bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Translational Porcine Model for Human Cell–Based Therapies in the Treatment of Posttraumatic Osteoarthritis After Anterior Cruciate Ligament Injury
Authors: Kremen Thomas J. , Stefanovic Tina , Tawackoli Wafa , Salehi Khosrowdad , Avalos Pablo , Reichel Derek , Perez J. Manuel , Glaeser Juliane D. , Sheyn Dmitriy 
Published: September 2020

Background: There is a high incidence of posttraumatic osteoarthritis (PTOA) after anterior cruciate ligament (ACL) injury, and these injuries represent an enormous health care economic burden. In an effort to address this unmet clinical need, there has been increasing interest in cell-based therapies. Purpose: To establish a translational large animal model of PTOA and demonstrate the feasibility of intra-articular human cell–based interventions. Study Design: Descriptive laboratory study. Methods: Nine Yucatan mini-pigs underwent unilateral ACL transection and were monitored for up to 12 weeks after injury. Interleukin 1 beta (IL-1β) levels and collagen breakdown were evaluated longitudinally using enzyme-linked immunosorbent assays of synovial fluid, serum, and urine. Animals were euthanized at 4 weeks (n = 3) or 12 weeks (n = 3) after injury, and injured and uninjured limbs underwent magnetic resonance imaging (MRI) and histologic analysis. At 2 days after ACL injury, an additional 3 animals received an intra-articular injection of 107 human bone marrow–derived mesenchymal stem cells (hBM-MSCs) combined with a fibrin carrier. These cells were labeled with the luciferase reporter gene (hBM-MSCs-Luc) as well as fluorescent markers and intracellular iron nanoparticles. These animals were euthanized on day 0 (n = 1) or day 14 (n = 2) after injection. hBM-MSC-Luc viability and localization were assessed using ex vivo bioluminescence imaging, fluorescence imaging, and MRI. Results: PTOA was detected as early as 4 weeks after injury. At 12 weeks after injury, osteoarthritis could be detected grossly as well as on histologic analysis. Synovial fluid analysis showed elevation of IL-1β shortly after ACL injury, with subsequent resolution by 2 weeks after injury. Collagen type II protein fragments were elevated in the synovial fluid and serum after injury. hBM-MSCs-Luc were detected immediately after injection and at 2 weeks after injection using fluorescence imaging, MRI, and bioluminescence imaging. Conclusion: This study demonstrates the feasibility of reproducing the chondral changes, intra-articular cytokine alterations, and body fluid biomarker findings consistent with PTOA after ACL injury in a large animal model. Furthermore, we have demonstrated the ability of hBM-MSCs to survive and express transgene within the knee joint of porcine hosts without immunosuppression for at least 2 weeks. Clinical Relevance: This model holds great potential to significantly contribute to investigations focused on the development of cell-based therapies for human ACL injury–associated PTOA in the future (see Appendix Figure A1 , available online).
Etomidate Induced Seizure: Adverse Drug Event Case Report
Authors: Rainess Rebecca Ann , Patel Vishal , Stander Eric 
Published: September 2020

Objective/purpose: To report a case of etomidate induced seizure in a patient that received 0.15 mg/kg of etomidate for a procedural sedation which resolved without intervention. Summary: A 68-year-old woman presented to the emergency department with a dislocated shoulder. Etomidate was given to the patient for procedural sedation to allow the physician to reduce the shoulder dislocation. Upon administration of the medication, the patient began seizing; this lasted for about 2 minutes. No medications were needed for cessation of the seizure. Conclusion: A causality assessment determined that the adverse effect of the epileptogenic action in etomidate was possible. Limited data is available in regard to the incidence rate of this adverse effect.
Juvenile lupus and serum vitamin D levels: A cross-sectional study
Authors: Tabra Samar abd Alhamed , Abdelnabi Hend Hassan , Darwish Nivine Fathi Mahmoud , El-Barbary Amal Mohammed , AbdelGhafar Muhammad Tarek , Abu-Zaid Mohammed Hassan 
Published: September 2020

