bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between intrahospital transfer and hospital-acquired infection in the elderly: a retrospective case–control study in a UK hospital network
Authors: Boncea Emanuela Estera , Expert Paul , Honeyford Kate , Kinderlerer Anne , Mitchell Colin , Cooke Graham S , Mercuri Luca , Costelloe Céire E 
Published: January 2021

BackgroundIntrahospital transfers have become more common as hospital staff balance patient needs with bed availability. However, this may leave patients more vulnerable to potential pathogen transmission routes via increased exposure to contaminated surfaces and contacts with individuals.ObjectiveThis study aimed to quantify the association between the number of intrahospital transfers undergone during a hospital spell and the development of a hospital-acquired infection (HAI).MethodsA retrospective case–control study was conducted using data extracted from electronic health records and microbiology cultures of non-elective, medical admissions to a large urban hospital network which consists of three hospital sites between 2015 and 2018 (n=24 240). As elderly patients comprise a large proportion of hospital users and are a high-risk population for HAIs, the analysis focused on those aged 65 years or over. Logistic regression was conducted to obtain the OR for developing an HAI as a function of intrahospital transfers until onset of HAI for cases, or hospital discharge for controls, while controlling for age, gender, time at risk, Elixhauser comorbidities, hospital site of admission, specialty of the dominant healthcare professional providing care, intensive care admission, total number of procedures and discharge destination.ResultsOf the 24 240 spells, 2877 cases were included in the analysis. 72.2% of spells contained at least one intrahospital transfer. On multivariable analysis, each additional intrahospital transfer increased the odds of acquiring an HAI by 9% (OR=1.09; 95% CI 1.05 to 1.13).ConclusionIntrahospital transfers are associated with increased odds of developing an HAI. Strategies for minimising intrahospital transfers should be considered, and further research is needed to identify unnecessary transfers. Their reduction may diminish spread of contagious pathogens in the hospital environment.
Is the use of two versus one long-acting bronchodilator by patients with COPD associated with a higher risk of acute coronary syndrome in real-world clinical practice?
Authors: Parkin Lianne , Williams Sheila , Barson David , Sharples Katrina , Horsburgh Simon , Jackson Rod , Dummer Jack 
Published: January 2021

BackgroundCardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2agonists (LABAs)) may further increase the risk of acute coronary events. Information about the impact of treatment intensification on acute coronary syndrome (ACS) risk in real-world settings is limited. We undertook a nationwide nested case–control study to estimate the risk of ACS in users of both a LAMA and a LABA relative to users of a LAMA.MethodsWe used routinely collected national health and pharmaceutical dispensing data to establish a cohort of patients aged>45 years who initiated long-acting bronchodilator therapy for COPD between 1 February 2006 and 30 December 2013. Fatal and non-fatal ACS events during follow-up were identified using hospital discharge and mortality records. For each case we used risk set sampling to randomly select up to 10 controls, matched by date of birth, sex, date of cohort entry (first LAMA and/or LABA dispensing), and COPD severity.ResultsFrom the cohort (n=83 417), we identified 5399 ACS cases during 281 292 person-years of follow-up. Compared with current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a higher risk of ACS (OR 1.28 (95% CI 1.13 to 1.44)). The OR in an analysis restricted to fatal cases was 1.46 (95% CI 1.12 to 1.91).ConclusionIn real-world clinical practice, use of two versus one long-acting bronchodilator by people with COPD is associated with a higher risk of ACS.
Pregnancy outcomes in women with neurofibromatosis 1: a Danish population-based cohort study
Authors: Kenborg Line , Boschini Cristina , Bidstrup Pernille E , Dalton Susanne O , Doser Karoline , Nielsen Thomas T , Krøyer Anja , Johansen Christoffer , Frederiksen Kirsten , Sørensen Sven Asger , Hove Hanne , Østergaard John R , Mulvihill John J , Winther Jeanette F 
Published: January 2021

