bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early specialised palliative care: interventions, symptoms, problems
Authors: Skjoedt Nete , Johnsen Anna Thit , Sjøgren Per , Neergaard Mette Asbjoern , Damkier Anette , Gluud Christian , Lindschou Jane , Fayers Peter , Higginson Irene J , Strömgren Annette S , Groenvold Mogens 
Published: March 2020

BackgroundFew studies have investigated the content of interventions provided in early specialised palliative care (SPC).ObjectivesTo characterise the content of interventions delivered in early SPC in the Danish Palliative Care Trial (DanPaCT), a multicentre trial with six participating sites.MethodsA retrospective qualitative and quantitative study coding all new interventions initiated by the palliative teams and documented in the medical records during the 8-week study period of DanPaCT. Interventions were categorised according to (a) symptom/problem prompting the intervention, (b) type of intervention and (c) professional(s) providing the intervention.ResultsIn total, 145 patients were randomised to the SPC teams. According to the medical records, patients received a median of 3.5 (range 0–22) new interventions in the 8-week intervention-period from the palliative teams. For 24 (18%) of the patients there was no documented interventions in the medical records. The most frequent symptom/problems treated were pain, (100 interventions; 20% of interventions given) and impaired physical function (62; 13% of interventions given). The most frequent type of intervention was pharmacological (232; 42% of interventions given).ConclusionsThis is one of the first studies to meticulously investigate the content of interventions documented in the medical records for patients receiving early SPC. Diverse symptoms were treated with many different interventions. However, a relatively low number of interventions were documented. This may explain the lack of effect in DanPaCT but also questions whether all interventions were adequately documentedTrial registration numberNCT01348048
British Society of Gastroenterology (BSG)-led multisociety consensus care bundle for the early clinical management of acute upper gastrointestinal bleeding
Authors: Siau Keith , Hearnshaw Sarah , Stanley Adrian J , Estcourt Lise , Rasheed Ashraf , Walden Andrew , Thoufeeq Mo , Donnelly Mhairi , Drummond Russell , Veitch Andrew M , Ishaq Sauid , Morris Allan John 
Published: March 2020

Medical care bundles improve standards of care and patient outcomes. Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency which has been consistently associated with suboptimal care. We aimed to develop a multisociety care bundle centred on the early management of AUGIB.Commissioned by the British Society of Gastroenterology (BSG), a UK multisociety task force was assembled to produce an evidence-based and consensus-based care bundle detailing key interventions to be performed within 24 hours of presentation with AUGIB. A modified Delphi process was conducted with stakeholder representation from BSG, Association of Upper Gastrointestinal Surgeons, Society for Acute Medicine and the National Blood Transfusion Service of the UK. A formal literature search was conducted and international AUGIB guidelines reviewed. Evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation tool and statements were formulated and subjected to anonymous electronic voting to achieve consensus. Accepted statements were eligible for incorporation into the final bundle after a separate round of voting. The final version of the care bundle was reviewed by the BSG Clinical Services and Standards Committee and approved by all stakeholder groups.Consensus was reached on 19 statements; these culminated in 14 corresponding care bundle items, contained within 6 management domains: Recognition, Resuscitation, Risk assessment, Rx (Treatment), Refer and Review.A multisociety care bundle for AUGIB has been developed to facilitate timely delivery of evidence-based interventions and drive quality improvement and patient outcomes in AUGIB.
Complete response to anti-PD-L1 antibody in a metastatic bladder cancer associated with novel MSH4 mutation and microsatellite instability
Authors: Yang Yuanquan , Jain Rohit K , Glenn Sean T , Xu Bo , Singh Prashant K , Wei Lei , Hu Qiang , Long Mark , Hutson Nicholas , Wang Jianming , Battaglia Sebastiano , George Saby 
Published: March 2020