Background Juvenile systemic lupus erythematosus (JSLE) is usually associated with vitamin D deficiency and low bone mineral density. Objectives To evaluate serum levels of 25-OH vitamin D in JSLE patients and to correlate these findings with disease activity and bone density. Methods This study was conducted on 100 patients with JSLE and 100 healthy children as controls. Disease duration and SLEDAI for disease activity were evaluated. CBC, anti-dsDNA, C3,C4,24hr urinary proteins, creatinine, estimated glomerular filtration rate(e-GFR),Ca,P,PTH, 25 (OH) D levels, and bone mineral density(BMD)Z score were measured. Results There were significant differences in mean 25(OH)D concentration between patients group (19.37 ± 9.72 ng/ml) and controls 35.90 ± 9.66 ng/ml(p < 0.05), with significant difference between active and inactive patients (p < 0.05).There were significant negative correlations between serum 25(OH)D and SLEDAI (r-0.545, p 0.001), steroid dose (r-0.561, p 0.001), anti-dsDNA (r-0.685, p 0.006), 24 hr-proteinuria (r-0.738, p 0.001) and PTH (r-0.335, p 0.001), significant positive correlations between 25(OH)D and C3 (r0.617, p 0.001),C4 (r0.544, p 0.001) serum Ca (r0.424, p 0.001) and Z score (r0.561, p 0.001),with non-significant correlations between 25(OH)D and serum P and both disease & steroid duration, (p > 0.05). Conclusion Vitamin D deficiency is common in JSLE, it’s correlated significantly with disease activity and bone mineral density.
Correlation Between Gastrocnemius Tightness and Heel Pain Severity in Plantar Fasciitis
Authors: Pearce Christopher J. , Seow Dexter , Lau Bernard P. 
Published: September 2020

Background: It is known that there is an association between gastrocnemius tightness and plantar fasciitis, but this has never been quantified. The purpose of the study was to determine the correlation between gastrocnemius tightness and the severity of heel pain in plantar fasciitis. Methods: Thirty-three patients were prescribed physiotherapist-directed gastrocnemius stretching exercises, a Strassburg Sock or night splint, and silicone heel insoles as required. Outcome measures included (1) gastrocnemius tightness, (2) 100-mm visual analog scale (VAS) for pain on the first steps in the morning, and (3) 100-mm VAS for the worst pain felt during the previous week. Gastrocnemius tightness was measured by the difference in maximal ankle dorsiflexion between knee bent and straight with a goniometer. Results: The mean gastrocnemius tightness was 22 degrees at baseline compared with 9 degrees at the final follow-up ( P < .01). A reduction in VAS for pain on the first steps in the morning and VAS for the worst pain felt during the previous week from baseline to final follow-up was observed ( P < .01). Correlation analysis of 105 data points between gastrocnemius tightness and VAS for pain on the first steps in the morning was R = 0.757 ( P < .001), and between gastrocnemius tightness and VAS for the worst pain felt during the previous week was R = 0.781 ( P < .001). Conclusion: The study observed a strong, statistically significant correlation between gastrocnemius tightness and the severity of heel pain in plantar fasciitis. Level of Evidence: Level IV, case series.
Nicotinic acetylcholine receptors α7 and α9 modifies tobacco smoke risk for multiple sclerosis
Authors: Briggs Farren BS 
Published: September 2020

Introduction: Tobacco smoke exposure is an established risk factor for multiple sclerosis (MS), yet how it confers risk is not known. Evidence from observational studies suggests nicotine may be a protective component. Animal studies further support this hypothesis, demonstrating nicotine’s protective effect in MS is mediated by the presence and absence of α7 and α9 nicotinic acetylcholine receptors (nAChRs), respectively. Objective: To determine if variation in the genes encoding α7 and α9 nAChRs (cholinergic receptor nicotinic alpha 7 ( CHRNA7) and alpha 9 ( CHRNA9)) will modify MS risk conferred by tobacco smoking. Methods: A multi-stage gene-environment (G×E) framework was utilized, including a case–control analysis (286 cases, 176 controls) with haplotype- and gene-based analyses, followed by an extension case-only (1053 cases) analysis for overlapping variants. Results: The results suggest that CHRNA7 and CHRNA9 modifies MS risk conferred by tobacco smoke, where risk among smokers was increased in carriers of the minor CHRNA9 haplotype and in non-carriers the minor CHRNA7 haplotype. The findings are consistent with the pharmacology of these receptors and animal studies of MS. Conclusion: This study implicates novel processes in MS initiation and demonstrate the need for further G×E studies to advancing our understanding of the missing heritability of MS.
Benefits and Harms of Exercise Therapy for Patients With Diabetic Foot Ulcers: A Systematic Review
Authors: Aagaard Thomas Vedste , Moeini Sahar , Skou Søren T. , Madsen Ulla Riis , Brorson Stig 
Published: September 2020