BackgroundThe probability of a pregnancy, live birth, stillbirth and abortion has never been assessed in women with neurofibromatosis 1 (NF1) in a large population-based study.MethodsWe included 1006 women (15–49 years) registered with NF1 in the Danish National Patient Registry or followed in two national Centers for Rare Diseases and 10 020 women from the Danish population. Information on pregnancy outcomes was ascertained from health registries. Cumulative incidence, mean cumulative count, hazard ratios (HRs) and proportion ratios (PRs) with 95% CIs were calculated.ResultsThe cumulative incidence of a first pregnancy at age 50 years was slightly lower in women with NF1 (74%; 95% CI 70 to 77) than in population comparisons (78%; 95% CI 77 to 79). When all pregnancies were included, two pregnancies were expected per woman at age of 50 years, irrespective of a NF1 diagnosis. The hazard of a pregnancy did not differ between women with NF1 (HR 1.03; 95% CI 0.95 to 1.11) and the comparisons after adjustment for somatic and psychiatric disease. The proportion of pregnancies that resulted in a live birth was 63% (783/1252) among women NF1 and 68% (8432/12 465) among the comparisons, yielding a PR of 0.95 (95% CI 0.90 to 1.00). The proportions of stillbirths (PR 2.83; 95% CI 1.63 to 4.93) and spontaneous abortions (PR 1.40; 95% CI 1.09 to 1.79) were increased in women with NF1.ConclusionsA similar hazard for pregnancy was observed for women with NF1 and population comparisons after adjustment for potential medical consequences of NF1. However, women with NF1 experienced more spontaneous abortions and stillbirths.
Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease
Authors: Nowak Albina , Beuschlein Felix , Sivasubramaniam Visnuka , Kasper David , Warnock David G 
Published: January 2021

BackgroundFabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (GLA) leading to deficiency of α-galactosidase A and ultimately in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3). The aim of the study was to assess plasma Lyso-Gb3 levels as a possible factor associated with adverse outcomes in FD.MethodsIn a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first.ResultsDuring the median follow-up time of 68 (40–80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04).ConclusionLyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.
Experience of video consultation during the COVID-19 pandemic in elderly population for Parkinson’s disease and movement disorders
Authors: Kumar Anil 
Published: January 2021

ABSTRACT
We have not been prepared for the current pandemic which has hit us hard. COVID-19, being a very contagious disease, one has to be very careful and diligent in caring for our patients keeping safety in mind all the time. For day-to-day care, new norms have been adopted for inpatient care. For outpatient care, the face-to-face (F2F) clinics were cancelled and instead telephone consultations were started. However, it has its own limitations. Unfortunately, there were patients who would need F2F consultation but could not come to the clinic due to the infection risks. For those patients, video consultation was started, which was an innovation in practice. The National Health Service has an Attend Anywhere clinic, as part of transformation in service, which enabled remote consultation with a better outcome than telephone clinics. However, it has its own limitation as not everyone could use it.
Multidisciplinary team intervention to reduce the nocebo effect when switching from the originator infliximab to a biosimilar
Authors: Petit Juliette , Antignac Marie , Poilverd Rose-Marie , Baratto Régine , Darthout Sylvie , Desouches Sandra , Louati Karine , Deparis Nathalie , Berenbaum Francis , Beauvais Catherine 
Published: January 2021

ObjectivesTo evaluate an intervention to reduce the nocebo effect (NE) when switching from the originator infliximab (OI) to the infliximab biosimilar SB2 in chronic inflammatory rheumatic disease (CIRD).MethodsAn intervention was built with healthcare professionals (HPs) and a patient representative, based on a systematic review of interventions reducing the NE in musculoskeletal diseases and semi-directed questioning of five patients. Our strategy consisted of training HPs, switch information given by the nurses, a consistent vocabulary. All CIRD patients switched from OI to SB2 were included for the intervention. The primary outcome was the SB2 retention rate (RR) at 34 weeks. Secondary outcomes were the SB2 RR at 12 months, discontinuation rates due to a possible NE and comparison with a historical cohort of CIRD patients receiving the OI and 6 published European cohorts.Results45 patients were included from March 2018 (rheumatoid arthritis, n=17, spondylarthritis, n=28). After 34 weeks, the SB2 RR was 91.2%, similar to the historical cohort RR (p=0.41) but higher than the 3 European cohort RRs (p<0.05). At 12 months, the SB2 RR was 84.5% vs 88.4% for the historical cohort (p=0.52). SB2 discontinuation due to a possible NE was 6.6% after 12 months.ConclusionsA tailored communication with a prominent role of nurses reduced the NE in non-medical switches from the OI to SB2 as compared to published results. The RR was similar to the historical cohort RR. The methodology used to construct this intervention may help improve the outcomes of switches with upcoming biosimilars.
Off-diagonal cosmological solutions in emergent gravity theories and Grigory Perelman entropy for geometric flows
Authors: Vacaru Sergiu I. , Veliev Elşen Veli , Bubuianu Laurenţiu 
Published: January 2021