BackgroundMicrosatellite instability (MSI) occurs in 3% of urothelial carcinomas as a result of germline or somatic loss of function mutation in mismatch repair (MMR) proteins.1 Although MSH4 is a member of the DNA MMR mutS family, the association of MSH4 mutation with MSI has not been described. We report a complete responder to PD-L1 blockade who had MSH4 mutated metastatic bladder cancer with mixed histology and MSI. The genomics of urothelial, plasmacytoid and squamous histology was characterized individually through microdissection.Case presentationAn 81-year-old man was diagnosed with metastatic urothelial carcinoma 8 months after a cystectomy for muscle invasive bladder cancer. His disease was primary refractory to first-line platinum-based chemotherapy but attained complete response to second-line atezolizumab. PCR-based assay revealed MSI high. The tumor mutational burden was elevated to 36.7 mut/Mb. However, immunohistochemistry of MLH1, MSH2, MSH6 and PMS2 was intact. Whole exome sequencing confirmed that the above mentioned four classic MMR genes were wild type but revealed a deleterious MSH4 L359I mutation with variant allele fraction of 30% and Polyphen2 score of 0.873. The association of MSH4 alterations and MSI-H was independently verified in two publicly available MSI-H colorectal cancer datasets.ConclusionsThe novel MSH4 L359I mutation is associated with MSI and high mutational burden leading to remarkable response to PD-L1 blockade. More studies are warranted to establish the causality relationship between MSH4 and MSI.
Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vδ2+T cells activities after hematopoietic transplantation for blood malignancies
Authors: Liu Jiangying , Gao Haitao , Xu Lan-Ping , Mo Xiao-Dong , Liu Ruoyang , Liang Shuang , Wu Ning , Wang Ming , Wang Zhidong , Chang Ying-Jun , Wang Yu , Zhang Xiao-Hui , Huang Xiao-Jun 
Published: March 2020

BackgroundFollowing the extensive use of immunosuppressive drugs in the clinic, immunosuppression-associated side effects have received increasing attention. Epstein-Barr virus (EBV) reactivation and related lymphoproliferative diseases (LPD) are the lethal complications observed after allogeneic hematopoietic cell transplantation (alloHCT). While studies generally suggest an association between immunosuppressants and EBV reactivation, the effects of specific immunosuppressive drugs and which T-cell subsets mediate these correlations are unclear. Vδ2+T cells are correlated with EBV reactivation after alloHCT. Researchers have not determined whether Vδ2+T-cell activities are affected by immunosuppressants and thereby facilitate EBV reactivation and related LPD.MethodsA clinical cohort study of 170 patients with hematopoietic malignancies who received haploidentical hematopoietic cell transplantation (haploHCT) was performed to investigate whether the early cessation of mycophenolate mofetil (MMF) decreases EBV reactivation and related LPD and to determine whether this change is associated with the recovery of Vδ2+T cells after transplantation. The effects of MMF on the expansion and anti-EBV capacity of Vδ2+T cells were detected in vitro and in an immunodeficient mouse model.ResultsA reduction in the course of MMF significantly improved the recovery of Vδ2+T cells from 30 to 90 days after haploHCT (p=0.002, p=0.042 and p=0.035, respectively), accompanied by a significant decrease in EBV reactivation (from 26% to 13%, p=0.033) and EBV-LPD (from 10.6% to 2.4%, p=0.029). The day-30 Vδ2+T level remained an independent factor for EBV reactivation in patients with different MMF durations (p=0.007). In the in-vitro experiments, MMF inhibited Vδ2+T-cell expansion and its cytotoxicity on EBV-transformed malignant cells. Furthermore, the therapeutic and prophylactic effects of adoptively transferred human Vδ2+T cells were attenuated by the MMF treatment in immunodeficient mice with EBV-LPD.ConclusionsThese results elucidated a negative effect of immunosuppressants on the anti-EBV capacity of Vδ2+T cells. Strategies that appropriately relieve the immunosuppression may improve anti-EBV immunity by increasing the activity of Vδ2+T cells after alloHCT.
EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1
Authors: Park Dong Jun , Sung Pil Soo , Kim Jung-Hee , Lee Gil Won , Jang Jeong Won , Jung Eun Sun , Bae Si Hyun , Choi Jong Young , Yoon Seung Kew 
Published: March 2020

