bluuebunny/crossref_metadata_2025_split huggingface dataset:
Streamlining the institutional review board process in pragmatic randomized clinical trials: challenges and lessons learned from the Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) trial
Authors: Marquis-Gravel Guillaume , Robertson Holly , Jones W. Schuyler , Riley Danielle , Ford Daniel E. , Crenshaw David , Joosten Yvonne A. , Rudov Lindsey , Hernandez Adrian F. , Hess Rachel 
Published: January 2021

Abstract
Background
New considerations during the ethical review processes may emerge from innovative, yet unfamiliar operational methods enabled in pragmatic randomized controlled trials (RCT), potentially making institutional review board (IRB) evaluation more complex. In this manuscript, key components of the pragmatic “Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE)” randomized trial that required a reappraisal of the IRB submission, review, and approval processes are discussed.

Main text
ADAPTABLE is a pragmatic, multicenter, open-label RCT evaluating the comparative effectiveness of two doses of aspirin widely used for secondary prevention (81 mg and 325 mg) in 15,000 patients with an established history of atherosclerotic cardiovascular disease. The electronic informed consent form is completed online by the participants at the time of enrollment, and endpoint ascertainment is conducted through queries of electronic health records.
IRB challenges encountered regarding centralized IRB evaluation, electronic informed consent, patient engagement, and risk determination in ADAPTABLE are described in this manuscript. The experience of ADAPTABLE encapsulates how pragmatic protocol components intended to facilitate the study conduct have been tempered by unexpected, yet justified concerns raised by local IRBs. How the lessons learned can be applied to future similar pragmatic trials is delineated.

Conclusion
Development of engaging communication channels between IRB and study personnel in pragmatic randomized trials as early as at the time of protocol design allows to reduce issues with IRB approval. Integrations of the lessons learned in ADAPTABLE regarding the IRB process for centralized IRBs, informed consent, patient engagement, and risk determination can be emulated and will be instrumental in future pragmatic studies.
Evaluating the effect of immersive virtual reality technology on gait rehabilitation in stroke patients: a study protocol for a randomized controlled trial
Authors: Cai Huihui , Lin Tao , Chen Lina , Weng Huidan , Zhu Ruihan , Chen Ying , Cai Guoen 
Published: January 2021

Abstract
Background
The high incidence of cerebral apoplexy makes it one of the most important causes of adult disability. Gait disorder is one of the hallmark symptoms in the sequelae of cerebral apoplexy. The recovery of walking ability is critical for improving patients’ quality of life. Innovative virtual reality technology has been widely used in post-stroke rehabilitation, whose effectiveness and safety have been widely verified. To date, however, there are few studies evaluating the effect of immersive virtual reality on stroke-related gait rehabilitation. This study outlines the application of immersive VR-assisted rehabilitation for gait rehabilitation of stroke patients for comparative evaluation with traditional rehabilitation.

Methods
The study describes a prospective, randomized controlled clinical trial. Thirty-six stroke patients will be screened and enrolled as subjects within 1 month of initial stroke and randomized into two groups. The VRT group (n = 18) will receive VR-assisted training (30 min) 5 days/week for 3 weeks. The non-VRT group (n = 18) will receive functional gait rehabilitation training (30 min) 5 days/week for 3 weeks. The primary outcomes and secondary outcomes will be conducted before intervention, 3 weeks after intervention, and 6 months after intervention. The primary outcomes will include time “up & go” test (TUGT). The secondary outcomes will include MMT muscle strength grading standard (MMT), Fugal-Meyer scale (FMA), motor function assessment scale (MAS), improved Barthel index scale (ADL), step with maximum knee angle, total support time, step frequency, step length, pace, and stride length.

Discussion
Virtual reality is an innovative technology with broad applications, current and prospective. Immersive VR-assisted rehabilitation in patients with vivid treatment scenarios in the form of virtual games will stimulate patients’ interest through active participation. The feedback of VR games can also provide patients with performance awareness and effect feedback, which could be incentivizing. This study may reveal an improved method of stroke rehabilitation which can be helpful for clinical decision-making and future practice.

