bluuebunny/crossref_metadata_2025_split huggingface dataset:
Twelve-month prevalence of haemarthrosis and joint disease using the Haemophilia Joint Health score: evaluation of the UK National Haemophilia Database and Haemtrack patient reported data: an observational study
Authors: Wilkins Richard A , Stephensen David , Siddle Heidi , Scott Martin J , Xiang Hua , Horn Elizabeth , Palmer Ben , Chapman Graham J , Richards Michael , Walwyn Rebecca , Redmond Anthony 
Published: January 2022

ObjectivesTo report the 12-month prevalence of joint bleeds from the National Haemophilia Database (NHD) and Haemtrack, a patient-reported online treatment diary and concurrent joint disease status using the haemophilia joint health score (HJHS) at individual joint level, in children and adults with severe haemophilia A and B (HA/HB) without a current inhibitor.DesignA 2018 retrospective database study of NHD from which 2238 cases were identified, 463 patients had fully itemised HJHS of whom 273 were compliant in recording treatment using Haemtrack.SettingEngland, Wales and Scotland, UK.ParticipantsChildren (<18 years) and adults (≥18 years) with severe HA and HB (factor VIII/factor IX, <0.01 iu/mL) without a current inhibitor.Primary and secondary outcomesPrevalence of joint haemarthrosis and concurrent joint health measured using the HJHS.ResultsThe median (IQR) age of children was 10 (6–13) and adults 40 (29–50) years. Haemarthrosis prevalence in HA/HB children was 33% and 47%, respectively, and 60% and 42%, respectively, in adults. The most common site of haemarthrosis in children was the knee in HA and ankle in HB. In adults, the incidence of haemarthrosis at the ankles and elbows was equal. The median total HJHS in HA/HB children was 0 and in adults with HA/HB, were 18 and 11, respectively. In adults with HA/HB, the median ankle HJHS of 4.0 was higher than the median HJHS of 1.0 for both the knee and elbow.ConclusionDespite therapeutic advances, only two-thirds of children and one-third of adults were bleed-free, even in a UK cohort selected for high compliance with prophylaxis. The median HJHS of zero in children suggests joint health is relatively unaffected during childhood. In adults, bleed rates were highest in ankles and elbows, but the ankles led to substantially worse joint health scores.
Impact of the COVID-19 pandemic on transplantation by income level and cumulative COVID-19 incidence: a multinational survey study
Authors: Sandal Shaifali , Massie Allan , Boyarsky Brian , Chiang Teresa Po-Yu , Thavorn Kednapa , Segev Dorry L , Cantarovich Marcelo 
Published: January 2022

ObjectivesThe COVID-19 pandemic significantly affected the provisions of health services to necessary but deprioritised fields, such as transplantation. Many programmes had to ramp-down their activity, which may significantly affect transplant volumes. We aimed to pragmatically analyse measures of transplant activity and compare them by a country’s income level and cumulative COVID-19 incidence (CCI).Design, setting and participantsFrom June to September 2020, we surveyed transplant physicians identified as key informants in their programmes. Of the 1267 eligible physicians, 40.5% from 71 countries participated.OutcomeFour pragmatic measures of transplant activity.ResultsOverall, 46.5% of the programmes from high-income countries anticipate being able to maintain >75% of their transplant volume compared with 31.6% of the programmes from upper-middle-income countries, and with 21.7% from low/lower-middle-income countries (p<0.001). This could be because more programmes in high-income countries reported being able to perform transplantation/s (86.8%%–58.5%–67.9%, p<0.001), maintain prepandemic deceased donor offers (31.0%%–14.2%–26.4%, p<0.01) and avoid a ramp down phase (30.9%%–19.7%–8.3%, p<0.001), respectively. In a multivariable analysis that adjusted for CCI, programmes in upper-middle-income countries (adjusted OR, aOR=0.47, 95% CI 0.27 to 0.81) and low/lower-middle-income countries (aOR 0.33, 95% CI 0.16 to 0.67) had lower odds of being able to maintain >75% of their transplant volume, compared with programmes in high-income countries. Again, this could be attributed to lower-income being associated with 3.3–3.9 higher odds of performing no transplantation/s, 66%–68% lower odds of maintaining prepandemic donor offers and 37%–76% lower odds of avoiding ramp-down of transplantation. Overall, CCI was not associated with these measures.ConclusionsThe impact of the pandemic on transplantation was more in lower-income countries, independent of the COVID-19 burden. Given the lag of 1–2 years in objective data being reported by global registries, our findings may inform practice and policy. Transplant programmes in lower-income countries may need more effort to rebuild disrupted services and recuperate from the pandemic even if their COVID-19 burden was low.
Evaluation of initial shockable rhythm as an indicator of short no-flow time in cardiac arrest: a national registry study
Authors: Shibahashi Keita , Sugiyama Kazuhiro , Ishida Takuto , Hamabe Yuichi 
Published: January 2022

