous iron—a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD)—can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI).DesignThis randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured.ResultsA total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: −42.8% (95% CI –57.1% to –24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration.ConclusionDespite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.
Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma
Authors: Church Candice , Pulliam Thomas , Longino Natalie , Park Song Y , Smythe Kimberly S , Makarov Vladimir , Riaz Nadeem , Jing Lichen , Amezquita Robert , Campbell Jean S , Gottardo Raphael , Pierce Robert H , Choi Jaehyuk , Chan Timothy A , Koelle David M , Nghiem Paul 
Published: September 2022

BackgroundMerkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens.MethodsA patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry.ResultsWES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet.ConclusionsWe identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.
Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis
Authors: Meinel Jakob A , Yumiceba Verónica , Künstner Axel , Schultz Kristin , Kruse Nathalie , Kaiser Frank J , Holterhus Paul-Martin , Claviez Alexander , Hiort Olaf , Busch Hauke , Spielmann Malte , Werner Ralf 
Published: September 2022

BackgroundDuplications at the Xp21.2 locus have previously been linked to 46,XY gonadal dysgenesis (GD), which is thought to result from gene dosage effects ofNR0B1(DAX1), but the exact disease mechanism remains unknown.MethodsPatients with 46,XY GD were analysed by whole genome sequencing. Identified structural variants were confirmed by array CGH and analysed by high-throughput chromosome conformation capture (Hi-C).ResultsWe identified two unrelated patients: one showing a complex rearrangement upstream ofNR0B1and a second harbouring a 1.2 Mb triplication, includingNR0B1. Whole genome sequencing and Hi-C analysis revealed the rewiring of a topological-associated domain (TAD) boundary close toNR0B1associated with neo-TAD formation and may cause enhancer hijacking and ectopicNR0B1expression. Modelling of previous Xp21.2 structural variations associated with isolated GD support our hypothesis and predict similar neo-TAD formation as well as TAD fusion.ConclusionHere we present a general mechanism how deletions, duplications or inversions at theNR0B1locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity ofNR0B1. This model not only allows better diagnosis of GD with copy number variations (CNVs) at Xp21.2, but also gives deeper insight on how spatiotemporal activation of developmental genes can be disrupted by reorganised TADs causing impairment of gonadal development.
Cuprotosis-Related Genes: Predicting Prognosis and Immunotherapy Sensitivity in Pancreatic Cancer Patients
Authors: Xu Yingkun , Li Han , Lan Ailin , Wu Qiulin , Tang Zhenrong , Shu Dan , Tan Zhaofu , Liu Xin , Liu Yang , Liu Shengchun 
Published: September 2022

Based on TCGA, GTEx, and TIMER databases and various bioinformatics analysis methods, the potential biological roles of cuprotosis-related genes in pancreatic cancer were deeply explored, and a predictive model for pancreatic cancer patients was constructed. We downloaded the RNA-Seq data and clinicopathological and predictive data of 179 pancreatic cancer tissues and 332 adjacent normal tissues from TCGA and GTEx databases. The differential expression of cuprotosis-related genes in pancreatic cancer tissue and adjacent normal tissue was analyzed, and the LASSO regression algorithm was used to construct a prediction model and verify the validity of the model prediction. Based on the LASSO regression algorithm, a predictive model composed of three genes LIPT1, LIAS, and DLAT was screened. The corresponding survival curves showed that the constructed prediction model could significantly distinguish the prognosis of pancreatic cancer patients, and the prognosis of patients in the high-risk group was worse (

P

= 0.00557). The ROC curve showed that the area under the curve of the predictive model for predicting the 4-, 5-, and 6-year survival rates in pancreatic cancer was 0.816, 0.836, and 0.956, respectively. The AUC value of this risk model was significantly higher than 0.7, which could more accurately predict the prognosis of pancreatic cancer patients. This study determined a risk-scoring model of cuprotosis-related genes, which can provide an essential basis for judging the prognosis of pancreatic cancer patients.
Smoking-associated Downregulation of FILIP1L Enhances Lung Adenocarcinoma Progression Through Mucin Production, Inflammation, and Fibrosis
Authors: Kwon Mijung , Rubio Genesaret , Wang Haitao , Riedlinger Gregory , Adem Asha , Zhong Hua , Slegowski Daniel , Post-Zwicker Louisa , Chidananda Anshruta , Schrump David S. , Pine Sharon R. , Libutti Steven K. 
Published: September 2022

