bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive impact of cerebral microbleeds in patients with symptomatic small vessel disease
Authors: Nannoni Stefania , Ohlmeier Laura , Brown Robin B , Morris Robin G , MacKinnon Andrew D , Markus Hugh S ,   for the DNA Lacunar 2 investigators
Published: April 2021

Background and aim Whether cerebral microbleeds cause cognitive impairment remains uncertain. We analyzed whether cerebral microbleeds are associated with cognitive dysfunction in patients with symptomatic cerebral small vessel disease, and whether this association is independent of other neuroimaging markers of cerebral small vessel disease. Methods We analyzed consecutive patients with MRI-confirmed lacunar stroke included in DNA-Lacunar-2 multicenter study. Cerebral microbleeds were graded using the Brain Observer Microbleed Rating Scale (BOMBS). Neuropsychological assessment was performed using the Brief Memory and Executive Test (BMET). We analyzed the association between cerebral microbleeds, BMET, and the following subdomains: executive function/processing speed and orientation/memory. We also searched for an independent association between cerebral microbleeds and vascular cognitive impairment, defined as BMET ≤ 13. Results Out of 688 included patients, cerebral microbleeds were detected in 192 (27.9%). After adjusting for white matter hyperintensities severity, lacune count, and other confounders, both the presence and the number of cerebral microbleeds were significantly associated with impaired cognitive performance [β = −13.0; 95% CI = (−25.3, −0.6) and β = −13.1; 95% CI = (−19.8, −6.4), respectively]. On analysis of specific cognitive domains, associations were present for executive function/processing speed [β = −5.8; 95% CI = (−9.3, −2.2) and β = −4.3; 95% CI = (−6.2, −2.4), respectively] but not for orientation/memory [β = −0.4; 95% CI = (−4.0, 3.2) and β = −2.1; 95% CI = (−4.0, 0.1), respectively]. We also found an independent association between the presence and the number of cerebral microbleeds and vascular cognitive impairment [adjusted OR = 1.48; 95% CI = (1.01, 2.18) and OR = 1.43; 95% CI = (1.15, 1.79), respectively]. Conclusion In a large cohort of symptomatic cerebral small vessel disease patients, after controlling for other neuroimaging markers of cerebral small vessel disease severity, cerebral microbleeds were associated with cognitive dysfunction. Executive function and processing speed were predominantly impaired. This might suggest a causal role of cerebral microbleeds in determining vascular cognitive impairment.
Rationale and design of a phase 3b, prospective, randomized, open label, blinded-endpoint, multicenter trial of the efficacy and safety of urokinase thrombolysis comparing with antiplatelet agents for patients with minor stroke
Authors: Zhao Lu , Jiang Chenyang , Tao Yongli , Gao Yuan , Xu Yafang , Zhang Rui , Liu Kai , Gu Hongqiu , Wang Yilong , Xu Yuming , Song Bo 
Published: April 2021

Rationale Minor ischemic stroke attack has taken a significant part of cerebrovascular disease burden. Benefits of thrombolysis in minor stroke is under debates and the use of urokinase in developing countries needs to be further explored. Aim TRUST (ThRombolysis of Urokinase for minor STroke) trial was designed to evaluate the efficacy and safety of intravenous urokinase for the treatment of acute minor ischemic stroke. Sample size estimates To reach a double-sided type I error rate of 0.05 to test our hypothesis, with β = 0.80, sample size of 1002 subjects were determined after further adjustment to account for up to 5% nonadherence. Methods and design TRUST trial was developed with PROBE design, as a multicenter, randomized, open label, single-blind clinical trial with the stage of phase 3b. Study outcomes The proportion of patients retaining full ability of independent living, which is defined as patients scoring 0–1 on modified Rankin Scale score at 90 days. Discussion TRUST trial may potentially provide promising and affordable thrombolysis for acute minor ischemic stroke in the developing parts of the world.
The role of eHealth, telehealth, and telemedicine for chronic disease patients during COVID-19 pandemic: A rapid systematic review
Authors: Bitar Hind , Alismail Sarah 
Published: April 2021