BackgroundThe duration from collapse to initiation of cardiopulmonary resuscitation (no-flow time) is one of the most important determinants of outcomes after out-of-hospital cardiac arrest (OHCA). Initial shockable cardiac rhythm (ventricular fibrillation or ventricular tachycardia) is reported to be a marker of short no-flow time; however, there is conflicting evidence regarding the impact of initial shockable cardiac rhythm on treatment decisions. We investigated the association between initial shockable cardiac rhythm and the no-flow time and evaluated whether initial shockable cardiac rhythm can be a marker of short no-flow time in patients with OHCA.MethodsPatients aged 18 years and older experiencing OHCA between 2010 and 2016 were selected from a nationwide population-based Japanese database. The association between the no-flow time duration and initial shockable cardiac rhythm was evaluated. Diagnostic accuracy was evaluated using the sensitivity, specificity and positive predictive value.ResultsA total of 177 634 patients were eligible for the analysis. The median age was 77 years (58.3%, men). Initial shockable cardiac rhythm was recorded in 11.8% of the patients. No-flow time duration was significantly associated with lower probability of initial shockable cardiac rhythm, with an adjusted OR of 0.97 (95% CI 0.96 to 0.97) per additional minute. The sensitivity, specificity and positive predictive value of initial shockable cardiac rhythm to identify a no-flow time of <5 min were 0.12 (95% CI 0.12 to 0.12), 0.88 (95% CI 0.88 to 0.89) and 0.35 (95% CI 0.34 to 0.35), respectively. The positive predictive values were 0.90, 0.95 and 0.99 with no-flow times of 15, 18 and 28 min, respectively.ConclusionsAlthough there was a significant association between initial shockable cardiac rhythm and no-flow time duration, initial shockable cardiac rhythm was not reliable when solely used as a surrogate of a short no-flow time duration after OHCA.
Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer
Authors: Reppel Loïc , Tsahouridis Ourania , Akulian Jason , Davis Ian J , Lee Hong , Fucà Giovanni , Weiss Jared , Dotti Gianpietro , Pecot Chad V , Savoldo Barbara 
Published: January 2022

BackgroundWe explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells.MethodsGD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated.ResultsGD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity.ConclusionsGD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.
Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study
Authors: Dorst Johannes , Doenz Judith , Kandler Katharina , Dreyhaupt Jens , Tumani Hayrettin , Witzel Simon , Schuster Joachim , Ludolph Albert C 
Published: January 2022

ObjectiveThere is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients offers optimal tolerability and weight gain.MethodsWe conducted a randomised controlled study (Safety and Tolerability of Ultra-high-caloric Food Supplements in Amyotrophic Lateral Sclerosis (ALS); TOLCAL-ALS study) in 64 patients with possible, probable or definite ALS according to El Escorial criteria. Patients were randomised into four groups: a high-caloric fatty supplement (HCFS; 405 kcal/day, 100% fat), an ultra-high-caloric fatty supplement (UHCFS; 810 kcal/day, 100% fat), an ultra-high-caloric, carbohydrate-rich supplement (UHCCS; 900 kcal/day, 49% carbohydrates) and an open control (OC) group without any supplement. The primary endpoint was tolerability. Patients were followed up over 4 weeks.ResultsGastrointestinal side effects were most frequent in the UHCFS group (75.0%), while loss of appetite was most frequent in the UHCCS group (35.3%). During intervention, patients gained +0.9 kg/month of body weight (IQR −0.9 to 1.5; p=0.03) in the HCFS group and +0.9 kg/month (IQR −0.8 to 2.0; p=0.05) in the UHCFS group. A non-significant trend for weight gain (+0.6 kg/month (IQR −0.3 to 1.9; p=0.08)) was observed in the UHCCS group. Patients in OC group continued to lose body weight (−0.5 kg/month, IQR −1.4 to 1.3; p=0.42).InterpretationThe findings suggest that HCSs frequently cause mild to moderate tolerability issues in patients with ALS, most notably gastrointestinal symptoms in high-fat supplements, and loss of appetite in high-carbohydrate supplements. All three HCSs tested are suited to increase body weight.
Clinical outcomes of rescue stenting for failed endovascular thrombectomy: a multicenter prospective registry
Authors: Baek Jang-Hyun , Kim Byung Moon , Ihm Eun Hyun , Kim Chang-Hyun , Kim Dong Joon , Heo Ji Hoe , Nam Hyo Suk , Kim Young Dae , Suh Sangil , Kim Byungjun , Won Yoodong , Baek Byung Hyun , Yoon Woong , Kwon Hyon-Jo , Chang Yoonkyung , Jung Cheolkyu , Jeong Hae Woong 
Published: January 2022

