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Nawal Merjaneh

and 8 more

Background: Maintaining dose-dense, interval-compressed chemotherapy improves survival in Ewing sarcoma patients but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). Methods: Patients aged between 3 and 33 years with Ewing sarcoma from 2010-2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher exact test was used for univariate analysis and Pearson’s correlation coefficient was used for the association between continuous variables. Results: 27 out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significant (p value=0.056). Ten patients received romiplostim. The median starting dose was 3 (range 1-5) mcg/kg. Doses were escalated weekly by 1-2 mcg/kg to 4-10 mcg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline r= 0.73 (p=0.04). No romiplostim-related adverse events were identified aside from mild headache. Conclusions: CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy is safe and feasible, and efficacy was associated with higher romiplostim doses.
In recent decades, warming temperatures and changes in land use are supposed to have enabled several tick species to expand their distribution limit northwards. The progression of ticks to new areas may introduce new and emerging tick-borne pathogens as well as increase existing diseases. Aside from climatic conditions, ticks are dependent on hosts for survival, and rodents often act as important hosts for ticks and as pathogen reservoirs. At northern latitudes, rodents often undergo multi-annual population cycles, and the periodic absence of hosts may inhibit the further progression of ticks. We investigated the potential role of common shrews (Sorex araneus) to serve as a stable host source to immature life stages of a generalist tick Ixodes ricinus and a specialist tick I. trianguliceps, during decreasing abundances of bank voles (Myodes glareolus). We tested whether ticks would have a propensity to parasitize a certain host type dependent on host population size and composition in two high latitude locations in southern Norway, by comparing tick burdens on trapped animals. We found that I. ricinus larvae showed an equal propensity to parasitize both host types as the host population composition changed, but voles had a higher level of parasitism by nymphs (p< 0.004). An overall larger host population size favored the parasitism of voles by larvae (p= 0.027), but not by nymphs (p= 0.074). I. trianguliceps larvae showed a higher propensity to parasitize shrews, regardless of host population size or composition (p= 0.004), while nymphs parasitized shrews more as vole abundance increased (p= 0.002). The results indicate that common shrews may have the potential to act as a replacement host during periods of low rodent availability, but long-term observations encompassing complete rodent cycles may determine whether shrews are able to maintain tick range expansion despite low rodent availability.

Haibo Song

and 8 more

Drug-related adverse reactions are among the main reasons for harm to patients under care worldwide and even their deaths. The pharmacovigilance system has been proven to be an effective method of avoiding or alleviating such adverse events. In 2019, after two decades of implementation of the drug-related adverse reaction reporting system, China formally implemented a pharmacovigilance system with the Pharmacovigilance Quality Management Standards and a series of supporting technical documents created to improve the safety of medication given to patients. China’s pharmacovigilance system has faced many problems and challenges during its implementation. This spontaneous reporting system is the main source of data for China’s medication vigilance activities, but it has not provided sufficiently powerful evidence for regulatory decision-making. In conformity to the health-centered drug regulatory concept, the Chinese government has accelerated the speed of examination and approval of urgently needed clinical drugs and orphan drugs along with the requirement to improve the safety supervision of these drugs after their listing. China’s marketing authorization holders(MAHs)must strengthen its pharmacovigilance capabilities as the primary responsible department for drug safety. Chinese medical schools generally lack professional courses on pharmacovigilance. The regulatory authorities have recognized such problems and have made efforts to improve the professional capacity of pharmacovigilance personnel and to strengthen cooperation with stakeholders through the implementation of an action plan of medication surveillance and the establishment of patient-based adverse events reporting system and active surveillance systems, which will help China bridge the gap to bring its pharmacovigilance practice up to standards.

