bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osimertinib combined with bevacizumab for leptomeningeal metastasis from EGFR‐mutation non‐small cell lung cancer: A phase II single‐arm prospective clinical trial
Authors: Lu Zhi‐qin , Cai Jing , Wang Xia , Wei Jian‐ping , Zeng Zhi‐min , Huang Long , Liu An‐wen 
Published: November 2020

BackgroundLeptomeningeal metastasis (LM) is associated with poor prognosis in non‐small cell lung cancer (NSCLC). The aim of this study was to investigate the efficacy and safety of osimertinib combined with bevacizumab for LM from epidermal growth factor receptor mutation (EGFRm) NSCLC.MethodsWe conducted a phase II single‐arm prospective clinical trial of EGFRm NSCLC with LM treated with osimertinib combined with bevacizumab. LM response assessment was based on the modified RANO LM radiological criteria; CNS and extra‐CNS response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary end points included LM progression‐free survival (PFS) and objective response rate (ORR); the secondary end points included safety and LM overall survival (OS).ResultsA total of 14 patients were included in the study, with a median age of 61 years, and they were predominantly female (64%). EGFR mutations were reported in exons 19 del (n = 7) and 21 L858R (n = 7). When LM was diagnosed, 12 (85.7%) patients had clinical symptoms, 71.4% (10/14) of patients were diagnosed with LM by cytology, and five (35.7%) patients had a performance status (PS) score > 2. The median LM PFS was 9.3 months (95% CI: 8.2–10.4), and the LM ORR was 50%. The safety findings in the present study were consistent with the known profile of osimertinib with bevacizumab; the median LM OS was 12.6 months, and the one‐year survival rate was 35.7%.ConclusionsOsimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC.Key pointsSignificant findings of the studyTo date, there is no prospective clinical study on the treatment of osimertinib combined with bevacizumab in EGFRm NSCLC with LM.What this study addsThe median LM PFS was 9.3 months (95% CI: 8.2–10.4), and the LM ORR was 50%, the median LM OS was 12.6 months, and the one‐year survival rate was 35.7%. Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC.
Risks and Benefits of Initial Coin Offerings: Evidence from impak Finance, a Regulated ICO*
Authors: Boulianne Emilio , Fortin Mélissa 
Published: November 2020

ABSTRACTThis study provides a better understanding of the business and the regulated environment surrounding initial coin offerings (ICOs). An ICO is a call for funding to raise funds through a blockchain, where cryptoassets are issued. Key stakeholders involved are the firms launching ICOs, the investors, and the financial regulators. We conducted a case study of a firm that launched an ICO, impak Finance, the first regulated ICO in Canada. Based on the interviews of key respondents, we developed a framework identifying the main risks and benefits for firms to performing an ICO, showing differences between unregulated and regulated ICOs. Our study makes a number of research and practical contributions. First, we document the case of the first regulated ICO in Canada. The interviews conducted provided access to privileged insider information. Second, very few studies have been conducted on the impact of blockchains as a financing vehicle. ICOs using blockchains may be disruptive not only from a technology standpoint but also from a financial standpoint. While the possible applications of blockchains are unknown to us to date, we do know that blockchains have the potential to challenge the traditional financial system monitored by financial regulators. Last, the study identifies, through a framework, the risks and benefits of performing an ICO in an unregulated versus a regulated context, which has practical implications for firms operating in the fintech space. We trust that this framework will be useful for firms using ICOs, for investors, and for financial regulators.
Effect of Using an Age‐adjusted D‐dimer to Assess for Pulmonary Embolism in Community Emergency Departments
Authors: Ghobadi Ali , Lin Bryan , Musigdilok Visanee V. , Park Stacy J. , Palmer‐Toy Darryl E. , Gould Michael K. , Vinson David R. , Hutchison Dana M. , Sharp Adam L. 
Published: November 2020