Trial registration
Chinese Clinical Trial Registry ChiCTR1900025375. Registered on 25 August 2019
Global distribution, host range and prevalence of Trypanosoma vivax: a systematic review and meta-analysis
Authors: Fetene Eyerusalem , Leta Samson , Regassa Fikru , Büscher Philippe 
Published: January 2021

AbstractBackgroundTrypanosomosis caused byTrypanosoma vivaxis one of the diseases threatening the health and productivity of livestock in Africa and Latin America.Trypanosoma vivaxis mainly transmitted by tsetse flies; however, the parasite has also acquired the ability to be transmitted mechanically by hematophagous dipterans. Understanding its distribution, host range and prevalence is a key step in local and global efforts to control the disease.MethodsThe study was conducted according to the methodological recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. A systematic literature search was conducted on three search engines, namely PubMed, Scopus and CAB Direct, to identify all publications reporting natural infection ofT. vivaxacross the world. All the three search engines were screened using the search termTrypanosoma vivaxwithout time and language restrictions. Publications onT. vivaxthat met our inclusion criteria were considered for systematic review and meta-analysis.ResultThe study provides a global database ofT. vivax, consisting of 899 records from 245 peer-reviewed articles in 41 countries. A total of 232, 6277 tests were performed on 97 different mammalian hosts, including a wide range of wild animals. Natural infections ofT. vivaxwere recorded in 39 different African and Latin American countries and 47 mammalian host species. All the 245 articles were included into the qualitative analysis, while information from 186 cross-sectional studies was used in the quantitative analysis mainly to estimate the pooled prevalence. Pooled prevalence estimates ofT. vivaxin domestic buffalo, cattle, dog, dromedary camel, equine, pig, small ruminant and wild animals were 30.6%, 6.4%, 2.6%, 8.4%, 3.7%, 5.5%, 3.8% and 12.9%, respectively. Stratified according to the diagnostic method, the highest pooled prevalences were found with serological techniques in domesticated buffalo (57.6%) followed by equine (50.0%) and wild animals (49.3%).ConclusionThe study provides a comprehensive dataset on the geographical distribution and host range ofT. vivaxand demonstrates the potential of this parasite to invade other countries out of Africa and Latin America.Graphical Abstract
Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus paclitaxel therapy trial
Authors: Kim Seung Tae , Sa Jason K. , Oh Sung Yong , Kim Kyung , Hong Jung Yong , Kang Won Ki , Kim Kyoung-Mee , Lee Jeeyun 
Published: January 2021

Abstract
Background
Gastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents.

Methods
We conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment.

Results
Sixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6–47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(−) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity.

Conclusions
Prospective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer.

Trial registration
The study was registered on ClinicalTrial.gov (NCT02628951) on June 12, 2015.
A bioavailable form of curcumin, in combination with vitamin-D- and omega-3-enriched diet, modifies disease onset and outcomes in a murine model of collagen-induced arthritis
Authors: Hemshekhar Mahadevappa , Anaparti Vidyanand , El-Gabalawy Hani , Mookherjee Neeloffer 
Published: January 2021