Aim Exercise therapy is a core element in the treatment of diabetes, but the benefits and harms for patients with a diabetic foot ulcer (DFU) are unknown. We therefore aimed to systematically review the benefits on health-related quality of life (HRQoL) and harms of exercise therapy for patients with DFU. Methods We searched 6 major databases. We performed citation and reference searches of included studies and contacted authors of ongoing trials. We included randomized controlled trials (RCTs) to assess potential benefits on HRQoL and harms of exercise therapy. Observational studies were included to identify potential harms of exercise therapy. Results We included 10 published publications of 9 trials and results from 2 unpublished trials including a total of 281 individuals with DFUs receiving various forms of exercise therapy. Due to lack of HRQoL measurements and high heterogeneity, it was not possible to perform meta-analyses. Results on HRQoL was present in one unpublished study. Harms reported ranged from musculoskeletal problems, increased wound size, to amputation; however, no safe conclusions could be drawn from the available data due to high heterogeneity and risk of bias in the trials. Conclusions/Interpretation Protective strategies are often preferred over therapeutic exercise that might have unforeseen consequences for patients over time. Based on the current literature, no evidence-based recommendations can be provided on the benefits and harms of exercise therapy for patients with DFUs. Well-conducted RCTs are needed to guide rehabilitation including detailed description of adverse events and an exercise program in a semisupervised or fully supervised setting.
Inhibition of ATR-Chk1 signaling blocks DNA double-strand-break repair and induces cytoplasmic vacuolization in metastatic osteosarcoma
Authors: Li Xiaoyang , Dean Dylan C. , Cote Gregory M. , Zou Lee , Hornicek Francis J. , Yu Shengji , Duan Zhenfeng 
Published: September 2020

Background: Ataxia-telangiectasia and Rad3 related protein kinase (ATR) is an essential regulator of the DNA damage response in various cancers; however, its expression and roles in osteosarcoma are unclear. We therefore chose to evaluate the significance and mechanism of ATR in metastatic osteosarcoma, as well as its potential to be a therapeutic target. Methods: The osteosarcoma tissue microarrays constructed from 70 patient specimens underwent immunohistochemistry to quantify ATR and activated phospho-ATR (pATR) expression and their correlation with clinical outcomes. ATR sublocalization within the metastatic osteosarcoma cells was confirmed by immunofluorescence assay. Cell proliferation, apoptosis, and migration were evaluated following treatment with ATR siRNA or the selective inhibitor Berzosertib. Antitumor effects were determined with ex vivo three-dimensional (3D) culture models, and the impacts on the DNA damage repair pathways were measured with Western blotting. Results: Elevated ATR and activated pATR expression correlated with shorter patient survival and less necrosis following neoadjuvant chemotherapy. Intranuclear sublocalization of ATR and pATR suggested a mechanism related to DNA replication. ATR knockdown with siRNA or inhibition with Berzosertib suppressed cell proliferation in a time- and dose-dependent manner and induced apoptosis. In addition, ATR inhibition decreased Chk1 phosphorylation while increasing γH2AX expression and PARP cleavage, consistent with the interference of DNA damage repair. The ATR inhibitor Berzosertib also produced the characteristic cytoplasmic vacuolization preceding cell death, and suppressed ex vivo 3D spheroid formation and cell motility. Conclusion: The faithful dependence of cells on ATR signaling for survival and progression makes it an emerging therapeutic target in metastatic osteosarcoma.
Risk Factors for Rhinosinusitis After Endoscopic Transsphenoidal Adenomectomy
Authors: Lee Clara H. , Ikeda Allison K. , Patel Shubham , Levy Joshua M. , Patel Zara M. , Solares C. Arturo , Oyesiku Nelson , Wise Sarah K. 
Published: September 2020