AbstractBackgroundThe objective of this study was to evaluate the effect of changing the laboratory‐reported D‐dimer reference intervals to age‐adjusted reference intervals on the use of advanced chest imaging and 30‐day adverse events among emergency department (ED) encounters.MethodsA retrospective interrupted time‐series analysis of ED encounters for patients > 50 years evaluated for suspected pulmonary embolism (PE) from April 2014 to April 2016. The primary outcome was use of advanced diagnostic imaging, and the secondary outcome was 30‐day mortality or PE diagnosis. Secondary analyses also quantified delayed PE diagnoses pre‐ and postintervention. A generalized estimating equation segmented logistic regression model, adjusting for patient and facility characteristics, was used to determine changes in odds of diagnostic imaging and 30‐day mortality or PE diagnoses.ResultsA total of 10,534 (5,153 pre‐ and 5,381 postimplementation) ED encounters were included. Advanced imaging was obtained in 35.9% of pre‐ versus 33% of postimplementation encounters. Age‐adjusted D‐dimer (AADD) showed a small and nonsignificant decrease in month‐to‐month trends of advanced chest imaging postimplementation (odds ratio [OR] = 0.98, 95% confidence interval [CI] = 0.96 to 1.00). Use of advanced imaging in patients with D‐dimer values lower than 500 ng/mL fibrinogen‐equivalent units (FEU) was similar in the preintervention (5.8%) and postintervention (6.8%) periods. However, imaging was obtained in 30% of patients postintervention with a D‐dimer result less than AADD reference interval , but more than the historical 500 ng/mL FEU reference interval. Implementing an AADD threshold demonstrated no change in the rate of 30‐day adverse events (missed PE or mortality).ConclusionChanging the laboratory‐reported D‐dimer reference intervals for evaluation of PE was not associated with reduction in advanced chest imaging and did not increase 30‐day adverse events. However, there was substantial noncompliance with the age‐adjusted reference intervals in the postintervention period likely blunting the impact of this intervention.
Social media reveals consistently disproportionate tourism pressure on a threatened marine vertebrate
Authors: Papafitsoros K. , Panagopoulou A. , Schofield G. 
Published: November 2020

AbstractEstablishing how wildlife viewing pressure is distributed across individual animals within a population can inform the management of this activity, and ensure targeted individuals or groups are sufficiently protected. Here, we used social media data to quantify whether tourism pressure varies in a loggerhead sea turtle Caretta caretta population and elucidate the potential implications. Laganas Bay (Zakynthos, Greece) supports both breeding (migratory, and hence transient) and foraging (resident) turtles, with turtle viewing representing a major component of the tourism industry. Social media entries spanning two seasons (April to November, 2018 and 2019) were evaluated, and turtles were identified via photo‐identification. For the 2 years, 1684 and 2105 entries of 139 and 122 unique turtles were obtained from viewings, respectively (boats and underwater combined). However, while residents represented less than one‐third of uniquely identified turtles, they represented 81.9 and 87.9% of all entries. Even when the seasonal breeding population was present (May to July), residents represented more than 60% of entries. Notably, the same small number of residents (<10), mostly males, were consistently viewed in both years; however, different individuals were targeted by boats versus underwater. Thus, turtles appear to remain in the area despite high viewing intensity, possibly indicating low disturbance. However, photo‐identification records revealed a high risk of propeller and boat strike to residents (30%) leading to trauma and mortality. To reduce this threat, we recommend the compulsory use of propeller guards for all boats, compliance with speed regulations and the creation of temporary ‘refuge’ zones for resident animals at viewing hotspots, with these suggestions likely being relevant for other wildlife with similar population dynamics. In conclusion, social media represents a useful tool for monitoring individuals at a population scale, evaluating the pressure under which they are placed, and providing sufficient data to refine wildlife viewing guidelines and/or zoning.
Impact of policy changes on the provision of naloxone by pharmacies in Ontario, Canada: a population‐based time–series analysis
Authors: Antoniou Tony , Martins Diana , Campbell Tonya , Tadrous Mina , Munro Charlotte , Leece Pamela , Mamdani Muhammad , Juurlink David N. , Gomes Tara 
Published: November 2020

AbstractBackground and aimsIn June 2016, the Ontario, Canada government implemented the Ontario Naloxone Program for Pharmacies (ONPP), authorizing pharmacists to provide injectable naloxone kits at no charge to all Ontario residents. In March 2018, the program was amended to include intranasal naloxone and remove the requirement to present a government health card to the dispensing pharmacist. We examined whether these changes increased naloxone dispensing through the ONPP.DesignPopulation‐based time–series analysis using interventional autoregressive integrated moving average models.SettingOntario, Canada.ParticipantsAll Ontario residents between 1 July 2016 and 31 March 2020.MeasurementsMonthly rates of pharmacy naloxone dispensing.FindingsOverall, 199 484 individuals were dispensed a naloxone kit during the study period. In the main analysis, the rate of pharmacy naloxone dispensing increased by 65.1% following program changes (55.6–91.8 kits per 100 000 population between February 2018 and May 2018; P = 0.01). In subgroup analyses, naloxone dispensing increased among individuals receiving opioid agonist therapy (OAT) (3374.9–7264.2 kits per 100 000 OAT recipients; P = 0.04) among individuals receiving other prescription opioids (192.8–381.8 kits per 100 000 population prescribed opioids; P < 0.01), among individuals with past opioid exposure (134.7–205.6 kits per 100 000 population with past opioid exposure; P < 0.01) and in urban centers (56.2–91.4 kits per 100 000 population; P < 0.01). We did not observe a clear impact on pharmacy‐dispensed naloxone to individuals with no or unknown opioid exposure (34.4–39.3 kits per 100 000 population with no/unknown opioid exposure; P = 0.42) and in rural regions (50.4–97.2 kits per 100 000 population; P = 0.09).ConclusionsChanges to the Ontario Naloxone Program for Pharmacies to add intranasal naloxone and remove the requirement to present a government health card appeared to increase pharmacy‐based naloxone dispensing uptake in Ontario, Canada, particularly among individuals at high risk of inadvertent opioid overdose.
Phenotype and biological characteristics of endometrial mesenchymal stem/stromal cells: A comparison between intrauterine adhesion patients and healthy women
Authors: Min Jiali , Lu Na , Huang Shengjian , Chai Xiahua , Wang Susu , Peng Lin , Wang Jian 
Published: November 2020

