bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia
Authors: Bourrier Nicole , Landego Ivan , Bucher Oliver , Squires Mandy , Streu Erin , Hibbert Irena , Whiteside Theresa , Gibson Spencer B. , Geirnaert Marc , Johnston James B. , Dawe David E. , Banerji Versha 
Published: February 2022

Abstract
Background
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB).

Methods
A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan–Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy.

Results
Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil.

Conclusions
In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.
Building organisations, setting minds: exploring how boards of Dutch medical specialist companies address physicians’ professional performance
Authors: Debets Maarten P. M. , Silkens Milou E. W. M. , Kruijthof Karen C. J. , Lombarts Kiki M. J. M. H. 
Published: February 2022

Abstract
Background
Governments worldwide are reforming healthcare systems to achieve high quality and safe patient care while maintaining costs. Self-employed physicians reorganise into novel organisations to meet reconfiguration demands, impacting their work environment and practice. This study explores what strategies these novel organisations use to address physicians’ professional performance and what they encounter when executing these strategies to achieve high quality and safe care.

Methods
This constructivist exploratory qualitative study used focus groups to answer our research question. Between October 2018 and May 2019, we performed eight focus group sessions with purposively sampled Medical Specialist Companies (MSCs), which are novel physician-led organisations in the Netherlands. In each session, board members of an MSC participated (n = 33).

Results
MSCs used five strategies to address physicians’ professional performance: 1) actively managing and monitoring performance, 2) building a collective mindset, 3) professionalising selection and onboarding, 4) improving occupational well-being, and 5) harmonising working procedures. The MSC’s unique context determined which strategies and quality and safety topics deserved the most attention. Physicians’ support, trusting relationships with hospital administrators, and the MSC’s organisational maturity seem critical to the quality of the strategies’ execution.

Conclusions
The five strategies have clear links to physicians’ professional performance and quality and safety. Insight into whether an MSC’s strategies together reflect medical professional or organisational values seems crucial to engage physicians and collaboratively achieve high quality and safe care.
DIX domain containing 1 (DIXDC1) modulates VEGFR2 level in vasculatures to regulate embryonic and postnatal retina angiogenesis
Authors: Kim Yeaji , Kim Dong Young , Zhang Haiying , Bae Cho-Rong , Seong Daehyeon , Kim Yeomyung , Song Jaewhan , Kim Young-Myeong , Kwon Young-Guen 
Published: February 2022

Abstract
Background
In sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ β-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ β-catenin signaling pathways.

Results
In mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/β-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis.

Conclusion
We have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.
Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases
Authors: Tarozzi M. , Bartoletti-Stella A. , Dall’Olio D. , Matteuzzi T. , Baiardi S. , Parchi P. , Castellani G. , Capellari S. 
Published: February 2022

Abstract
Background
Targeted Next Generation Sequencing is a common and powerful approach used in both clinical and research settings. However, at present, a large fraction of the acquired genetic information is not used since pathogenicity cannot be assessed for most variants. Further complicating this scenario is the increasingly frequent description of a poli/oligogenic pattern of inheritance showing the contribution of multiple variants in increasing disease risk. We present an approach in which the entire genetic information provided by target sequencing is transformed into binary data on which we performed statistical, machine learning, and network analyses to extract all valuable information from the entire genetic profile. To test this approach and unbiasedly explore the presence of recurrent genetic patterns, we studied a cohort of 112 patients affected either by genetic Creutzfeldt–Jakob (CJD) disease caused by two mutations in the PRNP gene (p.E200K and p.V210I) with different penetrance or by sporadic Alzheimer disease (sAD).

Results
Unsupervised methods can identify functionally relevant sources of variation in the data, like haplogroups and polymorphisms that do not follow Hardy–Weinberg equilibrium, such as the NOTCH3 rs11670823 (c.3837 + 21 T > A). Supervised classifiers can recognize clinical phenotypes with high accuracy based on the mutational profile of patients. In addition, we found a similar alteration of allele frequencies compared the European population in sporadic patients and in V210I-CJD, a poorly penetrant PRNP mutation, and sAD, suggesting shared oligogenic patterns in different types of dementia. Pathway enrichment and protein–protein interaction network revealed different altered pathways between the two PRNP mutations.