Objective Patients undergoing endoscopic transsphenoidal adenomectomy (eTSA) for pituitary tumors are at risk for postoperative complications, including rhinosinusitis. We aimed to determine if preoperative sinonasal disease is a risk factor for postoperative rhinosinusitis (PRS). Study Design Retrospective review. Setting Tertiary academic center in U.S. Subjects and Methods Patients with a diagnosis of pituitary adenoma who underwent eTSA between 2007-2016. PRS patients were matched to non-PRS patients or sex, age, tumor size, skull base reconstruction with intranasal tissue grafting, and concurrent septoplasty. Groups were statistically analyzed for potential preoperative risk factors of sinonasal disease (patient-reported, radiographic, endoscopic). Results 49 of 987 patients who underwent eTSA developed PRS (44.9% male, 71.4% Caucasian, mean age 49.3y). On analysis of individual risk factors, there was a significantly higher proportion of patients with a history of prior sinonasal surgery in the PRS group than the non-PRS group (25.5% vs. 6.5%, p = 0.01); however, this group difference became insignificant on multivariate analysis. There were no significant group differences with regard to history of sinus infections, nasal symptoms, seasonal allergies, radiographic abnormalities, or sinonasal disease on endoscopy. Conclusion This is the first study to investigate preoperative sinonasal disease as a risk factor for PRS after eTSA. The risk factors considered did not demonstrate definitive risk for PRS, although a history of prior sinonasal surgery should be investigated further.
Insufficient nocturnal sleep was associated with a higher risk of fibrosis in patients with diabetes with metabolic associated fatty liver disease
Authors: Zheng Jiaping , Chen Sijie , Cai Yuqing , Lin Su , Ke Sujie , Liu Libin 
Published: September 2020

Background: Metabolic associated fatty liver disease (MAFLD) refers to metabolic dysfunction associated with fatty liver disease, and liver fibrosis stage is closely connected with liver-related and all-cause mortality. This study aimed to explore the association of sleep duration with liver fibrosis in the diabetic subgroup of the MAFLD population. Methods: This retrospective study analyzed 342 patients with MAFLD. Anthropometric measurements, clinical and biochemical markers, and lifestyle parameters were collected. Fibrosis was defined as fibrosis-4 ⩾1.3. Propensity score matching (PSM) was performed to match cases. Student’s t-test and chi-square tests were applied for group comparisons, and binary regression models were used to explore the independent risk factors of liver fibrosis. Results: Among the 342 subjects, 87 (25.4%) were diagnosed with fibrosis and 255 (74.6%) without. Baseline characteristic comparisons showed differences in age and diabetes duration between the two groups, and adjustment was made by PSM. Ultimately, the fibrosis group and nonfibrosis group each had 87 patients. The fibrosis group had shorter duration of nocturnal sleep (6.77 ± 1.59 h) than the nonfibrosis group (7.77 ± 1.92 h, p < 0.001). More patients in the fibrosis group stayed up late at night (32.2% versus 14.9%, p < 0.01). Visceral adipose tissue (VAT) areas were larger in the fibrosis group than in the nonfibrosis group ( p < 0.001). Glycemic profile, lipid profile, gamma-glutamyl transferase level, and serum uric acid level were not significantly different between the two groups. In the multivariate regression analysis, nocturnal sleep and VAT areas were independently associated with liver fibrosis, with odds ratios of 0.694 [95% confidence interval (CI) 0.551–0.875, p < 0.01] for nocturnal sleep and 1.031 (95% CI 1.014–1.048, p < 0.001) for VAT areas. Conclusion: Insufficient nocturnal sleep was independently related to a higher risk of fibrosis. Sleep modification might be beneficial in promoting the health of patients with MAFLD.
Comparison of first-line and second-line use of fingolimod in relapsing MS: The open-label EARLIMS study
Authors: Fernández Oscar , Izquierdo Guillermo , Aguera Eduardo , Ramo Cristina , Hernandez Miguel , Silva Diego , Walker Rob , Butzkueven Helmut , Wang Chenyu , Barnett Michael ,   on behalf of the EARLIMS investigators
Published: September 2020