AbstractObjectiveCurcumin (CUR), vitamin D3(D3), and omega-3-fatty acids (O3FA) individually modulate inflammation and pain in arthritis. Although these supplements are widely used, their combinatorial effects have not been defined. In this study, we examined the effects of a D3 and O3FA (VO)-enriched diet in conjunction with a highly bioavailable form of CUR (Cureit/Acumin™) in a collagen-induced arthritis (CIA) murine model.MethodsMale DBA/1J mice were acclimatized to VO-enriched diet and challenged with bovine collagen II (CII). Bioavailable CUR was administered daily by oral gavage from the onset of CII challenge. Disease severity was determined by monitoring joint thickness and standardized clinical score. Cellular infiltration and cartilage degradation in the joints were assessed by histology, serum cytokines profiled by Meso Scale Discovery multiplex assay, and joint matrix metalloproteinases examined by western blots.ResultsCUR by itself significantly decreased disease severity by ~ 60%. Administration of CUR in CIA mice taking a VO-enriched diet decreased disease severity by > 80% and maximally delayed disease onset and progression. Some of the disease-modifying effects was mediated by CUR alone, e.g., suppression of serum anti-collagen antibodies and decrease of cellular infiltration and MMP abundance in the joints of CIA mice. Although CUR alone suppressed inflammatory cytokines in serum of CIA mice, the combination of CUR and VO diet significantly enhanced the suppression (> 2-fold compared to CUR) of TNF, IFN-γ, and MCP-1, all known to be associated with RA pathogenesis.ConclusionThis study provides proof-of-concept that the combination of bioavailable CUR, vitamin D3, and O3FA substantially delays the development and severity of CIA. These findings provide a rationale for systematically evaluating these widely available supplements in individuals at risk for developing future RA.
Supplementing wastewater with NPK fertilizer as a cheap source of nutrients in cultivating live food (Chlorella vulgaris)
Authors: Mtaki Kulwa , Kyewalyanga Margareth S. , Mtolera Matern S. P. 
Published: January 2021

AbstractIntroductionThe decline in fishery resources from the wild has led to an ever increasing focus on aquaculture in recent years. With increasing aquaculture of animal species, there is an increasing need for suitable microalgae in the production of these animals. However, cultivation of microalgae in expensive pure chemical media is one of the major challenges facing large-scale cultivation of microalgae.PurposeThe present study investigated the suitability of aquaculture wastewater (AWW) supplemented with NPK (nitrogen:phosphorus:potassium) fertilizer as a cheap source of nutrient to cultivate a microalgaChlorella vulgaris(C. vulgaris).MethodsC. vulgariswith an initial cell density of 0.8 × 106cells/mL was batch cultured in AWW supplemented with NPK at 0.1, 0.5, 1.0 g/L and BBM for 20 days under laboratory conditions using 2000 mL Erlenmeyer flasks. The proximate composition, chlorophyll, minerals, and vitamins analysis ofC. vulgarisbiomass were done using standard analytical methods.ResultsThe highest values in optical density (4.872 ± 0.025), dry cell weight (2.858 ± 0.015 g/L), specific growth rate (0.2097 ± 0.0038 day–1), and biomass productivity (0.1701 ± 0.0007 g/L/day) were obtained inC. vulgarisgrown in AWW + 1.0 NPK medium. The total chlorophyll, protein, lipid, and carbohydrate content of the microalgae biomass were in the range of 0.05–0.862%, 44.062–57.089%, 17.064–23.260%, and 15.217–21.896%, respectively. Furthermore, microalgae grown in AWW + 1.0 NPK showed good vitamin and mineral content compared to BBM grown alga.ConclusionThese findings indicated that the AWW + 0.1 NPK, AWW + 0.5 NPK, and AWW + 1.0 NPK are potential growth media forC. vulgariscultivation and can replace the BBM medium, which is very expensive and less accessible to users.
Systemic lupus erythematosus manifestation following COVID-19: a case report
Authors: Zamani Batool , Moeini Taba Seyed-Masoud , Shayestehpour Mohammad 
Published: January 2021

Abstract
Background
Systemic lupus erythematosus (SLE) is a complex and challenging autoimmune disease. Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a novel viral agent that can cause a life-threatening respiratory disorder named coronavirus disease 2019 (COVID‑19). Association between SARS‑CoV‑2 and SLE is not clear. We reported the first case of SLE manifestation following COVID-19.