BackgroundNatural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAMhighCSCs in HCC.MethodsEpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAMhighand EpCAMlowHuh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice.ResultsThe frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAMhighHCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAMhighHuh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1highcells. In mouse experiments with Hepa1–6 cells, EpCAMhighHepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM+HCC.ConclusionOur data demonstrated that EpCAMhighliver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.
Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients
Authors: Amaral Teresa , Kiecker Felix , Schaefer Sarah , Stege Henner , Kaehler Katharina , Terheyden Patrick , Gesierich Anja , Gutzmer Ralf , Haferkamp Sebastian , Uttikal Jochen , Berking Carola , Rafei-Shamsabadi David , Reinhardt Lydia , Meier Friedegund , Karoglan Ante , Posch Christian , Gambichler Thilo , Pfoehler Claudia , Thoms Kai , Tietze Julia , Debus Dirk , Herbst Rudolf , Emmert Steffen , Loquai Carmen , Hassel Jessica C , Meiss Frank , Tueting Thomas , Heinrich Vanessa , Eigentler Thomas , Garbe Claus , Zimmer Lisa 
Published: March 2020

BackgroundNivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM.MethodsPatients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS.ResultsThree hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119).ConclusionImmunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
Effect of weighting for sampling and non-response on estimates of STI prevalence in the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3)
Authors: Harling Guy , Copas Andrew , Clifton Soazig , Johnson Anne M , Field Nigel , Sonnenberg Pam , Mercer Catherine H 
Published: March 2020

ObjectivesIn addition to researcher-designed sampling biases, population-representative surveys for biomarker measurement of STIs often have substantial missingness due to non-contact, non-consent and other study-implementation issues. STI prevalence estimates may be biased if this missingness is related to STI risk. We investigated how accounting for sampling, interview non-response and non-provision of biological samples affects prevalence estimates in the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).MethodsNatsal-3 was a multistage, clustered and stratified probability sample of 16–74 year-olds conducted between 2010 and 2012. Individuals were sampled from all private residential addresses in Britain; respondents aged 16–44 were further sampled to provide a urine specimen based on characteristics including self-reported sexual behaviours. We generated prevalence estimates and confidence intervals for six STIs in five stages: first without accounting for sampling or non-response, then applying inverse-probability weights cumulatively accounting for interview sampling, interview non-response, urine sampling and urine non-response.ResultsInterview non-completion occurred for 42.3% of interview-sampled individuals; urine non-completion occurred for 43.5% of urine-sampled individuals. Interview-sampled individuals, interview respondents, those selected for urine samples and those providing urine samples were each in turn slightly more at-risk for most STIs, leading to lower prevalence estimates after incorporating each set of weights. Researcher-controlled sampling had more impact than respondent-controlled response.ConclusionsAccounting for both sampling structures and willingness to interview or provide urine specimens can affect national STI prevalence estimates. Using both types of weights, as was done in Natsal-3, is important in reporting on population-based biomarker surveys.
Double parton scattering in pA collisions at the LHC revisited
Authors: Blok Boris , Ceccopieri Federico Alberto 
Published: March 2020

AbstractWe consider the production of W-boson plus dijet, W-boson plus b-jets and same sign WW via double parton scattering (DPS) in pA collisions at the LHC and evaluate the corresponding cross sections. The impact of a novel DPS contribution pertinent to pA collisions is quantified. Exploiting the experimental capability of performing measurements differential in the impact parameter in pA collisions, we discuss a method to single out this novel DPS contribution. The method allows the subtraction of the leading twist (LT) single parton scattering background and it gives access in a very clean way to double parton distribution functions in the proton. We calculate leading twist and DPS cross sections and study the dependence of the observables on the cuts in the jets phase space. In the Wjj channel the observation of DPS is possible with data already accumulated in pA runs and the situation will greatly improve for the next high luminosity runs. For the $$Wb{\bar{b}}$$Wbb¯ final state, the statistics within the current data is too low, but there is possibility to observe DPS in this channel in future runs, albeit with much reduced sensitivity than in Wjj final state. Finally the DPS observation in the same sign WW channel will require either significant increase of integrated luminosity beyond that foreseen in next pA runs or improved methods for W reconstruction, along with its charge, in hadronic decay channels.
Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart
Authors: Chan Shyue-An , Vaseghi Marmar , Kluge Nicholas , Shivkumar Kalyanam , Ardell Jeffrey L. , Smith Corey 
Published: March 2020

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload. NEW & NOTEWORTHY Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.
Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus
Authors: Sun Zhen , Li Lihua , Zhang Lili , Yan Jinchuan , Shao Chen , Bao Zhengyang , Liu Jia , Li Yalan , Zhou Mengxue , Hou Lina , Jing Lele , Pang Qiwen , Geng Yue , Mao Xiang , Gu Wen , Wang Zhongqun 
Published: March 2020

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE−/−) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE−/−mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.