Objective To summarize the current status of, and the current expert opinions, recommendation and evidence associated with the use and implementation of electronic health (eHealth), telemedicine, and/or telehealth to provide healthcare services for chronic disease patients during the COVID-19 pandemic. Materials and methods We searched four electronic databases (PubMed, Google Scholar, Science Direct, and Web of Science Core Collection) to identify relevant articles published between 2019 and 2020. Searches were restricted to English language articles only. Two independent reviewers screened the titles, abstracts, and keywords for relevance. The potential eligible articles, papers with no abstract, and those that fall into the uncertain category were read in full text independently. The reviewers met and discussed which articles to include in the final review and reached a consensus. Results We identified 51 articles of which 25 articles met the inclusion criteria. All included articles indicated the promising potential of eHealth, telehealth, and/or telemedicine solutions in delivering healthcare services to patients living with chronic diseases/conditions during the COVID-19 pandemic. We synthesized the main findings into ten usages and eight recommendations concerning the different activities for delivering healthcare services remotely for those living with chronic diseases/conditions in the era of COVID-19. Discussion and conclusions There is limited evidence available about the effectiveness of such solutions. Further research is required during this pandemic to improve the credibility of evidence on telemedicine, telehealth, and/or eHealth-related outcomes for those living with chronic diseases.
What are the implications for patient safety and experience of a major healthcare IT breakdown? A qualitative study
Authors: Scantlebury Arabella , Sheard L , Fedell Cindy , Wright J 
Published: April 2021

Introduction To explore the impact of a three-week downtime to an electronic pathology system on patient safety and experience. Methods Qualitative study consisting of semi-structured interviews and a focus group at a large NHS teaching hospital in England. Participants included NHS staff ( n = 16) who represented a variety of staff groups (doctors, nurses, healthcare assistants) and board members. Data were collected 2–5 months after the outage and were analysed thematically. Results We present the implications which the IT breakdown had for both patient safety and patient experience. Whilst there was no actual recorded harm to patients during the crisis, there was strong and divided opinion regarding the potential for a major safety incident to have occurred. Formal guidance existed to assist staff to navigate the outage but there was predominantly a reliance on informal workarounds. Junior clinicians seemed to struggle without access to routine blood test results whilst senior clinicians seemed largely unperturbed. Patient experience was negatively affected due to the extensive wait time for manually processed diagnostic tests, increasing logistical problems for patients. Conclusion The potential negative consequences on patient safety and experience relating to IT failures cannot be underestimated. To minimise risks during times of crisis, clear communication involving all relevant stakeholders, and guidance and management strategies that are agreed upon and communicated to all staff are recommended. To improve patient experience flexible approaches to patient management are suggested.
Limited implementation of the Nordic hamstring exercise in professional and semi-professional soccer
Authors: Al Attar Wesam Saleh A , Komir Ramy , Alzubeadi Ali , Bukhari Ibrahim , Ghulam Hussain 
Published: April 2021

Background/Purpose: In soccer players, non-contact injuries are most common, especially hamstring muscle injuries, which can be prevented by the Nordic hamstring exercise (NHE). This study assessed the professional and semi-professional soccer players and coaches’ awareness, implementation, and opinion of the NHE efficacy in reducing hamstring injuries. Methods: A questionnaire regarding the awareness, implementation, and opinions of the NHE’s efficacy in reducing hamstring muscle injuries was distributed. Results: The survey was completed by 812 (88.3% male and 11.7% female) players and coaches. Of these, 395 (48.6%) were aware of the NHE, and 355 (43.7%) implemented it in their current practice. Those implementing NHE had a positive opinion about its efficacy in reducing hamstring injuries. Conclusion: Further efforts and research are warranted to increase the international awareness and implementation of the NHE and educate soccer players and coaches about the importance of its implementation and effectiveness in preventing hamstring injury.
Revision Rotator Cuff Repair Versus Primary Repair for Large to Massive Tears Involving the Posterosuperior Cuff: Comparison of Clinical and Radiological Outcomes
Authors: Meshram Prashant , Liu Bei , Kim Sang Woo , Heo Kang , Oh Joo Han 
Published: April 2021

