bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice
Authors: Reifsnyder Peter C. , Flurkey Kevin , Doty Rosalinda , Calcutt Nigel A. , Koza Robert A. , Harrison David E. 
Published: August 2022

AbstractRapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA‐IR, and inflammation, and prevented hyperinsulinemia and pre‐steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c‐reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin‐resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin‐induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of “insulin signaling restriction” that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin‐based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.
Extracorporeal membrane oxygenation versus conventional rewarming for severe hypothermia in an urban emergency department
Authors: Prekker Matthew E. , Rischall Megan , Carlson Michelle , Driver Brian E. , Touroutoutoudis Melissa , Boland Jessica , Hu Michael , Heather Beth , Simpson Nicholas S. 
Published: August 2022

AbstractBackgroundSevere hypothermia (core body temperature < 28°C) is life‐threatening and predisposes to cardiac arrest. The comparative effectiveness of different active internal rewarming methods in an urban U.S. population is unknown. We aim to compare outcomes between hypothermic emergency department (ED) patients rewarmed conventionally using an intravascular rewarming catheter or warm fluid lavage versus those rewarmed using extracorporeal membrane oxygenation (ECMO).MethodsWe performed a retrospective cohort analysis of adults with severe hypothermia due to outdoor exposure presenting to an urban ED in Minnesota, 2007–2021. The primary outcome was hospital survival. We also calculated the rewarming rate in the 4 h after ED arrival and compared these data between patients rewarmed with ECMO (the extracorporeal rewarming group) versus without ECMO (the conventional rewarming group). We repeated these analyses in the subgroup of patients with cardiac arrest.ResultsWe analyzed 44 hypothermic ED patients: 25 patients in the extracorporeal rewarming group (median temperature 24.1°C, 84% with cardiac arrest) and 19 patients in the conventional rewarming group (median temperature 26.3°C, 37% with cardiac arrest; 89% received an intravascular rewarming catheter). The median rewarming rate was greater in the extracorporeal versus conventional group (2.3°C/h vs. 1.5°C/h, absolute difference 0.8°C/h, 95% confidence interval [CI] 0.3–1.2°C/h) yet hospital survival was similar (68% vs. 74%). Among patients with cardiac arrest, hospital survival was greater in the extracorporeal versus conventional group (71% vs. 29%, absolute difference 42%, 95% CI 4%–82%).ConclusionsAmong ED patients with severe hypothermia and cardiac arrest, survival was significantly higher with ECMO versus conventional rewarming. Among all hypothermic patients, ECMO use was associated with faster rewarming than conventional methods.
Single‐cell profiles reveal distinctive immune response in atopic dermatitis in contrast to psoriasis
Authors: Zhang Bowen , Roesner Lennart M. , Traidl Stephan , Koeken Valerie A. C. M. , Xu Cheng‐Jian , Werfel Thomas , Li Yang 
Published: August 2022

AbstractBackgroundUnderstanding the complex orchestrated inflammation in atopic dermatitis (AD), one of the most common chronic inflammatory diseases worldwide, is essential for therapeutic approaches. However, a comparative analysis on the single‐cell level of the inflammation signatures correlated with the severity is missing so far.MethodsWe applied single‐cell RNA and T‐cell receptor (TCR) sequencing on immune cells enriched from skin biopsies and matched blood samples of AD in comparison with psoriasis (PS) patients.ResultsClonally propagated skin‐derived T cells showed disease‐specific TCR motifs shared between patients which was more pronounced in PS compared to AD. The disease‐specific T‐cell clusters were mostly of a Th2/Th22 sub‐population in AD and Th17/Tc17 in PS, and their numbers were associated with severity scores in both diseases. Herein, we provide for the first time a list that associates cell type‐specific gene expression with the severity of the two most common chronic inflammatory skin diseases. Investigating the cell signatures in the patients´ PBMCs and skin stromal cells, a systemic involvement of type‐3 inflammation was clearly detectable in PS circulating cells, while in AD inflammatory signatures were most pronounced in fibroblasts, pericytes, and keratinocytes. Compositional and functional analyses of myeloid cells revealed the activation of antiviral responses in macrophages in association with disease severity in both diseases.ConclusionDifferent disease‐driving cell types and subtypes which contribute to the hallmarks of type‐2 and type‐3 inflammatory signatures and are associated with disease activities could be identified by single‐cell RNA‐seq and TCR‐seq in AD and PS.
IL1RAP expression and the enrichment of IL‐33 activation signatures in severe neutrophilic asthma
Authors: Badi Yusef Eamon , Salcman Barbora , Taylor Adam , Rana Batika , Kermani Nazanin Zounemat , Riley John H. , Worsley Sally , Mumby Sharon , Dahlen Sven‐Eric , Cousins David , Bulfone‐Paus Silvia , Affleck Karen , Chung Kian Fan , Bates Stewart , Adcock Ian M. 
Published: August 2022