Rebecka Hansen

and 6 more

Objective:Compare the efficacy of intravenous ferric derisomaltose (FDI) with oral iron in pregnant women with persistent iron deficiency. Design:Single-centre, open-labelled, randomised controlled trial. Setting:Danish university hospital. Population:Women 14–21 weeks pregnant with persistent iron deficiency (ferritin <30 µg/L). Methods:Allocation to 1,000 mg intravenous FDI (single-dose) or 100 mg elemental oral iron daily (FA). Assessment of blood tests, patient reported outcomes (fatigue and quality of life) and adverse events throughout eighteen weeks’ follow-up. Main_outcome_measures:Proportion of non-anaemic (haemoglobin ≥11 g/dL) women throughout follow-up (primary endpoint), assessed by Kaplan-Meier estimates compared between groups by risk difference analysis. Change in haematological markers and patient reported outcomes, assessed by restricted maximum likelihood estimates compared between groups by a repeated measures mixed model. Results:From July 2017 through February 2020, 100 women were randomised to FDI and 101 to FA. In the FDI vs. FA group 89% vs. 88% were non-anaemic prior to inclusion. Throughout follow-up, 91% vs. 73% were non-anaemic in favor of FDI (18% difference, 95% CI 0.10–0.25, p<0.001). The haemoglobin least-squares mean increase was significantly greater in the FDI vs. FA group at week six (0.4 vs. -0.2 g/dL, p<0.001), twelve (0.5 vs. 0.1 g/dL, p<0.001) and eighteen (0.8 vs. 0.5 g/dL, p=0.01). Improvements in patient reported fatigue and psychological well-being were greater in the FDI group at weeks three and six. The incidence of treatment related adverse events was comparable across treatments. Conclusions:FDI was superior for avoiding anaemia compared to oral treatment, and biochemical superiority was accompanied by improved fatigue and psychological well-being.

Amna Qasim

and 7 more

Background: As pediatric implantable cardioverter defibrillator (ICD) utilization increases, hospital admission rates will increase. Data regarding hospitalizations among pediatric patients with ICDs is lacking. In addition, hospital mortality rates are unknown. This study aimed to evaluate 1) trends in hospitalization rates of admissions over 20 years, 2) hospital mortality, and 3) factors associated with hospital mortality among pediatric admissions with ICDs. Methods: The Kids’ Inpatient Database (2000-2016) was used to identify all hospitalizations with an existing ICD 20 years of age. ICD9/10 codes were used to stratify admissions by underlying diagnostic category as: 1) congenital heart disease (CHD), 2) primary arrhythmia, 3) primary cardiomyopathy, or 4) other. Trends were analyzed using linear regression. Hospital and patient characteristics among hospital deaths were compared to those surviving to discharge using mixed multivariable logistic regression, accounting for hospital clustering. Results: Of 42,570,716 hospitalizations, 4165 were admitted <21 years with an ICD. ICD admissions increased four-fold (p = 0.002) between 2000-2016. Hospital death occurred in 54 (1.3%). In multivariable analysis, cardiomyopathy (OR 3.5, 95%CI 1.1–11.2, p=0.04) and CHD (OR 4.8, 95%CI 1.5–15.6, p=0.01) were significantly associated with mortality. In further exploratory multivariable analysis incorporating a coexisting diagnosis of heart failure, only the presence of heart failure remained associated with mortality (OR 8.6, 95%CI 3.7-20.0, p<0.0001). Conclusions: Pediatric ICD hospitalization are increasing over time and hospital mortality is low (1.3%). Hospital mortality is associated with cardiomyopathy or CHD; however, the underlying driver for in-hospital death may be heart failure.

