bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between right-to-left shunt and sudden sensorineural hearing loss: protocol for a case–control study
Authors: Zheng Jianrong , Zhan Ying , Cheng Yajing , Liu Cong , Lu Bihua , Yang Weiqiang , Hu Jun 
Published: November 2023

Background and purposeSudden sensorineural hearing loss (SSNHL) is a neurological and otolaryngological emergency during which rapid diagnosis and early treatment are of great importance. Clinical experience indicates that a considerable number of patients with SSNHL have concurrent right-to-left shunt (RLS). With limited reports, the association between SSNHL and RLS is yet unclear and there is a need for large observational studies to explore their latent relationship.Methods and analysisThis proposed study is a prospective, observational case–control study. A total of 194 eligible participants matched in age and sex will be divided equally into two groups: 97 patients with SSNHL included in the case group and 97 individuals without SSNHL in the control group. Medical evaluations, including clinical characteristics, laboratory examination, audiological examination and ultrasonography examination, will be performed in all subjects. The primary outcome of the study is the difference in RLS rates between the groups. Differences in patent foramen ovale rates and other measured variables will be further assessed. A conditional logistic regression as a correlation analysis will be used to evaluate the relationship between RLS and SSNHL.DiscussionThis study may provide evidence on the correlation between RLS and SSNHL in order to enrich the aetiology of SSNHL.Ethics and disseminationThe study protocol has been approved by the Ethics Committee of Peking University Shenzhen Hospital. A written informed consent form will be signed and dated by the participants and the researchers before the study begins. The results will be disseminated in peer-reviewed publications.Trial registration numberChiCTR2200064067.
Infographic summaries for clinical practice guidelines: results from user testing of the BMJ Rapid Recommendations in primary care
Authors: Van Bostraeten Pieter , Aertgeerts Bert , Bekkering Geertruida E , Delvaux Nicolas , Dijckmans Charlotte , Ostyn Elise , Soontjens Willem , Matthysen Wout , Haers Anna , Vanheeswyck Matisse , Vandekendelaere Alexander , Van der Auwera Niels , Schenk Noémie , Stahl-Timmins Will , Agoritsas Thomas , Vermandere Mieke 
Published: November 2023

ObjectivesInfographics have the potential to enhance knowledge translation and implementation of clinical practice guidelines at the point of care. They can provide a synoptic view of recommendations, their rationale and supporting evidence. They should be understandable and easy to use. Little evaluation of these infographics regarding user experience has taken place. We explored general practitioners’ experiences with five selected BMJ Rapid Recommendation infographics suited for primary care.MethodsAn iterative, qualitative user testing design was applied on two consecutive groups of 10 general practitioners for five selected infographics. The physicians used the infographics before clinical encounters and we performed hybrid think-aloud interviews afterwards. 20 interviews were analysed using the Qualitative Analysis Guide of Leuven.ResultsMany clinicians reported that the infographics were simple and rewarding to use, time-efficient and easy to understand. They were perceived as innovative and their knowledge basis as trustworthy and supportive for decision-making. The interactive, expandable format was preferred over a static version as general practitioners focused mainly on the core message. Rapid access through the electronic health record was highly desirable. The main issues were about the use of complex scales and terminology. Understanding terminology related to evidence appraisal as well as the interpretation of statistics and unfamiliar scales remained difficult, despite the infographics.ConclusionsGeneral practitioners perceive infographics as useful tools for guideline translation and implementation in primary care. They offer information in an enjoyable and user friendly format and are used mainly for rapid, tailored and just in time information retrieval. We recommend future infographic producers to provide information as concise as possible, carefully define the core message and explore ways to enhance the understandability of statistics and difficult concepts related to evidence appraisal.Trial registration numberMP011977.
Implementing paediatric patient-reported outcome measures in outpatient asthma clinics: a feasibility assessment study
Authors: Bele Sumedh , Paolucci Elizabeth Oddone , Johnson David W , Quan Hude , Santana Maria-Jose 
Published: November 2023