AbstractBackgroundInterleukin (IL)‐33 is an upstream regulator of type 2 (T2) eosinophilic inflammation and has been proposed as a key driver of some asthma phenotypes.ObjectiveTo derive gene signatures from in vitro studies of IL‐33‐stimulated cells and use these to determine IL‐33‐associated enrichment patterns in asthma.MethodsSignatures downstream of IL‐33 stimulation were derived from our in vitro study of human mast cells and from public datasets of in vitro stimulated human basophils, type 2 innate lymphoid cells (ILC2), regulatory T cells (Treg) and endothelial cells. Gene Set Variation Analysis (GSVA) was used to probe U‐BIOPRED and ADEPT sputum transcriptomics to determine enrichment scores (ES) for each signature according to asthma severity, sputum granulocyte status and previously defined molecular phenotypes.ResultsIL‐33‐activated gene signatures were cell‐specific with little gene overlap. Individual signatures, however, were associated with similar signalling pathways (TNF, NF‐κB, IL‐17 and JAK/STAT signalling) and immune cell differentiation pathways (Th17, Th1 and Th2 differentiation). ES for IL‐33‐activated gene signatures were significantly enriched in asthmatic sputum, particularly in patients with neutrophilic and mixed granulocytic phenotypes. IL‐33 mRNA expression was not elevated in asthma whereas the expression of mRNA for IL1RL1, the IL‐33 receptor, was up‐regulated in the sputum of severe eosinophilic asthma. The mRNA expression for IL1RAP, the IL1RL1 co‐receptor, was greatest in severe neutrophilic and mixed granulocytic asthma.ConclusionsIL‐33‐activated gene signatures are elevated in neutrophilic and mixed granulocytic asthma corresponding with IL1RAP co‐receptor expression. This suggests incorporating T2‐low asthma in anti‐IL‐33 trials.
The reciprocal interplay of physical activity and health‐related quality of life in children and adolescents: Evidence for both upward and downward spirals
Authors: Groß Daniel , Schröder Ines , Wasserfall Nicola , Eschenbeck Heike , Kohlmann Carl‐Walter 
Published: August 2022

AbstractObjectiveThis study examines the bidirectional effect between physical activity (PA) and health‐related quality of life in children and adolescents, focusing on within‐person effects.MethodsPA and health‐related quality of life were assessed in children and adolescents (N = 685, age: M = 10.29 years, SD = 1.35, range = 8–14), via self‐report across four waves, each 6 months apart, and a random‐intercept cross‐lagged panel model with time‐invariant cross‐lagged effects was calculated.ResultsPositive cross‐lagged effects between prior PA and health‐related quality of life 6 months later (
= 0.536, 95% CI [0.016, 1.055], p = .043, d = 0.11) and vice versa (
= 0.015, 95% CI [0.001, 0.030], p = .039, d = 0.12) were found. Furthermore, the random intercept correlation was significant (
= 3.622, 95% CI [2.204, 5.041], p < .001, d = 0.27).ConclusionsThe findings confirm known correlations between PA and health‐related quality of life and extends them by indicating both an upward and downward spiral of PA and health‐related quality of life in children and adolescents.
Preoperative indocyanine green fluorescence injection to accurately determine a proximal margin during robotic distal gastrectomy
Authors: Nakanishi Koki , Tanaka Chie , Kanda Mitsuro , Shimizu Dai , Furukawa Kazuhiro , Fujiwara Michitaka , Kawashima Hiroki , Kodera Yasuhiro 
Published: August 2022