Conclusions
We propose this workflow as a possible approach to gain deeper insights into the genetic information derived from target sequencing, to identify recurrent genetic patterns and improve the understanding of complex diseases. This work could also represent a possible starting point of a predictive tool for personalized medicine and advanced diagnostic applications.
MCM6 versus Ki-67 in diagnosis of luminal molecular subtypes of breast cancers
Authors: Sadeghian Dorsay , Saffar Hana , Mahdavi Sharif Pouya , Soleimani Vahid , Jahanbin Behnaz 
Published: February 2022

AbstractBackgroundCurrently, breast cancers are divided into four major molecular subtypes. The distinction between the luminal A and luminal B subtypes is mainly based on the cellular proliferation indices and is assessed by the Ki-67 scoring. Due to the limitations in the assessment and expression of Ki-67, we hypothesized that minichromosome maintenance protein 6 (MCM6) might be taken as a surrogate marker to differentiate molecular subtypes and aid in more precise grading of tumors.MethodsWe performed a retrospective, cross-sectional study on 124 samples of breast cancer and 40 samples of normal breast tissue. Relevant clinical information was retrieved from the Cancer Institute database.ResultsMCM6 could discriminate between various categories of histologic grades, tubule formation, mitotic indices, and nuclear pleomorphism (P = 0.002 for tubule formation andP < 0.001 for other). Moreover, the MCM6 score exhibited a significant correlation with the mitotic count (P < 0.001). However, the Ki-67 score could not discriminate subgroups of the mitotic index and nuclear pleomorphism. Compared to the luminal A subtype, luminal B exhibited a higher MCM6 score (P = 0.01). Besides, MCM6 scores were higher for certain subtypes with more aggressive behaviors, such as hormone receptor (HR)-negative disease, and human epidermal growth factor receptor 2 (HER2)-enriched and triple-negative breast cancers, as there was a significantly higher MCM6 mean score in the HR-negative in comparison to the luminal breast cancers (P < 0.001). Similarly, higher MCM6 scores were observed among samples with more advanced nuclear grades, tubule formation, and overall grades.ConclusionMCM6 can differentiate luminal A and luminal B subtypes and is correlated with mitotic counts. However, this study was unable to prove the superiority of MCM6 in differentiating between molecular subtypes compared to the Ki-67 score. Nevertheless, in our study, MCM6 was superior to Ki-67 in exhibiting correlations with the mitotic grade, tubule formation, and nuclear grades. More studies are needed to standardize its assessment methods, determine more robust cut-off values, and evaluate its associations with prognostic features of breast cancer.
Vasospasm following low-velocity penetrating pediatric intracranial trauma
Authors: Almojuela Alysa , Kaderali Zul , McEachern James , Kazina Colin , Serletis Demitre 
Published: February 2022

Abstract
Background
BB guns or non-powder guns created in the modern era are able to reach exceedingly fast velocities as a result of advances in compressed-gas technology. While missile penetrating trauma has been well documented in neurosurgical literature, penetrating intracranial injury secondary to non-powder guns, along with their associated complications and treatments, is not well described, and even less so in the pediatric population.

Case presentation
Here, we describe an unusual case of a 6-year-old Indigenous child who was accidentally shot with a BB gun to the head. He subsequently developed delayed acute right-sided weakness due to symptomatic vasospasm. His symptoms resolved following hypertensive therapy, balloon angioplasty intervention, and intra-arterial milrinone therapy.

Conclusions
This case highlights the unique complication of delayed symptomatic vasospasm in a child following a non-missile intracranial penetrating injury. Intracranial vasospasm needs to be considered in the presence of delayed neurological deficit given its potential reversibility. This case also emphasizes the importance of gun safety and education when handling and storing these potential weapons around children.
Barriers and facilitators associated with the use of mental health services among immigrant students in high-income countries: a scoping review protocol
Authors: Dombou Christelle , Omonaiye Olumuyiwa , Fraser Sarah , Cénat Jude Mary , Yaya Sanni 
Published: February 2022

Abstract
Background
While the mental health of immigrants is a growing issue that is attracting increasing interest from researchers, the same cannot be said for the mental health of immigrant students especially for international students. Indeed, the mental health of immigrant students and their use of mental health services are still poorly documented despite the significant increase in the number of these students in many high-income countries. This scoping review aims to providing an overview and exploring gaps in existing research regarding access to mental health care among immigrant students by identifying barriers and facilitators associated with the use of mental health services in high-income countries.