AbstractProblemIntrauterine adhesion (IUA) is a uterine disorder with partial or total obstruction of the uterine cavity and/or the cervical canal primarily caused by intrauterine operations and infections. It is the most common cause of uterine infertility and recurrent abortion. However, the reasons for endometrium repair disorders in patients with IUA are still unclear. While increasing evidence demonstrates that endometrial mesenchymal stem/stromal cells (EMSCs) contribute to the regeneration and repair of endometrium, the roles of EMSCs in the pathogenesis of IUA have not been reported.Methods and studyWe investigated the differences of phenotype and biological characteristics between EMSCs from women with IUA and healthy women. Firstly, the fibrosis of endometrium were measured by immunohistochemistry and Masson staining. Second, we used immunofluorescence to detect the location of EMSCs in endometrial tissue, and the proportion of CD146+CD140b+ in the two groups was compared by flow cytometry. Then, plate colony formation experiment, CCK‐8 assay, flow cytometry, would‐healing assay, and transwell invasion experiment were used to compare the cloning ability, proliferation, cell cycle, migration and invasion capabilities respectively. Finally, we compared the potential angiogenesis and immunosuppression capabilities.ResultsOur results showed that there were fewer CD146+CD140b+ cells in patients with IUA, and the clone‐forming, migration, invasion, angiogenic and immunosuppressive abilities of the EMSCs of patients with IUA were significantly decreased compared with those of healthy women.ConclusionThere are some differences between the EMSCs of IUA patients and healthy women, which may be related to the occurrence of IUA and dysfunction of endometrium.
The impact of the origin of surgical sperm retrieval on placental and embryonic development: The Rotterdam Periconception cohort
Authors: Hoek Jeffrey , Boellaard Willem P. A. , van Marion Eva S. , Willemsen Sten P. , Baart Esther.B. , Steegers‐Theunissen Régine P. M. , Schoenmakers Sam 
Published: November 2020

AbstractBackgroundIn patients with azoospermia, pregnancy can be achieved after surgical techniques using sperm retrieved from the testis or epididymis, which can impact on DNA integrity and epigenetics. DNA of the fetus and placenta is equally derived from both parents; however, genes important for placental development are expressed from the paternal alleles. Therefore, the origin of sperm may affect fetal and placental development.ObjectivesTo investigate whether first‐trimester trajectories of embryonic and placental development of pregnancies conceived after intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA), are different from pregnancies after ICSI with ejaculated sperm or natural conceptions.Materials and methodsA total of 147 singleton ICSI pregnancies, including pregnancies conceived after TESE (n = 23), MESA (n = 25) and ejaculated sperm (n = 99), and 380 naturally conceived and 140 after IVF treatment without ICSI were selected from the prospective Rotterdam periconception cohort. Crown‐rump length (CRL), embryonic volume (EV), Carnegie stages, and placental volume (PV) at 7, 9, and 11 weeks of gestation were measured using 3D ultrasound and virtual reality technology.ResultsLinear mixed model analysis showed no differences in trajectories of CRL, EV, and Carnegie stages between pregnancies conceived after ICSI with testicular, epididymal, and ejaculated sperm. A significantly positive association was demonstrated for PV between pregnancies conceived after TESE‐ICSI (adjusted beta: 0.28(95%CI: 0.05‐0.50)) versus ICSI with ejaculated sperm. Retransformation to original values showed that the PV of pregnancies after TESE‐ICSI is 14.6% (95%CI: 1.4%‐25.5%) larger at 11 weeks of gestation compared to ICSI pregnancies conceived with ejaculated sperm.Discussion and ConclusionHere we demonstrate that the first‐trimester growth trajectory of the placenta is increased in pregnancies conceived after TESE‐ICSI compared to those conceived after ICSI with ejaculated sperm. Findings are discussed in the light of known differences in sperm DNA integrity, epigenetics, and placental gene expression.
Longitudinal versus transverse incision for common femoral artery exposure: a systematic review and meta‐analysis
Authors: Ng Jun Jie , Tan Jarrod K. H. , Lee James W. K. , Choong Andrew M. T. L. 
Published: November 2020