Rohit Madani

and 8 more

Introduction: A subset of patients who develop post-surgical heart block have recovery of atrioventricular-node function. Factors predicting recovery are not understood. We sought to investigate our center’s incidence of post-surgical heart block and examine factors associated with recovery of atrioventricular-node function. Methods: Patients 0 – 21 years who underwent cardiac surgery between January 2010 – December 2019 at a free-standing children’s hospital and experienced postoperative heart block were included. Demographics, clinical and operative variables were analyzed. Results: Of 6333 surgical hospitalizations, 128 (2%) patients were included. Of the 128 patients included, 90 (70%) had return of atrioventricular-node function, and 38 (30%) had permanent pacemaker placement. Of the 38 patients who underwent pacemaker placement, 6 (15.8%) had recovery of atrioventricular-node function noted on long-term follow-up. Median time to from onset of heart block to late atrioventricular-node recovery was 13 days (IQR 5 – 117). Patients with single-ventricle physiology ( p = 0.04), greater weight ( p = 0.03) and shorter cardiopulmonary bypass time ( p =0.015) were more likely to have recovery. The use of postoperative steroids was similar between all groups ( p = 0.445). Infectious or wound complications were similar between pacemaker groups ( p = 1). Conclusions: Two percent of patients who underwent cardiac surgery developed postoperative heart block, and 0.6% underwent pacemaker placement. Early recovery of atrioventricular-node was associated with greater weight at time of surgery, single-ventricle physiology and shorter cardiopulmonary bypass time. Late recovery of atrioventricular-node conduction following pacemaker placement occurred in 15.8% of patients.

Sanne Bakker

and 5 more

Liang-Cheng Xu

and 2 more

Herein, we report the mechanism of Ir(III)-catalyzed intermolecular branch-selective allylic C−H amidation, including the influence of substituent effect on yield and regioselectivity. The sequence of amidation reaction is alkene coordination, allylic C−H activation, oxidative addition of methyl dioxazolone, reductive elimination of allyl-Ir-nitrenoid complex, amine protonation and proto-demetallation. The apparent activation energy of amidation between hexene and methyl dioxazolone is 17.8 kcal/mol, and the energy difference between two transition state for formation amide is only 2.8 kcal/mol. The introduction of more electron-deficient groups at the allyl terminal increases the apparent activation energy, conversely, the introduction of electron-donating groups significantly reduces the apparent activation energy. Among them, the apparent activation energy of the reaction between aniline group substituted allyl and methyl dioxazolone is only 13.8 kcal/mol, which further improves the reaction yield. In addition, the introduction of more electron-withdrawing groups on dioxazolone can significantly improve the regioselectivity. When 3,4,5,-trifluorophenyl substituted dioxazolone and hexene occur C−N bond coupling reaction, the energy difference of the two transition states is as high as 9.0 kcal/mol, indicating that the regioselectivity is greatly improved. The mechanism explanation of allylic C−H amidation will provide strong theoretical support for streamlined synthesis of allyl branched amides.

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Sangjun Yoo

and 7 more

Introduction: We assessed the effects of preoperative bladder compliance on the long-term functional outcomes, especially focused on postoperative storage symptom changes, after laser prostatectomy. Materials and Methods: From January 2008 to March 2014, 1608 men who underwent laser prostatectomy, including holmium laser enucleation or photo-vaporization of the prostate, were included in the analysis. We divided patients into 3 groups according to bladder compliance on a baseline urodynamic study: < 12.5; 12.5–25.0; ≥25 mL/cm H2O. A multivariable analysis was performed to determine the impact of bladder compliance on long-term functional outcomes after laser prostatectomy. Results: Bladder compliance was less than 12.5 ml/cm H2O in 50 (3.1%), 12.5-25 ml/cm H2O in 232 (14.4%) patients. As bladder compliance decreased, the baseline International Prostate Symptom (I-PSS) total score and storage sub-score were increased; the voiding sub-score remain unchanged. At postoperative 36 months, improvements in the I-PSS total score and storage sub-score were significantly higher in < 12.5 mL/cm H2O group compared to other groups, although those were equivalent at postoperative 1 and 12 months. On the multivariable analysis, decreased bladder compliance < 12.5 mL/cm H2O was significantly associated with superior improvement in storage sub-score at postoperative 36 months, although it was not associated with voiding sub-score. Conclusion: In patients with preoperative bladder compliance < 12.5 mL/cm H2O, storage symptoms could be further improved at 36 months after laser prostatectomy compared to others. Thus, laser prostatectomy could be a considerable treatment option for patients with severely decreased bladder compliance