BackgroundMechanical thrombectomy (MT) is a primary endovascular modality for acute intracranial large vessel occlusion. However, further treatment, such as rescue stenting, is occasionally necessary for refractory cases. We aimed to investigate the efficacy and safety of rescue stenting in first-line MT failure and to identify the clinical factors affecting its clinical outcome.MethodsA multicenter prospective registry was designed for this study. We enrolled consecutive patients who underwent rescue stenting for first-line MT failure. Endovascular details and outcomes, follow-up patency of the stented artery, and clinical outcomes were summarized and compared between the favorable and unfavorable outcome groups.ResultsA total of 78 patients were included. Intracranial atherosclerotic stenosis was the most common etiology for rescue stenting (97.4%). Seventy-seven patients (98.7%) were successfully recanalized by rescue stenting. A favorable outcome was observed in 66.7% of patients. Symptomatic intracranial hemorrhage and mortality were observed in 5.1% and 4.0% of patients, respectively. The stented artery was patent in 82.1% of patients on follow-up angiography. In a multivariable analysis, a patent stent on follow-up angiography was an independent factor for a favorable outcome (OR 87.6; 95% CI 4.77 to 1608.9; p=0.003). Postprocedural intravenous maintenance of glycoprotein IIb/IIIa inhibitor was significantly associated with the follow-up patency of the stented artery (OR 5.72; 95% CI 1.45 to 22.6; p=0.013).ConclusionsIn this multicenter prospective registry, rescue stenting for first-line MT failure was effective and safe. For a favorable outcome, follow-up patency of the stented artery was important, which was significantly associated with postprocedural maintenance of glycoprotein IIb/IIIa inhibitors.
Association of perioperative midazolam use and complications: a population-based analysis
Authors: Athanassoglou Vassilis , Cozowicz Crispiana , Zhong Haoyan , Illescas Alex , Poeran Jashvant , Liu Jiabin , Poultsides Lazaros , Memtsoudis Stavros G 
Published: January 2022

IntroductionThe benzodiazepine midazolam is the main sedative used in the perioperative setting, resulting in anxiolysis and a reduction in anesthetic dose requirements. However, benzodiazepine use is also associated with potentially serious side effects including respiratory complications, and postoperative delirium (POD). A paucity of population level data exists on current perioperative midazolam use in adult orthopedic surgery and its effects on complications. Using a large national dataset, we aimed to determine perioperative midazolam utilization patterns and to analyze its effect on postoperative outcomes.MethodsPatients who underwent total knee and hip arthroplasty (TKA/THA) were identified from Premier database (2006–2019). Primary exposure of interest was midazolam use on the day of surgery. Multivariable logistic regression models were run to determine if midazolam was associated with postoperative cardiac and pulmonary complications, delirium, and in-hospital falls.ResultsAmong 2,848,897 patients, more than 75% received midazolam perioperatively. This was associated with increased adjusted odds for in-hospital falls in TKA/THA (OR 1.1, 95% CI 1.07 to 1.14)/(OR 1.1, 95% CI 1.06 to 1.16), while a decrease in the adjusted odds for cardiac complications in TKA/THA (OR 0.94, 95% CI 0.91 to 0.97)/(OR 0.93, 95% CI 0.89 to 0.97), and pulmonary complications (OR 0.92, 95% CI 0.87 to 0.96) (all p<0.001) was seen. Most notably, the concurrent use of midazolam and gabapentinoids significantly increased the adjusted odds for postoperative complications, including pulmonary complications (OR 1.22, 95% CI 1.18 to 1.27)/(OR 1.29, 95% CI 1.22 to 1.37), naloxone utilization (OR 1.56, 95% CI 1.51 to 1.60)/(OR 1.49, 95% CI 1.42 to 1.56), and POD (OR 1.45, 95% CI 1.38 to 1.52)/(OR 1.32, 95% CI 1.23 to 1.34) in THA/TKA.ConclusionPerioperative midazolam use was associated with an increase in postoperative patient falls, and a decrease in cardiac complications. Notably, the combined use of midazolam and gabapentinoids was associated with a substantial increase in the odds for respiratory failure and delirium. Given the high prevalence of benzodiazepines perioperatively, the risk benefit profile should be more clearly established to inform perioperative decision making.
Naturally leading: a content analysis of terms, themes and word associations in Natural American Spirit advertising, 2000–2020
Authors: Gratale Stefanie K , Ganz Ollie , Wackowski Olivia A , Lewis M Jane 
Published: January 2022