ObjectiveImplementation of patient-reported outcome measures (PROMs) is limited in paediatric routine clinical care. The KidsPRO programme has been codesigned to facilitate the implementation of PROMs in paediatric healthcare settings. Therefore, this study (1) describes the development of innovative KidsPRO programme and (2) reports on the feasibility of implementing PedsQL (Pediatric Quality of Life Inventory) PROM in asthma clinics using the KidsPRO programme.DesignFeasibility assessment study.SettingOutpatient paediatric asthma clinics in the city of Calgary, Canada.ParticipantsFive paediatric patients, four family caregivers and three healthcare providers were recruited to pilot the implementation of PedsQL PROM using KidsPRO. Then, a survey was used to assess its feasibility among these study participants.Main outcome measuresParticipants’ understanding of using PROMs, the adequacy of support provided to them, the utility of using PROMs as part of their appointment, and their satisfaction with using PROMs.AnalysesThe quantitative data generated through closed-ended questions was analysed and represented in the form of bar charts for each category of study participants (ie, patients, their family caregivers and healthcare providers). The qualitative data generated through the open-ended questions were content analysed and categorised into themes.ResultsThe experience of using PROMs was overwhelmingly positive among patients and their family caregivers, results were mixed among healthcare providers. Qualitative data collected through open-ended questions also complemented the quantitative findings.ConclusionThe evidence from this study reveals that the implementation of PROMs in routine paediatric clinical care asthma clinics in Alberta is seems to be feasible.
First contact with the health system: a survey study in northern Portugal
Authors: Granja Mónica , Alves Luís , Correia Sofia 
Published: November 2023

ObjectiveThe objective of this study is to characterise the self-reported first contact with the health system and the reasons stated for each choice, testing associations with population characteristics.DesignCross-sectional survey.SettingPrimary care department of a local health unit in northern Portugal.ParticipantsRandom sample of 4286 persons, retrieved from all registered adults.OutcomesParticipants who stated they usually see the same doctor when a health problem arises were considered to adopt first-contact care and were asked to identify their regular doctor. Participants were asked why they adopt first-contact care or why they choose to do otherwise. Associations between personal characteristics and the adoption of first-contact care were tested using logistic regression.ResultsThere were 808 valid questionnaires received (19% response rate). The mean age of respondents was 53 years, 58% were women and 60% had a high school or higher degree. Most (71%) stated always seeing the same doctor when facing a health problem. This was a general practitioner (GP) in 84%. The main reasons were previous knowledge and trust in the doctor. When this doctor was not a GP, the main reason was the need to obtain an appointment quickly. Participants who chose first-contact care were less likely to have university degrees than those who did not (OR 0.31; 95% CI 0.13 to 0.76). Being registered with the same GP for over 1 year increased the odds of adopting first-contact care: twice as likely for those registered for 1–4 years with the same GP (2.07; 95% CI 1.04 to 4.11), and three times more likely for those registered for over 10 years (3.21; 95% CI 1.70 to 6.08).ConclusionsThe high adoption of first-contact care and the reasons given for this suggest a strong belief in primary care in this population. The longer patients experience continuity, the more they adopt first-contact care. The preferences of higher-educated patients regarding first-contact care deserve reflection.
Novel insights into causal effects of serum lipids and lipid-modifying targets on cholelithiasis
Authors: Chen Lanlan , Qiu Wei , Sun Xiaodong , Gao Menghan , Zhao Yuexuan , Li Mingyue , Fan Zhongqi , Lv Guoyue 
Published: November 2023

ObjectiveDifferent serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question.DesignWe prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets’ effects on cholelithiasis, includingHMGCR,NPC1L1,PCSK9,APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARDandPPARG.ResultsWe found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted ‘U-shaped’ relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested thatHMGCRinhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis.ConclusionLower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use ofHMGCRinhibitors should prevent its risk.
Lymphoma triage from H&E using AI for improved clinical management
Authors: Tsakiroglou Anna Maria , Bacon Chris M , Shingleton Daniel , Slavin Gabrielle , Vogiatzis Prokopios , Byers Richard , Carey Christopher , Fergie Martin 
Published: November 2023