AbstractIntroductionAdequate surgical margins following gastrectomy for gastric cancer are required. In addition, a method for accurately detecting tumor location without palpation is needed during robotic surgery. Although several methods have been reported, most of these either lack accuracy or require increased time and effort during intraoperative detection. Herein, we introduce a new method for detecting tumor location using preoperative indocyanine green (ICG) marking and the built‐in ICG detection system of the da Vinci Xi Surgical System in robotic gastrectomy to determine appropriate surgical margins.Materials and Surgical TechniqueWe used this method to determine the resection line in six patients who underwent robotic distal gastrectomy for clinical T1 gastric cancer. One to three days before surgery, ICG was diluted to 1.0 mg/mL, and 0.1 mL of this diluted ICG solution was endoscopically injected at one site into the submucosal layer of the stomach, 1 cm proximal to the tumor edge. Gastrectomy was performed using the da Vinci Xi surgical platform, equipped with a near‐infrared fluorescence imaging system (Firefly®). The diameter of the fluorescent signal during gastrectomy was estimated to be approximately 2 cm. The resection line was determined on the outer edge of the fluorescent signal, which ensured a tumor‐free margin of ≥2 cm. Fluorescent signals were successfully observed in all cases. Moreover, the required 2‐cm surgical margin was achieved in all cases.DiscussionWe could successfully determine proximal margins using preoperative ICG injection marking during robotic distal gastrectomy for gastric cancer.
Association of income and educational levels on initiation of oral anticoagulant therapy in patients with incident atrial fibrillation: A Finnish nationwide cohort study
Authors: Teppo Konsta , Jaakkola Jussi , Biancari Fausto , Halminen Olli , Linna Miika , Haukka Jari , Putaala Jukka , Mustonen Pirjo , Kinnunen Janne , Hartikainen Juha , Airaksinen K. E. Juhani , Lehto Mika 
Published: August 2022

AimsSocioeconomic disparities have been reported in the outcomes of patients with atrial fibrillation (AF). We assessed the hypothesis that AF patients with higher income or educational level are more frequently initiated with oral anticoagulant (OAC) therapy for stroke prevention.MethodsThe nationwide registry‐based Finnish AntiCoagulation in Atrial Fibrillation cohort covers all patients with AF from all levels of care in Finland. Patients were divided into income quartiles according to their highest annual income during 2004‐2018 and into three categories based on educational attainment. The outcome was the first redeemed OAC prescription.ResultsWe identified 239 222 patients (mean age 72.7 ± 13.2 years, 49.8% female) with incident AF during 2007‐2018. Higher income was associated with higher OAC initiation rate: compared to the lowest income quartile the adjusted SHRs (95% CI) for OAC initiation were 1.09 (1.07‐1.10), 1.13 (1.11‐1.14) and 1.13 (1.12‐1.15) in the second, third and fourth income quartiles, respectively. Patients in the highest educational category had a slightly lower OAC initiation rate than patients in the lowest educational category (adjusted SHR 0.92 [95% CI 0.90‐0.93]). Income‐related disparities were larger and education‐related disparities only marginal among patients at high risk of ischemic stroke. The socioeconomic disparities in OAC initiation within 1‐year follow‐up decreased from 2007 to 2018. The adoption of direct OACs as the initial anticoagulant was faster among patients with higher income or educational levels.ConclusionThese findings highlight potential missed opportunities in stroke prevention, especially among AF patients with low income, whereas the education‐related disparities in OAC initiation appear controversial.
Is routine laboratory testing in healthy young patients taking isotretinoin necessary: a critically appraised topic
Authors: Affleck Andrew , Jackson David , Williams Hywel C. , Chavez Patricia , Albrecht Joerg 
Published: August 2022