Background: The retear rate after revision rotator cuff repair (rRCR) ranges from 50% to 90%. Patients who undergo primary RCR (pRCR) for large to massive rotator cuff tear (mRCT) also have unpredictable outcomes. Purpose: To compare the clinical outcomes after rRCR for a posterosuperior rotator cuff tear of any size with those after pRCR for mRCT and to identify the risk factors for poor outcomes and retear after rRCR. Study Design: Cohort study; Level of evidence, 3. Methods: Among patients with posterosuperior cuff tear treated between 2010 and 2017, the clinical outcomes of 46 patients who underwent rRCR were compared with 106 patients who underwent pRCR for mRCT. Between-group differences in patient-reported outcomes (visual analog scale [VAS] for pain, VAS for satisfaction and American Shoulder and Elbow Surgeons [ASES] and Constant scores) at final follow-up were evaluated and compared with previously published minimal clinically important difference (MCID) values. Radiological outcomes were evaluated using magnetic resonance imaging or ultrasonography at a minimum 1-year follow-up. Multivariate linear regression analysis was performed to identify the risk factors for poor ASES score, and multivariate logistic regression analysis was used to assess the risk factors for retear after rRCR. Results: The mean follow-up was 26.4 months (range, 24-81 months). Although final VAS for pain, VAS for satisfaction, and ASES scores in the rRCR group were significantly worse than those in the pRCR group, the Constant score was similar between the groups. These differences in outcomes did not exceed the MCID threshold. The retear rate in the rRCR group was 50% compared with 39% for the pRCR group ( P = .194). In the rRCR group, risk factors for worse ASES score were retear ( P = .043; r = –11.3), lower body mass index ( P = .032; r = 1.9), and lower preoperative VAS for pain ( P = .038; r = 2.3), and risk factors for retear were preoperative high-grade fatty degeneration (Goutallier grades 3 and 4) of the supraspinatus muscle ( P = .026; odds ratio, 5.2) and serum hyperlipidemia ( P = .035; odds ratio, 11.8). Conclusion: Both study groups had similar clinical and radiological outcomes. Patients with symptomatic failed rotator cuff repairs having high-grade fatty degeneration of the supraspinatus muscle and/or serum hyperlipidemia had a greater likelihood of retear after rRCR.
SASH3variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation
Authors: Delmonte Ottavia M. , Bergerson Jenna R. E. , Kawai Tomoki , Kuehn Hye Sun , McDermott David H. , Cortese Irene , Zimmermann Michael T. , Dobbs A. Kerry , Bosticardo Marita , Fink Danielle , Majumdar Shamik , Palterer Boaz , Pala Francesca , Dsouza Nikita R. , Pouzolles Marie , Taylor Naomi , Calvo Katherine R. , Daley Stephen R. , Velez Daniel , Agharahimi Anahita , Myint-Hpu Katherine , Dropulic Lesia K. , Lyons Jonathan J. , Holland Steven M. , Freeman Alexandra F. , Ghosh Rajarshi , Similuk Morgan B. , Niemela Julie E. , Stoddard Jennifer , Kuhns Douglas B. , Urrutia Raul , Rosenzweig Sergio D. , Walkiewicz Magdalena A. , Murphy Philip M. , Notarangelo Luigi D. 
Published: April 2021

AbstractSterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias. Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia. Lentivirus-mediated transfer of the SASH3 complementary DNA–corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1–/– and Sly1Δ/Δ mutations, highlighting an important role of SASH3 in human lymphocyte function and survival.
A novel and highly effective mitochondrial uncoupling drug in T-cell leukemia
Authors: da Silva-Diz Victoria , Cao Bin , Lancho Olga , Chiles Eric , Alasadi Amer , Aleksandrova Maya , Luo Shirley , Singh Amartya , Tao Hanlin , Augeri David , Minuzzo Sonia , Indraccolo Stefano , Khiabanian Hossein , Su Xiaoyang , Jin Shengkan , Herranz Daniel 
Published: April 2021

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and metabolite depletion, which severely impaired nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted adenosine monophosphate–activated serine/threonine protein kinase (AMPK) activation and downregulation of mammalian target of rapamycin (mTOR) signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring either murine NOTCH1-induced primary leukemias or human T-ALL patient-derived xenografts (PDXs) led to potent antileukemic effects with a significant extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47–driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
Marginal zone B cells mediate a CD4 T-cell–dependent extrafollicular antibody response following RBC transfusion in mice
Authors: Zerra Patricia E. , Patel Seema R. , Jajosky Ryan Philip , Arthur Connie M. , McCoy James W. , Allen Jerry William Lynn , Chonat Satheesh , Fasano Ross M. , Roback John D. , Josephson Cassandra D. , Hendrickson Jeanne E. , Stowell Sean R. 
Published: April 2021

AbstractRed blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme [HEL] and ovalbumin [OVA] fused with the human RBC antigen Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they colocalize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited immunoglobulin M (IgM) and IgG anti-HOD antibody formation, whereas CD4 T-cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild-type or MZ B-cell–deficient recipients, suggesting that IgG formation is not dependent on MZ B-cell–mediated CD4 T-cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response, and no increase in antigen-specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest that MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.
Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
Authors: Schmitt Anja , Xu Wendan , Bucher Philip , Grimm Melanie , Konantz Martina , Horn Heike , Zapukhlyak Myroslav , Berning Philipp , Brändle Marc , Jarboui Mohamed-Ali , Schönfeld Caroline , Boldt Karsten , Rosenwald Andreas , Ott German , Grau Michael , Klener Pavel , Vockova Petra , Lengerke Claudia , Lenz Georg , Schulze-Osthoff Klaus , Hailfinger Stephan 
Published: April 2021