AbstractBackgroundA longitudinal or a transverse incision is routinely used for common femoral artery (CFA) exposure. Some believe a transverse incision is associated with a lower incidence of postoperative complications. We performed a systematic review and meta‐analysis to evaluate the risk of postoperative surgical site infection, lymphatic complications, wound dehiscence and haematoma formation when using a longitudinal or transverse incision for CFA exposure.MethodsPreferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines were adhered to. We searched various databases such as MEDLINE via PubMed and Embase for relevant studies from inception till 31 May 2020. Relevant search terms such as ‘longitudinal’, ‘transverse’, ‘vertical’, ‘horizontal’, ‘femoral’, ‘incision’ were used. We included both randomized controlled trials and case‐controlled studies, and extracted data related to study characteristics and postoperative complications. We assessed risk of bias using the Cochrane risk of bias tool and the Newcastle‐Ottawa scale. A random‐effects meta‐analysis was performed to obtain the pooled proportions and risk ratios (RR) for our study outcomes.ResultsWe included seven studies with a total of 5922 groin incisions. A longitudinal incision was associated with a significantly higher incidence of wound infection (RR 2.93, 95% confidence interval (CI) 1.12–7.70, P = 0.03) and wound dehiscence (RR 2.87, 95% CI 1.06–7.77, P = 0.04). The risk of lymphatic complications (RR 1.09, 95% CI 0.39–3.05, P = 0.87) and wound haematoma (RR 2.85, 95% CI 0.88–9.21, P = 0.08) were similar.ConclusionsA longitudinal incision may be associated with a higher incidence of wound infection and wound dehiscence, as compared to using a transverse incision for CFA exposure.
Severe congenital neutropenia‐associated JAGN1 mutations unleash a calpain‐dependent cell death programme in myeloid cells
Authors: Khandagale Avinash , Holmlund Teresa , Entesarian Miriam , Nilsson Daniel , Kalwak Krzysztof , Klaudel‐Dreszler Maja , Carlsson Göran , Henter Jan‐Inge , Nordenskjöld Magnus , Fadeel Bengt 
Published: November 2020

SummarySevere congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life‐threatening infections. Using whole‐exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann‐like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL‐60 as a model, we found that overexpression of patient‐derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro‐apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium‐dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN‐associated JAGN1 mutations unleash a calcium‐ and calpain‐dependent cell death in myeloid cells.
Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib
Authors: Castillo Jorge J. , Abeykoon Jithma P. , Gustine Joshua N. , Zanwar Saurabh , Mein Kirsten , Flynn Catherine A. , Demos Maria G. , Guerrera Maria L. , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nickolas , King Rebecca , Yang Guang , Hunter Zachary R. , Advani Ranjana H. , Palomba Maria Lia , Ansell Stephen M. , Gertz Morie A. , Kapoor Prashant , Treon Steven P. 
Published: November 2020

SummaryIbrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six monthsversusnot were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38;P = 0·01] and validation cohorts (HR 0·18;P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.
Gastric cancer–secreted exosomal X26nt increases angiogenesis and vascular permeability by targeting VE‐cadherin
Authors: Chen Xiaocui , Zhang Shuqiong , Du Kun , Zheng Naisheng , Liu Yi , Chen Hui , Xie Guohua , Ma Yanhui , Zhou Yunlan , Zheng Yingxia , Zeng Lingfang , Yang Junyao , Shen Lisong 
Published: November 2020

AbstractAngiogenesis is closely associated with tumorigenesis, invasion, and metastasis by providing oxygen and nutrients. Recently, increasing evidence indicates that cancer‐derived exosomes which contain proteins, coding, and noncoding RNAs (ncRNAs) were shown to have proangiogenic function in cancer. A 26‐nt‐long ncRNA (X26nt) is generated in the process of inositol‐requiring enzyme 1 alpha (IRE1α)‐induced unspliced XBP1 splicing. However, the role of X26nt in the angiogenesis of gastric cancer (GC) remains largely unknown. In the present study, we found that X26nt was significantly elevated in GC and GC exosomes. Then, we verified that X26nt could be delivered into human umbilical vein endothelial cells (HUVECs) via GC cell exosomes and promote the proliferation, migration, and tube formation of HUVECs. We revealed that exosomal X26nt decreased vascular endothelial cadherin (VE‐cadherin) by directly combining the 3′UTR of VE‐cadherin mRNA in HUVECs, thereby increasing vascular permeability. We further demonstrated that X26nt accelerates the tumor growth and angiogenesis in a mouse subcutaneous tumor model. Our findings investigate a unique intercellular communication mediated by cancer‐derived exosomes and reveal a novel mechanism of exosomal X26nt in the regulation of tumor vasculature.