Colum Keohane

and 6 more

Abstract Objective To determine whether the introduction of a one-stop see and treat clinic offering early reflux ablation for Venous Leg Ulcer (VLU) patients in July 2016 has affected rates of unplanned inpatient admissions due to venous ulceration. Design Review of inpatient admission data and analysis of related costs. Materials The Hospital Inpatient Enquiry collects data from acute public hospitals in Ireland on admissions and discharges, coded by diagnosis and acuity. This was the primary source of all data relating to admissions and length of stay. Costs were calculated from data published by the Health Service Executive in Ireland on average costs per inpatient stay for given diagnosis codes. Methods Data were collected on admission rates, length of stay, overall bed day usage, and costs across a four-year period; the two years since the introduction of the rapid access clinic, and the two years immediately prior as a control. Results 218 patients admitted with VLUs accounted for a total of 2,529 inpatient bed-days, with 4.5(2-6) unplanned admissions, and a median hospital stay of 7(4-13) days per month. Median unplanned admissions per month decreased from 6(2.5-8.5) in the control period, to 3.5(2-5) after introduction of the clinic p=.040. Bed-day usage was significantly reduced from median 62.5(27-92.5), to 36.5(21-44) bed-days per month (p=.035), though length of stay remained unchanged (p=.57). Cost of unplanned inpatient admissions fell from median \euro33,336.25(\euro14,401.26-\euro49,337.65) per month to \euro19,468.37(\euro11,200.98-\euro22,401.96) (p=.03). Conclusions Admissions for inpatient management of VLUs have fallen after beginning aggressive endovenous treatment of venous reflux in a dedicated one-stop see-and-treat clinic for these patients. As a result, bed-day usage has also fallen, leading to cost savings.

Mürşide Zengin

and 2 more

Aim: The aim of this study was to determine the anxiety levels of parents with children aged 3-6 years due to the Coronavirus Disease-2019 (COVID-19) pandemic and to examine the effects of Solution-Focused Support Program (SFSP) applied to parents with high level of anxiety. Methods: The study was conducted as a parallel-group, randomized controlled design. The sample of the study consisted of 77 parents who were randomly assigned to the experimental and control groups (control group n = 40; intervention group n = 37). One session of online SFSP was applied to the intervention group each week and 4 sessions were applied in total. No intervention was applied to the control group. The data were collected using introductory information form and State-Trait Anxiety Inventory (STAI). Statistical Package for the Social Sciences (SPSS) programme and Analysis of Moment Structures (AMOS) 23 application were used in the analysis of the data.  Structural Equation Modeling (SEM) was used to examine a hypothesized model that SFSP has both direct and indirect effects on anxiety levels of parents.Results: The state and trait anxiety mean scores of the intervention group decreased compared to the pre-intervention mean scores after the implemented programme. While this difference between state anxiety scores was statistically significant (p≤ .001), the difference between trait anxiety scores was not statistically significant (p> .05). There was no statistically significant difference between the pre-test and post-test STAI total scores of the control group.Conclusions: In the study, it has been found that SFSP applied to parents with high level of anxiety is an effective method in reducing the state anxiety levels of parents. Clinical trial number: NCT04609722 (Registration date: 30.10.2020)

Mohammed Al-Sadawi

and 7 more

Abstract: Background: This meta-analysis assessed the relationship between Obstructive Sleep Apnea (OSA) and echocardiographic parameters of diastolic dysfunction (DD), which are used in the assessment of Heart Failure with Preserved Ejection Fraction (HFpEF). Methods: We searched the databases including Ovid MEDLINE, Ovid Embase Scopus, Web of Science, Google Scholar, and EBSCO CINAHL from inception up to December 26th, 2020. The search was not restricted to time, publication status or language. Comparisons were made between patients with OSA, diagnosed in-laboratory polysomnography (PSG) or home sleep apnea testing (HSAT), and patients without OSA in relation to established markers of diastolic dysfunction. Results: Primary search identified 2512 studies. A total of 18 studies including 2509 participants were included. The two groups were free of conventional cardiovascular risk factors. Significant structural changes were observed between the two groups. Patients with OSA exhibited greater LAVI (3.94 CI [0.8, 7.07]; p=0.000) and left ventricular mass index (11.10 CI [2.56,19.65]; p=0.000) as compared to control group. The presence of OSA was also associated with more prolonged DT (10.44 ms CI [0.71,20.16]; p=0.04), IVRT (7.85 ms CI[4.48, 11.22]; p=0.000), and lower E/A ratio (-0.62 CI [-1,-0.24]; p=0.001) suggestive of early DD. The E/e’ ratio (0.94 CI[0.44, 1.45]; p=0.000) was increased. Conclusion: An association between OSA and echocardiographic parameters of DD was detected that was independent of conventional cardiovascular risk factors. OSA may be independently associated with DD perhaps due to higher LV mass. Investigating the role of CPAP therapy in reversing or ameliorating diastolic dysfunction is recommended.