Abstract
Despite the development of novel targeted drugs, the molecular heterogeneity of diffuse large B-cell lymphoma (DLBCL) still poses a substantial therapeutic challenge. DLBCL can be classified into at least 2 major subtypes (germinal center B cell [GCB]-like and activated B cell [ABC]-like DLBCL), each characterized by specific gene expression profiles and mutation patterns. Here we demonstrate a broad antitumor effect of dimethyl fumarate (DMF) on both DLBCL subtypes, which is mediated by the induction of ferroptosis, a form of cell death driven by the peroxidation of phospholipids. As a result of the high expression of arachidonate 5-lipoxygenase in concert with low glutathione and glutathione peroxidase 4 levels, DMF induces lipid peroxidation and thus ferroptosis, particularly in GCB DLBCL. In ABC DLBCL cells, which are addicted to NF-κB and STAT3 survival signaling, DMF treatment efficiently inhibits the activity of the IKK complex and Janus kinases. Interestingly, the BCL-2–specific BH3 mimetic ABT-199 and an inhibitor of ferroptosis suppressor protein 1 synergize with DMF in inducing cell death in DLBCL. Collectively, our findings identify the clinically approved drug DMF as a promising novel therapeutic option in the treatment of both GCB and ABC DLBCLs.
The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL
Authors: Parikh Sameer A. , Rabe Kari G. , Kay Neil E. , Call Timothy G. , Ding Wei , Leis Jose F. , Kenderian Saad S. , Muchtar Eli , Wang Yucai , Koehler Amber B. , Schwager Susan M. , Lesnick Connie E. , Kleinstern Geffen , Van Dyke Daniel , Hanson Curtis A. , Braggio Esteban , Slager Susan L. , Shanafelt Tait D. 
Published: April 2021

Abstract
The utility of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI) in predicting outcomes of individuals with Rai 0 stage CLL and monoclonal B-cell lymphocytosis (MBL) is unclear. We identified 969 individuals (415 MBL and 554 Rai 0 CLL; median age, 64 years; 65% men) seen at Mayo Clinic between 1 January 2001 and 1 October 2018, and ascertained time to first therapy (TTFT) and overall survival (OS). After a median follow up of 7 years, the risk of disease progression needing therapy was 2.9%/y for MBL (median, not reached) and 5%/y for Rai 0 CLL (median, 10.4 years). Among patients with low, intermediate, and high/very high-risk CLL-IPI risk groups, the estimated 5-year risk of TTFT was 13.5%, 30%, and 58%, respectively, P&lt; .0001 (c-statistic = 0.69); and the estimated 5-year OS was 96.3%, 91.5%, and 76%, respectively, P&lt; .0001 (c-statistic = 0.65). In a multivariable analysis of absolute B-cell count with individual factors of the CLL-IPI, the absolute B-cell count was associated with shorter TTFT (hazard ratio [HR] for each 10 × 109/L increase: 1.31; P&lt; .0001) and shorter OS (HR: 1.1; P = .02). The OS of the entire cohort was similar to that of the age- and sex-matched general population of Minnesota (P = .17), although Rai 0 CLL patients with high and very high-risk CLL-IPI score had significantly shorter OS (P= .01 and P= .0001, respectively). The results of this study demonstrate the ability of CLL-IPI to predict time from diagnosis to first treatment (an end point not affected by therapy) in a large cohort of patients whose only manifestation of disease is a circulating clonal lymphocyte population.
A flexible ChIP-sequencing simulation toolkit
Authors: Zheng An , Lamkin Michael , Qiu Yutong , Ren Kevin , Goren Alon , Gymrek Melissa 
Published: April 2021

Abstract
Background
A major challenge in evaluating quantitative ChIP-seq analyses, such as peak calling and differential binding, is a lack of reliable ground truth data. Accurate simulation of ChIP-seq data can mitigate this challenge, but existing frameworks are either too cumbersome to apply genome-wide or unable to model a number of important experimental conditions in ChIP-seq.

Results
We present ChIPs, a toolkit for rapidly simulating ChIP-seq data using statistical models of key experimental steps. We demonstrate how ChIPs can be used for a range of applications, including benchmarking analysis tools and evaluating the impact of various experimental parameters. ChIPs is implemented as a standalone command-line program written in C++ and is available from https://github.com/gymreklab/chips.

Conclusions
ChIPs is an efficient ChIP-seq simulation framework that generates realistic datasets over a flexible range of experimental conditions. It can serve as an important component in various ChIP-seq analyses where ground truth data are needed.