Case presentation
A 39-year-old Iranian/Persian man with complaints of fever, scaling on the palms of the hands and feet, lower extremity edema, and ankle swelling was referred to Kashan Rheumatology Clinic in 2020. He was infected with SARS-CoV-2 2 months ago. The patient had proteinuria and was positive for SLE laboratory tests. After one week of treatment with prednisolone (30 mg daily) and hydroxychloroquine, paresthesia, proteinuria, and edema continued. The patient was treated with pulse methylprednisolone (1000 mg for three consecutive days), gabapentin, and vitamin B (300 mg daily), which reduced paresthesia.

Conclusions
This is the first case of SLE manifestation following COVID-19. SARS-CoV-2 may produce autoantibodies or develop the clinical features of subclinical SLE.
Advancements in stem cell-derived hepatocyte-like cell models for hepatotoxicity testing
Authors: Jin Meixian , Yi Xiao , Liao Wei , Chen Qi , Yang Wanren , Li Yang , Li Shao , Gao Yi , Peng Qing , Zhou Shuqin 
Published: January 2021

AbstractDrug-induced liver injury (DILI) is one of the leading causes of clinical trial failures and high drug attrition rates. Currently, the commonly used hepatocyte models include primary human hepatocytes (PHHs), animal models, and hepatic cell lines. However, these models have disadvantages that include species-specific differences or inconvenient cell extraction methods. Therefore, a novel, inexpensive, efficient, and accurate model that can be applied to drug screening is urgently needed. Owing to their self-renewable ability, source abundance, and multipotent competence, stem cells are stable sources of drug hepatotoxicity screening models. Because 3D culture can mimic the in vivo microenvironment more accurately than can 2D culture, the former is commonly used for hepatocyte culture and drug screening. In this review, we introduce the different sources of stem cells used to generate hepatocyte-like cells and the models for hepatotoxicity testing that use stem cell-derived hepatocyte-like cells.
Increased [18F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors
Authors: Shimizu Yoichi , Nakai Yukihiro , Watanabe Hiroyuki , Iikuni Shimpei , Ono Masahiro , Saji Hideo , Kuge Yuji , Saga Tsuneo , Nakamoto Yuji 
Published: January 2021

Abstract
Background
[18F]Fluoromisonidazole ([18F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [18F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [18F]FMISO uptake level varied depending on the cellular glutathione conjugation and excretion ability such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1, an efflux transporter), in addition to the cellular hypoxic state. In this study, we evaluated whether MRP1 activity affected [18F]FMISO PET imaging.

Methods
FaDu human pharyngeal squamous cell carcinoma cells were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, incubated with [18F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [18F]FMISO, and PET/CT images were acquired at 4 h post-injection (1st PET scan). Two days later, the same mice were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, and PET/CT images were acquired (2nd PET scan).

Results
FaDu cells pretreated with MRP1 inhibitors exhibited significantly higher radioactivity than those without inhibitor treatment (cyclosporine A: 6.91 ± 0.27, lapatinib: 10.03 ± 0.47, MK-571: 10.15 ± 0.44%dose/mg protein, p < 0.01). In the in vivo PET study, the SUVmean ratio in tumors [calculated as after treatment (2nd PET scan)/before treatment of MRP1 inhibitors (1st PET scan)] of the mice treated with MRP1 inhibitors was significantly higher than those of control mice (cyclosporine A: 2.6 ± 0.7, lapatinib: 2.2 ± 0.7, MK-571: 2.2 ± 0.7, control: 1.2 ± 0.2, p < 0.05).