Laura Küpfer

and 6 more

Background. The treatment of childhood acute lymphoblastic leukemia (ALL) remains challenging in low-income countries. Here we evaluate the experience with a modified Berlin-Frankfurt-Münster (BFM) treatment protocol ALL-Moscow Berlin (MB)-91 at the Kantha Bopha hospitals, a charity-funded institution providing free pediatric care in Cambodia. Methods. This is a retrospective study including 110 unselected patients aged 9 months to 14 years diagnosed with ALL between 2015 and 2017. Patients were stratified in high- (HR) and standard-risk (SR) groups based on clinical criteria. The cumulative doses of anthracyclines were reduced to 120 mg/m2 for SR patients and consolidation was based on Capizzi methotrexate elements instead of cyclophosphamide, cytarabine and high dose methotrexate. Supportive empiric antibiotic treatment and whole blood transfusions were possible. Results. 63 patients (57 %) were HR, mostly based on high leukemia burden with hyperleukocytosis > 50 G/l, massive lymph node and hepato-splenic involvement, reflecting a high disease burden. 72 patients (65.5%) reached complete remission (CR) on day 36. The estimated 3-year overall survival (OS) was 34.9 %, 50.5 % for SR and 23.4 % for HR patients. Most events were due to severe infections (40 (53.3 %)) and bleeding (15 (20 %)), mostly during induction and consolidation. Relapse was confirmed in 13 cases (11.8 %). No patients abandoned treatment. Conclusion. ALL chemotherapy is feasible in a charity-funded public institution with results comparable to other low-middle income countries, but treatment-related mortality remains limiting. This will justify investments in diagnostics to stratify more patients for reduced intensity treatment and in supportive care.