SummaryClinical questionIs monitoring of liver function, lipids and full blood count necessary in healthy people taking isotretinoin?BackgroundRoutine blood testing was recommended in the original licence for Roaccutane™ (isotretinoin) in 1983. In recent years, less frequent monitoring has been suggested by various authors.Data sourcesWe performed four individual systematic searches of the MEDLINE database, via PubMed, from origin to 2 May 2021, supplemented by a hand search of all references in the identified papers.Study selectionInclusion criteria were any description of clinical symptoms, laboratory abnormalities and/or physical findings, and any paper that explicitly described the patients as asymptomatic, during treatment with oral isotretinoin.Data extractionTwo independent reviewers (J.A. and D.J.) assessed articles for eligibility of inclusion. Evaluation of the data was done also by two of the authors (A.A., D.J. and J.A.) for each section, with the aim to use the presented evidence including guidelines, databases, case series, case reports, cohort studies and randomized clinical trials to delineate the clinical presentation and frequency of adverse events that might be amenable to laboratory monitoring.ResultsWe identified 407 papers in our searches and reviewed 125 papers in four sections. Overall, reported adverse events were very rare (&lt; 1 in 10 000) and were either idiosyncratic or not preventable by monitoring, accompanied by symptoms, or seen in identifiable predisposed individuals who might benefit from monitoring because of pre-existing conditions.Recommendation for clinical careWe could not find evidence to support the benefit of monitoring to detect adverse events. We suggest that in healthy young people laboratory monitoring for oral isotretinoin is unnecessary and risks detecting nonserious biochemical abnormalities. However, we recognize that new information about adverse events may change that recommendation.
Management of small testicular masses: outcomes from a single‐centre specialist multidisciplinary team
Authors: Wardak Shafi , Pang Karl H. , Castiglione Fabio , Lindsay Jamie , Walkden Miles , Ho Dan Heffernan , Kirkham Alex , Hadway Paul , Nigam Raj , Rees Rowland , Alifrangis Constantine , Alnajjar Hussain M. , Muneer Asif 
Published: August 2022

ObjectivesTo report the management outcomes of men with ≤20‐mm small testicular masses (STMs) and to identify clinical and histopathological factors associated with malignancy.Patients and methodsA retrospective analysis of men managed at a single centre between January 2010 and December 2020 with a STM ≤20 mm in size was performed.ResultsOverall, 307 men with a median (interquartile range [IQR]) age of 36 (30–44) years were included. Of these, 161 (52.4%), 82 (26.7%), 62 (20.2%) and 2 men (0.7%) underwent surveillance with interval ultrasonography (USS), primary excisional testicular biopsy (TBx) or primary radical orchidectomy (RO), or were discharged, respectively. The median (IQR) surveillance duration was 6 (3–18) months. The majority of men who underwent surveillance had lesions <5 mm (59.0%) and no lesion vascularity (67.1%) on USS. Thirty‐three (20.5%) men undergoing surveillance had a TBx based on changes on interval USS or patient choice; seven (21.2%) were found to be malignant. The overall rate of malignancy in the surveillance cohort was 4.3%. The majority of men who underwent primary RO had lesions ≥10 mm (85.5%) and the presence of vascularity (61.7%) on USS. Nineteen men (23.2%) who underwent primary TBx (median lesion size 6 mm) had a malignancy confirmed on biopsy and underwent RO. A total of 88 men (28.7%) underwent RO, and malignancy was confirmed in 73 (83.0%) of them. The overall malignancy rate in the whole STM cohort was 23.8%. Malignant RO specimens had significantly larger lesion sizes (median [IQR] 11 [8–15] mm, vs benign: median [IQR] 8 [5–10] mm; P = 0.04).ConclusionsSmall testicular masses can be stratified and managed based on lesion size and USS features. The overall malignancy rate in men with an STM was 23.8% (4.3% in the surveillance group). Surveillance should be considered in lesions <10 mm in size, with a TBx or frozen‐section examination offered prior to RO in order to preserve testicular function.
A novel chemokine‐based signature for prediction of prognosis and therapeutic response in glioma
Authors: Fan Wenhua , Wang Di , Li Guanzhang , Xu Jianbao , Ren Changyuan , Sun Zhiyan , Wang Zhiliang , Ma Wenping , Zhao Zheng , Bao Zhaoshi , Jiang Tao , Zhang Ying 
Published: August 2022