AimsIn routine diagnosis of lymphoma, initial non-specialist triage is carried out when the sample is biopsied to determine if referral to specialised haematopathology services is needed. This places a heavy burden on pathology services, causes delays and often results in over-referral of benign cases. We aimed to develop an automated triage system using artificial intelligence (AI) to enable more accurate and rapid referral of cases, thereby addressing these issues.MethodsA retrospective dataset of H&E-stained whole slide images (WSI) of lymph nodes was taken from Newcastle University Hospital (302 cases) and Manchester Royal Infirmary Hospital (339 cases) with approximately equal representation of the 3 most prevalent lymphoma subtypes: follicular lymphoma, diffuse large B-cell and classic Hodgkin’s lymphoma, as well as reactive controls. A subset (80%) of the data was used for training, a further validation subset (10%) for model selection and a final non-overlapping test subset (10%) for clinical evaluation.ResultsAI triage achieved multiclass accuracy of 0.828±0.041 and overall accuracy of 0.932±0.024 when discriminating between reactive and malignant cases. Its ability to detect lymphoma was equivalent to that of two haematopathologists (0.925, 0.950) and higher than a non-specialist pathologist (0.75) repeating the same task. To aid explainability, the AI tool also provides uncertainty estimation and attention heatmaps.ConclusionsAutomated triage using AI holds great promise in contributing to the accurate and timely diagnosis of lymphoma, ultimately benefiting patient care and outcomes.
The physical acceptability conditions and the strategies to obtain anisotropic compact objects
Authors: Suárez-Urango Daniel , Becerra Laura M. , Ospino Justo , Núñez Luis A. 
Published: November 2023

AbstractWe studied five methods to include anisotropy, or unequal stress distributions, in general relativistic matter configurations. We used nine acceptability conditions that the metric and physical variables must meet to determine if our models were astrophysically viable. Our analysis found the most effective way to introduce anisotropy while keeping a simple density profile. We also found a practical “rule of thumb” that relates the density at the boundary to the density at the centre of relativistic matter distributions. Additionally, we calculated the configuration radius and encountered that values observed by NICER for PSR J0740+6620 are consistent with several acceptable matter configurations, both isotropic and anisotropic.
Resolution of the n-person Prisoners’ Dilemma by Kalai’s Preplay Negotiation Procedure
Authors: Nishihara Ko 
Published: November 2023

In this paper, we apply the preplay negotiation procedure proposed by Kalai [1981] [Preplay negotiations and the prisoner’s dilemma, Math. Soc. Sci. 1, 375–379] to the [Formula: see text]-person prisoners’ dilemma with [Formula: see text] and examine whether it promotes cooperation. First, we demonstrate that every perfect equilibrium is a proper equilibrium for any extensive-form game in which players have only two alternatives in each information set. We show that if the preplay is carried out once, the preplay game has a proper equilibrium that realizes cooperation. We also show that if the preplay is executed twice, the game has a proper equilibrium that realizes cooperation regardless of the entering action profile (the starting point of the preplays). Finally, we demonstrate that the preplay game consisting of at least two preplays has a proper equilibrium that realizes cooperation.
Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum
Authors: Grabski Isabella N. , Heymach John V. , Kehl Kenneth L. , Kopetz Scott , Lau Ken S. , Riely Gregory J. , Schrag Deborah , Yaeger Rona , Irizarry Rafael A. , Haigis Kevin M. 
Published: November 2023

Abstract

Background:
KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.

Methods:
We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival.

Results:
KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types.

Conclusions:
KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions.