Lung adenocarcinoma (LUAD) is the major subtype in lung cancer, and cigarette smoking is essentially linked to its pathogenesis. We show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of LUAD progression. Cigarette smoking causes its downregulation by promoter methylation in LUAD. Loss of FILIP1L increases xenograft growth, and, in lung-specific knockout mice, induces lung adenoma formation and mucin secretion. In syngeneic allograft tumors, reduction of FILIP1L and subsequent increase in its binding partner, prefoldin 1 (PFDN1) increases mucin secretion, proliferation, inflammation, and fibrosis. Importantly, from the RNA-sequencing analysis of these tumors, reduction of FILIP1L is associated with upregulated Wnt/β-catenin signaling, which has been implicated in proliferation of cancer cells as well as inflammation and fibrosis within the tumor microenvironment. Overall, these findings suggest that down-regulation of FILIP1L is clinically relevant in LUAD, and warrant further efforts to evaluate pharmacologic regimens that either directly or indirectly restore FILIP1L-mediated gene regulation for the treatment of these neoplasms.Significance:This study identifies FILIP1L as a tumor suppressor in LUADs and demonstrates that downregulation of FILIP1L is a clinically relevant event in the pathogenesis and clinical course of these neoplasms.
AcT Trial: Protocol for a Pragmatic Registry‐Linked Randomized Clinical Trial
Authors: Sajobi Tolulope , Singh Nishita , Almekhlafi Mohammed A. , Buck Brian , Ademola Ayoola , Coutts Shelagh B. , Deschaintre Yan , Khosravani Houman , Appireddy Ramana , Moreau Francois , Phillips Stephen , Gubitz Gord , Tkach Aleksander , Catanese Luciana , Dowlatshahi Dar , Medvedev George , Mandzia Jennifer , Pikula Aleksandra , Shankar J.J. , Williams Heather , Field Thalia S. , Manosalva Alejandro , Siddiqui Muzaffar , Zafar Atif , Imoukhoude Oje , Hunter Gary , Sehgal Arshia , Zhang Qiao , Doram Craig , Hill Michael D. , Shamy Michel , Kenney Carol , Swartz Richard H. , Menon Bijoy K. 
Published: September 2022

Background
Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke.

Methods
This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate <5%.

Results
The blinded primary end point is the proportion of subjects achieving a 90‐day modified Rankin Scale score of 0 to 1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within a 24‐hour period will be reported and coded using the Medical Dictionary for Regulatory Activities. Outcomes are collected either centrally (primary, key secondary, and safety end points) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions.

Conclusions
Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke presenting early after stroke onset.
Subdivisions and crossroads: Identifying hidden community structures in a data archive’s citation network
Authors: Lafia Sara , Fan Lizhou , Thomer Andrea , Hemphill Libby 
Published: September 2022

Abstract
Data archives are an important source of high-quality data in many fields, making them ideal sites to study data reuse. By studying data reuse through citation networks, we are able to learn how hidden research communities—those that use the same scientific data sets—are organized. This paper analyzes the community structure of an authoritative network of data sets cited in academic publications, which have been collected by a large, social science data archive: the Interuniversity Consortium for Political and Social Research (ICPSR). Through network analysis, we identified communities of social science data sets and fields of research connected through shared data use. We argue that communities of exclusive data reuse form “subdivisions” that contain valuable disciplinary resources, while data sets at a “crossroads” broadly connect research communities. Our research reveals the hidden structure of data reuse and demonstrates how interdisciplinary research communities organize around data sets as shared scientific inputs. These findings contribute new ways of describing scientific communities to understand the impacts of research data reuse.
Bethel, Dark Woods, and Taboo: 1 Kings 13 as a Cautionary Tale
Authors: Hong Koog P. 
Published: September 2022

Abstract
1 Kings 13 in its present form features key traits of the cautionary tale. Through a comparison with Little Red Riding Hood, it is argued that many of the enigmatic features of 1 Kings 13 dissolve when read as a cautionary tale. On the surface, this tale functions as a didactic tale that warns against the naïve trust of a stranger on the road. On a deeper level, it inevitably colors Bethel as a dangerous and unruly place that doomed the protagonist to a tragic death.
Taking Care of Orphans’ Properties: the Funds for Orphans in the Danube Vilayet of the Ottoman Empire (1864–78)
Authors: Manolova-Nikolova Nadya , Atanasov Hristiyan 
Published: September 2022

Abstract
The article discusses the funds for orphans (eytam sandıkları) in the Danube Vilayet of the Ottoman Empire during the 1860s and 1870s. Information from Ottoman and Bulgarian sources—registers (kondiki) of Orthodox church boards, official Ottoman yearbooks (salname), the loan register of the fund for orphans in the town of Trân, and others—has been collected, statistically processed and analysed. The macro- and micro-level analysis is focused on the capital and administrators (müdür) of the funds for orphans, while we also discuss the interest rates that they charged. A comparison with another credit institution (menafi-i umumiye sandıkları) allows us to point to differences that are essential for understanding credit practices in the Ottoman Empire in the period under consideration.
Weather Observations Reach the Summit of Mount Everest
Authors: Matthews Tom , Perry Baker , Khadka Arbindra , Sherpa Tenzing Gyalzen , Shrestha Dibas , Aryal Deepak , Tuldahar Subash , Thapa Nirakar , Pradhananga Niraj , Athans Peter , Sherpa Dawa Yangzum , Guy Heather , Seimon Anton , Elmore Aurora , Li Kristina , Alexiev Nicole 
Published: September 2022

Abstract
The predictability of the weather on Mount Everest’s upper slopes can be a matter of life or death for those trying to climb the world’s highest mountain, yet the performance of forecasts has been almost unknown due to a lack of surface observations. The extent to which climate change may be affecting this iconic location is also uncertain for the same reason. To address this data limitation, the National Geographic and Rolex Perpetual Planet Expedition installed the world’s highest weather station network (reaching within 420 m of the summit) on the Nepal side of Mount Everest in 2019. Its observations have already generated considerable advances in understanding the meteorological environment on the mountain’s upper slopes, but the network was compromised by damage to the highest stations in recent years. Here, we describe the expedition that upgraded the network and took it to new heights, focusing on the installation at the Bishop Rock (8,810 m MSL), just below the summit. Almost 70 years after Everest was first climbed successfully, we can now provide open access data to illuminate conditions at Earth’s highest climate frontier.