AbstractWe develop an approach to the theory of relativistic geometric flows and emergent gravity defined by entropy functionals and related statistical thermodynamics models. Nonholonomic deformations of G. Perelman’s functionals and related entropic values used for deriving relativistic geometric evolution flow equations. For self-similar configurations, such equations describe generalized Ricci solitons defining modified Einstein equations. We analyse possible connections between relativistic models of nonholonomic Ricci flows and emergent modified gravity theories. We prove that corresponding systems of nonlinear partial differential equations, PDEs, for entropic flows and modified gravity posses certain general decoupling and integration properties. There are constructed new classes of exact and parametric solutions for nonstationary configurations and locally anisotropic cosmological metrics in modified gravity theories and general relativity. Such solutions describe scenarios of nonlinear geometric evolution and gravitational and matter field dynamics with pattern-forming and quasiperiodic structure and various space quasicrystal and deformed spacetime crystal models. We analyse new classes of generic off-diagonal solutions for entropic gravity theories and show how such solutions can be used for explaining structure formation in modern cosmology. Finally, we speculate why the approaches with Perelman–Lyapunov type functionals are more general or complementary to the constructions elaborated using the concept of Bekenstein–Hawking entropy.
Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET
Authors: Nagle Veronica L. , Henry Kelly E. , Hertz Charli Ann J. , Graham Maya S. , Campos Carl , Parada Luis F. , Pandit-Taskar Neeta , Schietinger Andrea , Mellinghoff Ingo K. , Lewis Jason S. 
Published: January 2021

Abstract

Purpose:
Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET.

Experimental Design:
We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells.

Results:
Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors.

Conclusions:
Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.
Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial
Authors: Cousin Sophie , Cantarel Coralie , Guegan Jean-Philippe , Gomez-Roca Carlos , Metges Jean-Philippe , Adenis Antoine , Pernot Simon , Bellera Carine , Kind Michèle , Auzanneau Céline , Le Loarer François , Soubeyran Isabelle , Bessede Alban , Italiano Antoine 
Published: January 2021

Abstract

Purpose:
Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models.

Patients and Methods:
This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1.

Results:
Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8–5.4] and 10.8 months (95% CI, 5.9–NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome.

Conclusions:
The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.
Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer
Authors: Petroni Giulia , Buqué Aitziber , Yamazaki Takahiro , Bloy Norma , Liberto Maurizio Di , Chen-Kiang Selina , Formenti Silvia C. , Galluzzi Lorenzo 
Published: January 2021

AbstractPurpose:Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor–positive (ER+) breast cancer to radiotherapy. However, these findings were obtained in human ER+ breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.Experimental Design:We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER+ and ER-negative (ER−) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival in vitro, as well as tumor growth, overall survival, and metastatic dissemination in vivo.Results:Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects in vitro, correlating with suboptimal tumor control in vivo. However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested in vitro with enhanced cytostasis and loss of clonogenic potential, as well as in vivo with improved local and systemic tumor control.Conclusions:Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast cancer.
Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion
Authors: Tilak Manali , Alural Begüm , Wismer Sarah E. , Brasher Megan I. , New Laura A. , Sheridan Steven D. , Perlis Roy H. , Coppolino Marc G. , Lalonde Jasmin , Jones Nina 
Published: January 2021

Abstract

Gliomas are characterized by diffuse infiltration of tumor cells into surrounding brain tissue, and this highly invasive nature contributes to disease recurrence and poor patient outcomes. The molecular mechanisms underlying glioma cell invasion remain incompletely understood, limiting development of new targeted therapies. Here, we have identified phosphotyrosine adaptor protein ShcD as upregulated in malignant glioma and shown that it associates with receptor tyrosine kinase Tie2 to facilitate invasion. In human glioma cells, we find that expression of ShcD and Tie2 increases invasion, and this significant synergistic effect is disrupted with a ShcD mutant that cannot bind Tie2 or hyperphosphorylate the receptor. Expression of ShcD and/or Tie2 further increases invadopodia formation and matrix degradation in U87 glioma cells. In a coculture model, we show that U87-derived tumor spheroids expressing both ShcD and Tie2 display enhanced infiltration into cerebral organoids. Mechanistically, we identify changes in focal adhesion kinase phosphorylation in the presence of ShcD and/or Tie2 in U87 cells upon Tie2 activation. Finally, we identify a strong correlation between transcript levels of ShcD and Tie2 signaling components as well as N-cadherin in advanced gliomas and those with classical or mesenchymal subtypes, and we show that elevated expression of ShcD correlates with a significant reduction in patient survival in higher grade gliomas with mesenchymal signature. Altogether, our data highlight a novel Tie2–ShcD signaling axis in glioma cell invasion, which may be of clinical significance.

Implications:
ShcD cooperates with Tie2 to promote glioma cell invasion and its elevated expression correlates with poor patient outcome in advanced gliomas.
Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice
Authors: Han Huajun , Davidson Laurie A. , Hensel Martha , Yoon Grace , Landrock Kerstin , Allred Clinton , Jayaraman Arul , Ivanov Ivan , Safe Stephen H. , Chapkin Robert S. 
Published: January 2021

Abstract

The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of “cooperation response genes” to modulate the function of cancer “driver” genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell–targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis.

Implications:
Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.