Hans Fangohr

and 2 more

Guest Editors’ IntroductionNotebook interfaces – documents combining executable code with output and notes – first became popular as part of computational mathematics software such as Mathematica and Maple. The Jupyter Notebook, which began as part of the IPython project in 2012, is an open source notebook that can be used with a wide range of general-purpose programming languages.Before notebooks, a scientist working with Python code, for instance, might have used a mixture of script files and code typed into an interactive shell. The shell is good for rapid experimentation, but the code and results are typically transient, and a linear record of everything that was tried would be long and not very clear. The notebook interface combines the convenience of the shell with some of the benefits of saving and editing code in a file, while also incorporating results, including rich output such as plots, in a document that can be shared with others.The Jupyter Notebook is used through a web browser. Although it is often run locally, on a desktop or a laptop, this design means that it can also be used remotely, so the computation occurs, and the notebook files are saved, on an institutional server, a high performance computing facility or in the cloud. This simplifies access to data and computational power, while also allowing researchers to work without installing any special software on their own computer: specialized research software environments can be provided on the server, and the researcher can access those with a standard web browser from their computer.These advantages have led to the rapid uptake of Jupyter notebooks in many kinds of research. The articles in this special issue highlight this breadth, with the authors representing various scientific fields. But more importantly, they describe different aspects of using notebooks in practice, in ways that are applicable beyond a single field.We open this special issue with an invited article by Brian Granger and Fernando Perez – two of the co-founders and leaders of Project Jupyter. Starting from the origins of the project, they introduce the main ideas behind Jupyter notebooks, and explore the question of why Jupyter notebooks have been so useful to such a wide range of users. They have three key messages. The first is that Notebooks are centered around the humans using them and building knowledge with them. Next, notebooks provide a write-eval-think loop that lets the user have a conversation with the computer and the system under study, which can be turned into a persistent narrative of computational exploration. The third idea is that Project Jupyter is more than software: it is a community that is nourished deliberately by its members and leaders.The following five articles in this special issue illustrate the key features of Project Jupyter effectively. They show us a small sample of where researchers can go when empowered by the tool, and represent a range of scientific domains.Stephanie Juneau et al. describe how Jupyter has been used to ‘bring the compute to the data’ in astrophysics, allowing geographically distributed teams to work efficiently on large datasets. Their platform is also used for education & training, including giving school students a realistic taste of modern science.Ryan Abernathey et al. , of the Pangeo project, present a similar scenario with a focus on data from the geosciences. They have enabled analysis of big datasets on public cloud platforms, facilitating a more widely accessible ‘pay as you go’ style of analysis without the high fixed costs of buying and setting up powerful computing and storage hardware. Their discussion of best practices includes details of the different data formats required for efficient access to data in cloud object stores rather than local filesystems.Marijan Beg et al. describe features of Jupyter notebooks and Project Jupyter that help scientists make their research reproducible. In particular, the work focuses on the use of computer simulation and mathematical experiments for research. The self-documenting qualities of the notebook—where the response to a code cell can be archived in the notebook—is an important aspect. The paper addresses wider questions, including use of legacy computational tools, exploitation of HPC resources, and creation of executable notebooks to accompany publications.Blaine Mooers describes the use of a snippet library in the context of molecular structure visualization. Using a Python interface, the PyMOL visualization application can be driven through commands to visualize molecular structures such as proteins and nucleic acids. By using those commands from the Jupyter notebook, a reproducible record of analysis and visualizations can be created. The paper focuses on making this process more user-friendly and efficient by developing a snippet library, which provides a wide selection of pre-composed and commonly used PyMOL commands, as a JupyterLab extension. These commands can be selected via hierarchical pull-down menus rather than having to be typed from memory. The article discusses the benefits of this approach more generally.Aaron Watters describes a widget that can display 3D objects using webGL, while the back-end processes the scene using a data visualization pipeline. In this case, the front-end takes advantage of the client GPU for visualization of the widget, while the back-end takes advantage of whatever computing resources are accessible to Python.The articles for this special issue were all invited submissions, in most cases from selected presentations given at JupyterCon in October 2020. Each article was reviewed by three independent reviewers. The guest editors are grateful to Ryan Abernathey, Luca de Alfaro, Hannah Bruce MacDonald, Christopher Cave-Ayland, Mike Croucher, Marco Della Vedova, Michael Donahue, Vidar Fauske, Jeremy Frey, Konrad Hinsen, Alistair Miles, Arik Mitschang, Blaine Mooers, Samual Munday, Chelsea Parlett, Prabhu Ramachandran, John Readey, Petr Škoda and James Tocknell for their work as reviewers, along with other reviewers who preferred not to be named. The article by Brian Granger and Fernando Perez was invited by the editor in chief, and reviewed by the editors of this special issue.Hans Fangohr is currently heading the Computational Science group at the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and is a Professor of Computational Modelling at the University of Southampton, UK. A physicist by training, he received his PhD in Computer Science in 2002. He authored more than 150 scientific articles in computational science and materials modelling, several open source software projects, and a text book on Python for Computational Science and Engineering. Contact him at hans.fangohr@mpsd.mpg.deThomas Kluyver is currently a software engineer at European XFEL. Since gaining a PhD in plant sciences from the University of Sheffield in 2013, he has been involved in various parts of the open source & scientific computing ecosystems, including the Jupyter & IPython projects. Contact him at thomas.kluyver@xfel.euMassimo Di Pierro is a Professor of Computer Science at DePaul University. He has a PhD in Theoretical Physics from the University of Southampton and is an expert in Numerical Algorithms, High Performance Computing, and Machine Learning. Massimo is the lead developer of many open source projects including web2py, py4web, and pydal. He has authored more than 70 articles in Physics, Computer Science, and Finance and has published three books. Contact him at

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