Methods
With the help of a professional librarian, we will develop a search strategy including several keywords such as mental health, mental illness, immigrant, students, immigrant students, or international students and access to care or use of mental health services. The following electronic databases will be searched (from their inception onwards): MEDLINE, APA PsycINFO, CINAHL, Web of Science Core Collection, Education Source, and Embase. Studies addressing access to and use of mental health care conducted on immigrant students (adolescent and above) in high-income countries will be included. Two reviewers will independently screen all citations, full-text articles, and abstract data. A narrative summary of findings will be conducted. Data analysis will involve quantitative (e.g., frequencies) and qualitative (e.g., content and thematic analysis) methods.

Discussion
The purpose of this scoping review is to better map the literature on the mental health of immigrant students and their use of mental health care services. In doing so, we aim to identify barriers and facilitators to access and use of mental health care. Identifying barriers and facilitators of mental health services by immigrant students will support the development of appropriate interventions that can help improve access and use of mental health services by immigrant students in high-income countries.

Systematic review registration
Open Science Framework (osf.io/a2rk6)
Economic purification of recombinant uricase by artificial oil bodies
Authors: Saadat Fatemeh , Macheroux Peter , Alizadeh Houshang , Razavi Seyed Hadi 
Published: February 2022

AbstractRasburicase is an expensive treatment used to control hyperuricemia caused by tumour lysis syndrome (TLS). In this study, a non-chromatographic method was designed based on nano-oil bodies for convenient and economical purification of the recombinant uricase. For this purpose, two chimaeras were synthesized with a different arrangement of the uricase, caleosin and intein fragments. After confirming the protein expression by measuring the uricase activity at 293 nm, purification was conducted through oil-body construction. The results were resolved on the 12% SDS-PAGE gel. Finally, the stability of the oil bodies was examined against different salts, surfactants, temperatures, and pH values. According to our results, the overexpression of uricase–caleosin chimaera under the T7 promoter in Escherichia coli led to the production of soluble protein, which was successfully purified by artificial oil bodies. The active uricase was subsequently released through the self-splicing of intein. Further investigations highlighted the importance of the free C-terminus of caleosin in constructing artificial oil bodies. Moreover, surfactants and low temperature, in contrast to salts, improved the stability of oil bodies. In conclusion, caleosins are an efficient purification tag reducing the cost of purification compared to conventional chromatography methods.
Graphical Abstract
Predicting the Likelihood of Carrying a BRCA1 or BRCA2 Mutation in Asian Patients With Breast Cancer
Authors: Ang Boon Hong , Ho Weang Kee , Wijaya Eldarina , Kwan Pui Yoke , Ng Pei Sze , Yoon Sook Yee , Hasan Siti Norhidayu , Lim Joanna M.C. , Hassan Tiara , Tai Mei-Chee , Allen Jamie , Lee Andrew , Taib Nur Aishah Mohd , Yip Cheng Har , Hartman Mikael , Lim Swee Ho , Tan Ern Yu , Tan Benita K.T. , Tan Su-Ming , Tan Veronique K.M. , Ho Peh Joo , Khng Alexis J. , Dunning Alison M. , Li Jingmei , Easton Douglas F. , Antoniou Antonis C. , Teo Soo Hwang 
Published: February 2022