BackgroundNatural American Spirit (NAS) is a cigarette brand distinguished by supposed ‘natural’, ‘additive-free’ characteristics, marketing of which is tied to misperceptions of reduced harm. In 2017, NAS’s manufacturer agreed (with the Food and Drug Administration) to remove ‘natural’/‘additive-free’ from US marketing. Prior research has explored NAS marketing immediately post-agreement. This study sought to identify prominent post-agreement terms and themes and analyse how they had been used in pre-agreement ads.MethodsWe conducted a content analysis of NAS ads from 2000 to 2020 (N=176), documenting prominent pre-agreement and post-agreement terms/themes and examining how they are used in NAS ads. We coded for descriptors, themes, imagery and promotions, and extended prior research by analysing how leading post-agreement terms were used in conjunction and thematically associated with ‘additive-free’ and ‘natural’ before the agreement.ResultsResults indicated ‘tobacco and water’ and ‘Real. Simple. Different.’ increased post-agreement, as did environmental imagery. ‘Organic’ was prominent pre-agreement and post-agreement. The descriptors used most often in post-agreement ads almost always appeared in conjunction with (and were thematically linked to) ‘natural’ and ‘additive-free’ in pre-agreement ads.ConclusionsIn the years since the agreement, NAS ads have heavily relied on still-allowable descriptors that may invite reduced risk misperceptions. Notably, these descriptors were consistently used alongside the banned terminology before the agreement and presented as if affiliated conceptually, possibly prompting similar connotations. Findings indicate a continuing need for research into NAS advertising effects and a potential role for additional regulatory action.
High-intensity interval resistance training (HIIRT) improves liver gluconeogenesis from lactate in Swiss mice
Authors: Muller Gabrielle Yasmin , Matos Felipe de Oliveira , Perego Junior Julio Ernesto , Kurauti Mirian Ayumi , Diaz Pedrosa Maria Montserrat 
Published: January 2022

High-intensity physical exercise favors anaerobic glycolysis and increases lactatemia. Lactate is converted back to glucose in the liver, so that the lactate threshold, an indicator of physical performance, must be related to the gluconeogenic capacity of the liver. This research assessed the effect of a high-intensity interval resistance training (HIIRT) on liver gluconeogenesis from lactate. Swiss mice were trained (groups T) on vertical ladder with overload of 90% of their maximal load. Control animals remained untrained (groups C0 and C8). In situ liver perfusion with lactate and adrenaline was performed in rested mice after 6 hours of food deprivation. There were larger outputs of glucose (T6, 71.90%; T8, 54.53%) and pyruvate (T8, 129.28%) (representative values for 4 mM lactate) in the groups trained for 6 or 8 weeks (T6 and T8), and of glucose in the presence of adrenaline in group T8 (280%). The content of PEPCK, an important regulatory enzyme of the gluconeogenic pathway, was 69.13% higher in group T8 than in the age-matched untrained animals (C8). HIIRT augmented liver gluconeogenesis from lactate and this might improve the lactate threshold. Novelty: The liver metabolizes lactate from muscle into glucose. Physical training may enhance the gluconeogenic capacity of the liver. As lactate clearance by the liver improves, lactate threshold is displaced to higher exercise intensities.
NOTCH-Induced MDSC Recruitment after oHSV Virotherapy in CNS Cancer Models Modulates Antitumor Immunotherapy
Authors: Otani Yoshihiro , Yoo Ji Young , Lewis Cole T. , Chao Samantha , Swanner Jessica , Shimizu Toshihiko , Kang Jin Muk , Murphy Sara A. , Rivera-Caraballo Kimberly , Hong Bangxing , Glorioso Joseph C. , Nakashima Hiroshi , Lawler Sean E. , Banasavadi-Siddegowda Yeshavanth , Heiss John D. , Yan Yuanqing , Pei Guangsheng , Caligiuri Michael A. , Zhao Zhongming , Chiocca E. Antonio , Yu Jianhua , Kaur Balveen 
Published: January 2022