Impact:
Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.
PDGFRβ Signaling Cooperates with β-Catenin to Modulate c-Abl and Biologic Behavior of Desmoid-Type Fibromatosis
Authors: Hu Jia , Hameed Meera R. , Agaram Narasimhan P. , Whiting Karissa A. , Qin Li-Xuan , Villano Anthony M. , O'Connor Rachael B. , Rozenberg Julian M. , Cohen Sonia , Prendergast Katherine , Kryeziu Sara , White Richard L. , Posner Mitchell C. , Socci Nicholas D. , Gounder Mrinal M. , Singer Samuel , Crago Aimee M. 
Published: November 2023

Abstract

Purpose:
This study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.

Experimental Design:
In vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.

Results:
CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1A inhibited desmoid cell–induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.

Conclusions:
The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.
Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models
Authors: Friese-Hamim Manja , Ortiz Ruiz Maria J. , Bogatyrova Olga , Keil Marina , Rohdich Felix , Blume Beatrix , Leuthner Birgitta , Czauderna Frank , Hahn Diane , Jabs Julia , Jaehrling Frank , Heinrich Timo , Kellner Roland , Chan Katherine , Tong Amy H.Y. , Wienke Dirk , Moffat Jason , Blaukat Andree , Zenke Frank T. 
Published: November 2023

Abstract
N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.
Protein Tyrosine Phosphatase SHP2 in Macrophages Acts as an Antiatherosclerotic Regulator in Mice
Authors: Wu Chenxia , Zheng Peiyao , Ma Lan , Xu Chen , Hu Luoxia , Yang Zhiyi , Fei Fan , Shen Zhuxia , Zhang Xue , Wu Ziheng , Cheng Hongqiang , Mao Wei , Ke Yuehai 
Published: November 2023

BACKGROUND:
Macrophages have versatile roles in atherosclerosis. SHP2 (Src homology 2 containing protein tyrosine phosphatase 2) has been demonstrated to play a critical role in regulating macrophage activation. However, the mechanism of SHP2 regulation of macrophage function in an atherosclerotic microenvironment remains unknown.

METHODS:

APOE (apolipoprotein E) or LDLR (low-density lipoprotein receptor) null mice treated with SHP099 were fed a Western diet for 8 weeks, while
Shp2

MKO

:ApoE

−/−

or
Shp2

MKO

:Ldlr

−/−

mice and exo-AAV8-SHP2
E76K
/
ApoE

−/−

mice were fed a Western diet for 12 weeks. In vitro, levels of proinflammatory factors and phagocytic function were then studied in mouse peritoneal macrophages. RNA sequencing was used to identify PPARγ (peroxisome proliferative activated receptor γ) as the key downstream molecule. A PPARγ agonist was used to rescue the phenotypes observed in SHP2-deleted mice.

RESULTS:
Pharmacological inhibition and selective deletion in macrophages of SHP2 aggravated atherosclerosis in APOE and LDLR null mice with increased plaque macrophages and apoptotic cells. In vitro, SHP2 deficiency in APOE and LDLR null macrophages enhanced proinflammatory polarization and its efferocytosis was dramatically impaired. Conversely, the expression of gain-of-function mutation of SHP2 in mouse macrophages reduced atherosclerosis. The SHP2 agonist lovastatin repressesed macrophage inflammatory activation and enhanced efferocytosis. Mechanistically, RNA sequencing analysis identified PPARγ as a key downstream transcription factor. PPARγ was decreased in macrophages upon SHP2 deletion and inhibition. Importantly, PPARγ agonist decreased atherosclerosis in SHP2 knockout mice, restored efferocytotic defects, and reduced inflammatory activation in SHP2 deleted macrophages. PPARγ was decreased by the ubiquitin-mediated degradation upon SHP2 inhibition or deletion. Finally, we found that SHP2 was downregulated in atherosclerotic vessels.

CONCLUSIONS:
Overall, SHP2 in macrophages was found to act as an antiatherosclerotic regulator by stabilizing PPARγ in APOE/LDLR null mice.