PURPOSE With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. METHODS In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. RESULTS Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy. CONCLUSION Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.
Levels and Correlates of Objectively Measured Sedentary Behavior in Young Children: SUNRISE Study Results from 19 Countries
Authors: KARIIPPANON KATHARINA E. , CHONG KAR HAU , JANSSEN XANNE , TOMAZ SIMONE A. , RIBEIRO EVELYN H. C. , MUNAMBAH NYARADZAI , CHAN CECILIA H. S. , CHATHURANGANA PW PRASAD , DRAPER CATHERINE E. , EL HAMDOUCHI ASMAA , FLORINDO ALEX A. , GUAN HONGYAN , HA AMY S. , HOSSAIN MOHAMMAD SOROWAR , KIM DONG HOON , VAN KIM THANH , KOH DENISE C. L. , LÖF MARIE , PHAM BANG NGUYEN , POH BEE KOON , REILLY JOHN J. , STAIANO AMANDA E. , SUHERMAN ADANG , TANAKA CHIAKI , TANG HONG KIM , TREMBLAY MARK S. , WEBSTER E. KIPLING , WICKRAMASINGHE V. PUJITHA , WONG JYH EIIN , OKELY ANTHONY D. 
Published: February 2022

ABSTRACT

Purpose
There is a paucity of global data on sedentary behavior during early childhood. The purpose of this study was to examine how device-measured sedentary behavior in young children differed across geographically, economically, and sociodemographically diverse populations, in an international sample.

Methods
This multinational, cross-sectional study included data from 1071 children 3–5 yr old from 19 countries, collected between 2018 and 2020 (pre-COVID). Sedentary behavior was measured for three consecutive days using activPAL accelerometers. Sedentary time, sedentary fragmentation, and seated transport duration were calculated. Linear mixed models were used to examine the differences in sedentary behavior variables between sex, country-level income groups, urban/rural settings, and population density.

Results
Children spent 56% (7.4 h) of their waking time sedentary. The longest average bout duration was 81.1 ± 45.4 min, and an average of 61.1 ± 50.1 min·d−1 was spent in seated transport. Children from upper-middle–income and high-income countries spent a greater proportion of the day sedentary, accrued more sedentary bouts, had shorter breaks between sedentary bouts, and spent significantly more time in seated transport, compared with children from low-income and lower-middle–income countries. Sex and urban/rural residential setting were not associated with any outcomes. Higher population density was associated with several higher sedentary behavior measures.

Conclusions
These data advance our understanding of young children’s sedentary behavior patterns globally. Country income levels and population density appear to be stronger drivers of the observed differences, than sex or rural/urban residential setting.
Curative intent Stereotactic Ablative Radiation Therapy (SABR) for treatment of lung oligometastases from head and neck squamous cell carcinoma (HNSCC): a multi-institutional retrospective study
Authors: Debbi Kamel , Loganadane Gokoulakrichenane , To Nhu Hanh , Kinj Remy , Husain Zain A , Chapet Sophie , Nguyen Nam P , Barillot Isabelle , Benezery Karen , Belkacemi Yazid , Calais Gilles 
Published: February 2022

Objectives: The aim of this retrospective study was to assess outcomes of SABR for metachronous isolated lung oligometastases from HNSCC. Methods: For patients who developed isolated, 1 or 2 lungs lesions (<5cm) consistent with metastases from HNSCC, the indication of SABR was validated in a multidisciplinary tumor board. All patients were monitored by CT or PET CT after SABR (Stereotactic Ablative Body Radiation) for HNSCC. Results: Between November 2007 and February 2018, 52 patients were treated with SABR for metachronous lung metastases. The median time from the treatment of the primary HNSCC to the development of lung metastases was 18 months (3-93). The cohort’s median age was 65.5 years old (50-83). The vast majority (94.2%) received 60 Gy in three fractions. Forty-one patients (78.5%) presented a solitary lung metastasis, while 11 patients (21.5%) had two lung metastases. With a median follow-up of 45.3 months, crude local and metastatic control rates were 74 and 38%, respectively. 1 year and 2 year Overall Survival (OS) were 85.8 and 65.9%, respectively. The median OS was 46.8 months. About one-fourth of patients were retreated by SABR for distant pulmonary recurrence. The treatment was well tolerated with only one patient who reported ≥ grade 3 toxicity (1.9%). Conclusion: In selected metastatic HNSCC patients, early detection and treatment of lung metastases with SABR is effective and safe. Prospective studies are required to validate this potential shift. Advances in knowledge: Patients with oligometastases and controlled primary HNSCC seem to benefit from metastasis directed therapies.