Conclusion
In this study, we revealed that MRP1 inhibitors increase [18F]FMISO accumulation in hypoxic cells. This suggests that [18F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state.
Cost containment by peer prior authorization program for second line treatment in patients with retinal disease
Authors: Rosenblatt Amir , Hekselman Igal , Rosenblatt Irit , Hekselman Idan , Gaton Dan 
Published: January 2021

Abstract
Background
High and increasing drug prices have prompted the establishment of a broad range of cost-containment treatment policies in health systems globally. In 2012, the supplemental insurance program of a large Israeli health maintenance organization (Clalit Health Services) introduced a prior authorization process for second-line use of ranibizumab in patients with retinal disease for whom treatment with bevacizumab proved to be ineffective. A Clalit steering committee established authorization criteria based on cost and periodically updated clinical considerations, while a team of ophthalmic specialists evaluated their colleagues’ individual patient subsidization requests, based on the funding criteria. The objectives of this study were to detail this unique authorization process and study its effectiveness in limiting unwarranted spending, while allowing for a smooth transition to a second-line more expensive drug when needed.

Methods
A retrospective cohort study including all applications for a first or ongoing treatment with ranibizumab, for one or both eyes, received during March 1, 2012 - December 31, 2015. The key parameters examined were percentages of requests from patients treated by first line treatment bevacizumab, requests approved, reapplications, and results. Requests studied include reapplications and requests for treatment continuation.

Results
During the study period, Clalit affiliated ophthalmologists’ submitted 16,778 funding applications for intravitreal ranibizumab treatment on behalf of 5642 patients who applied for approximately three applications. An efficient sentinel effect was achieved, resulting in only 31% of patients treated with bevacizumab applying for treatment, while maintaining extremely high accessibility to second line treatment with almost 95% of requests being approved.

Conclusions
The data presented shows a low request rate for funding with a high approval rate, proving this peer reviewed report-based authorization process successfully achieved a sentinel effect while controlling cost. We suggest this innovative model be considered in similar decisions processes.
Clinical signs of brachycephalic ocular syndrome in 93 dogs
Authors: Costa Joana , Steinmetz Andrea , Delgado Esmeralda 
Published: January 2021

AbstractBackgroundBrachycephalic breeds have anatomical skull changes that are responsible for ocular clinical signs, known as the brachycephalic ocular syndrome (BOS). Their popularity has increased in recent years but the excessive pressure of selection lead to extreme conformation of skull shapes, resulting in facial alterations that can put these dogs’ vision at risk.ObjectivesThis study aimed to analyse the ocular disorders in a sample of 93 brachycephalic dogs to better characterize the disease complex BOS.Material and methodsBrachycephalic dogs were submitted to a complete ophthalmological examination. The studied parameters included animal’s sex, age and breed, age, ophthalmological tests performed, results of complementary exams, clinical signs, ocular disorders, treatment protocols and their outcomes. Data were organized using Microsoft Office Excel 2007® and statistical analysis was performed with IBM SPSS Statistics 20®.ResultsThe studied population included 93 brachycephalic dogs 45 males (48%) and 48 females (52%) from different breeds: French Bulldog (n = 38), Shih-Tzu (n = 22), Pug (n = 17), English Bulldog (n = 5), Pekingese (n = 4), Boxer (n = 4) and Boston Terrier (n = 3), aged between 0.2–16 years, median 4.65 years. The most frequent ocular abnormalities were corneal ulcers in 44%, corneal pigmentation in 36%, corneal fibrosis in 25% and entropion in 22% of the animals. There was a higher incidence of corneal pigmentary keratitis in Pugs (53%) and corneal fibrosis in Shih Tzus (36%). The most common surgical techniques were medial canthoplasty in 22%, conjunctival flap in 10% and electroepilation in 7% of the cases, without post-operative complications. Conclusions: This study contributed to a better characterization of the disease complex brachycephalic ocular syndrome. The percentage of ocular disorders like entropion, corneal pigmentation, fibrosis and ulcers was high, highlighting the importance of a regular ophthalmological check-up, and early diagnosis of the primary disorders. A higher incidence of corneal pigmentation was noticed in Pugs and corneal fibrosis in Shih Tzus, which suggests that some brachycephalic breeds may be predisposed to certain ocular abnormalities. A responsible reproductive strategy should be implemented to avoid undesired transmission of the abnormal traits to the offspring.