AbstractPurpose:Oncolytic herpes simplex virus-1 (oHSV) infection of brain tumors activates NOTCH, however the consequences of NOTCH on oHSV-induced immunotherapy is largely unknown. Here we evaluated the impact of NOTCH blockade on virus-induced immunotherapy.Experimental Design:RNA sequencing (RNA-seq), TCGA data analysis, flow cytometry, Luminex- and ELISA-based assays, brain tumor animal models, and serum analysis of patients with recurrent glioblastoma (GBM) treated with oHSV was used to evaluate the effect of NOTCH signaling on virus-induced immunotherapy.Results:TCGA data analysis of patients with grade IV glioma and oHSV treatment of experimental brain tumors in mice showed that NOTCH signaling significantly correlated with a higher myeloid cell infiltration. Immunofluorescence staining and RNA-seq uncovered a significant induction of Jag1 (NOTCH ligand) expression in infiltrating myeloid cells upon oHSV infection. Jag1-expressing macrophages further spread NOTCH activation in the tumor microenvironment (TME). NOTCH-activated macrophages increased the secretion of CCL2, which further amplified myeloid-derived suppressor cells. CCL2 and IL10 induction was also observed in serum of patients with recurrent GBM treated with oHSV (rQnestin34.5; NCT03152318). Pharmacologic blockade of NOTCH signaling rescued the oHSV-induced immunosuppressive TME and activated a CD8-dependent antitumor memory response, resulting in a therapeutic benefit.Conclusions:NOTCH-induced immunosuppressive myeloid cell recruitment limited antitumor immunity. Translationally, these findings support the use of NOTCH inhibition in conjunction with oHSV therapy.
MUC1-C Dictates JUN and BAF-Mediated Chromatin Remodeling at Enhancer Signatures in Cancer Stem Cells
Authors: Bhattacharya Atrayee , Fushimi Atsushi , Yamashita Nami , Hagiwara Masayuki , Morimoto Yoshihiro , Rajabi Hasan , Long Mark D. , Abdulla Maha , Ahmad Rehan , Street Kelly , Liu Song , Liu Tao , Kufe Donald 
Published: January 2022

Abstract

The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) cells. Chromatin remodeling is critical for the cancer stem cell (CSC) state; however, there is no definitive evidence that MUC1-C regulates chromatin accessibility and thereby expression of stemness-associated genes. We demonstrate that MUC1-C drives global changes in chromatin architecture in the dedifferentiation of CRPC and TNBC cells. Our results show that MUC1-C induces differentially accessible regions (DAR) across their genomes, which are significantly associated with differentially expressed genes (DEG). Motif and cistrome analysis further demonstrated MUC1-C–induced DARs align with genes regulated by the JUN/AP-1 family of transcription factors. MUC1-C activates the BAF chromatin remodeling complex, which is recruited by JUN in enhancer selection. In studies of the NOTCH1 gene, which is required for CRPC and TNBC cell self-renewal, we demonstrate that MUC1-C is necessary for (i) occupancy of JUN and ARID1A/BAF, (ii) increases in H3K27ac and H3K4me3 signals, and (iii) opening of chromatin accessibility on a proximal enhancer–like signature. Studies of the EGR1 and LY6E stemness–associated genes further demonstrate that MUC1-C–induced JUN/ARID1A complexes regulate chromatin accessibility on proximal and distal enhancer–like signatures. These findings uncover a role for MUC1-C in chromatin remodeling that is mediated at least in part by JUN/AP-1 and ARID1A/BAF in association with driving the CSC state.

Implications:
These findings show that MUC1-C, which is necessary for the CRPC and TNBC CSC state, activates a novel pathway involving JUN/AP-1 and ARID1A/BAF that regulates chromatin accessibility of stemness-associated gene enhancers.