AbstractAimsGliomas are the primary malignant brain tumor and characterized as the striking cellular heterogeneity and intricate tumor microenvironment (TME), where chemokines regulate immune cell trafficking by shaping local networks. This study aimed to construct a chemokine‐based gene signature to evaluate the prognosis and therapeutic response in glioma.MethodsIn this study, 1024 patients (699 from TCGA and 325 from CGGA database) with clinicopathological information and mRNA sequencing data were enrolled. A chemokine gene signature was constructed by combining LASSO and SVM‐RFE algorithm. GO, KEGG, and GSVA analyses were performed for function annotations of the chemokine signature. Candidate mRNAs were subsequently verified through qRT‐PCR in an independent cohort including 28 glioma samples. Then, through immunohistochemical staining (IHC), we detected the expression of immunosuppressive markers and explore the role of this gene signature in immunotherapy for glioma. Lastly, the Genomics of Drug Sensitivity in Cancer (GDSC) were leveraged to predict the potential drug related to the gene signature in glioma.ResultsA constructed chemokine gene signature was significantly associated with poorer survival, especially in glioblastoma, IDH wildtype. It also played an independent prognostic factor in both datasets. Moreover, biological function annotations of the predictive signature indicated the gene signature was positively associated with immune‐relevant pathways, and the immunosuppressive protein expressions (PD‐L1, IBA1, TMEM119, CD68, CSF1R, and TGFB1) were enriched in the high‐risk group. In an immunotherapy of glioblastoma cohort, we confirmed the chemokine signature showed a good predictor for patients' response. Lastly, we predicted twelve potential agents for glioma patients with higher riskscore.ConclusionIn all, our results highlighted a potential 4‐chemokine signature for predicting prognosis in glioma and reflected the intricate immune landscape in glioma. It also threw light on integrating tailored risk stratification with precision therapy for glioblastoma.
Navigating a shifting agri‐environment policy landscape to conserve butterflies
Authors: Stewart Linnea B. , Bonsall Michael B. , Cusworth George , Corrigan Christopher , Dicks Lynn V. , Hall Jilly , Plackett Jenny , Spray Martin , Strevens Chloë 
Published: August 2022

AbstractFor decades, agri‐environment schemes (AES) within the United Kingdom have served as a policy tool for conserving butterflies. However, the UK's 2016 decision to leave the European Union (EU) means the overarching framework for AES, the EU Common Agriculture Policy (CAP), is being replaced by a new independent agri‐environment policy, the Environmental Land Management (ELM) scheme. Here, we examine the shift from CAP towards ELM and explore its implications for butterfly conservation across England, as a devolved administration, within the United Kingdom. We identify the key changes between the current Countryside Stewardship scheme and the incoming ELM scheme and present recommendations for policymakers to ensure policy design and delivery can benefit efforts to conserve butterflies, and indeed wildlife more generally, in England. This is an opportune moment to contribute to discussions on the emerging agri‐environment scheme policy within the United Kingdom as the ELM scheme is trialed, revised, and implemented.