Background Treatment of MS often begins with low-efficacy injectable disease-modifying therapy (iDMT). Objectives To compare the effect of fingolimod 0.5 mg/day on clinical, MRI, patient-reported, and safety outcomes, in treatment-naïve and previously treated (≥1 iDMT) patients with early MS. Methods EARLIMS was a multicentre, open-label, non-randomized, parallel-group phase 3 b/4 study in Australia and Spain. Patients with relapsing–remitting MS, Expanded Disability Status Scale (EDSS) score <4.0, and ≥1–5 years since diagnosis, received daily fingolimod for 48 weeks. The primary endpoint was annualized relapse rate (ARR). Results Of 347 patients enrolled at 51 sites (treatment-naïve, 200 [57.6%]; previously treated, 147 [42.4%]), 320 completed the study (treatment-naïve, 184 [92.0%]; previously treated, 136 [92.5%]), but the study remained underpowered (planned enrolment, n = 432). Fingolimod reduced ARR to similar levels in both treatment-naïve (mean ARR [95% confidence interval], 0.21 [0.14, 0.29]) and previously treated groups (0.30 [0.20, 0.41]; p = 0.1668). There were no new safety signals. Conclusions Fingolimod appeared equally effective as first- or second-line therapy in relapsing MS. There was a trend for better outcomes with fingolimod in treatment-naïve patients than in those previously treated with >1 iDMT.
CD81 knockout promotes chemosensitivity and disrupts in vivo homing and engraftment in acute lymphoblastic leukemia
Authors: Quagliano Anthony , Gopalakrishnapillai Anilkumar , Kolb E. Anders , Barwe Sonali P. 
Published: September 2020

AbstractRelapse remains a major obstacle to achieving 100% overall survival rate in pediatric hematologic malignancies like acute lymphoblastic leukemia (ALL). Relapse often results from the development of chemoresistance. One of the mechanisms of chemoresistance involves ALL cell interactions with the bone marrow (BM) microenvironment, providing a sanctuary. This phenomenon is known as BM microenvironment-induced chemoprotection. Members of the transmembrane 4 superfamily (tetraspanins; TSPANs) are known to mediate microenvironmental interactions and have been extensively studied in solid tumors. Although the TSPAN family member CD81 is a minimal residual disease marker, its biological role in ALL is not well characterized. We show for the first time that CD81 knockout induces chemosensitivity, reduces cellular adhesion, and disrupts in vivo BM homing and engraftment in B-ALL. This chemosensitization is mediated through control of Bruton tyrosine kinase signaling and induction of p53-mediated cell death. We then show how CD81-related signaling can be disrupted by treatment with the epigenetic drug combination of DNA hypomethylating agent azacitidine (aza) and histone deacetylase inhibitor panobinostat (pano), which we previously used to sensitize ALL cells to chemotherapy under conditions that promote BM microenvironment-induced chemoprotection. Aza/pano-mediated modulation of CD81 surface expression is involved in decreasing BM load by promoting ALL cell mobilization from BM to peripheral blood and increasing response to chemotherapy in disseminated patient-derived xenograft models. This study identifies the novel role of CD81 in BM microenvironment-induced chemoprotection and delineates the mechanism by which aza/pano successfully sensitizes ALL cells via modulation of CD81.
Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma
Authors: Jain Neeraj , Singh Satishkumar , Laliotis Georgios , Hart Amber , Muhowski Elizabeth , Kupcova Kristyna , Chrbolkova Tereza , Khashab Tamer , Chowdhury Sayan Mullick , Sircar Anuvrat , Shirazi Fazal , Singh Ram Kumar , Alinari Lapo , Zhu Jiangjiang , Havranek Ondrej , Tsichlis Philip , Woyach Jennifer , Baiocchi Robert , Samaniego Felipe , Sehgal Lalit 
Published: September 2020

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-β expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-β/δ. Treatment with the selective PI3K-β/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.
Successful management of SARS-CoV-2 acute respiratory distress syndrome and newly diagnosed acute lymphoblastic leukemia
Authors: Phillips Lia , Pavisic Jovana , Kaur Dominder , Dorrello N. Valerio , Broglie Larisa , Hijiya Nobuko 
Published: September 2020

Key Points
Standard chemotherapy can still be used for new diagnosis of acute lymphoblastic leukemia in patients with SARS-CoV-2. Corticosteroid can be given safely to patients with SARS-CoV-2 presenting with acute respiratory distress syndrome and ALL.