Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-Acting Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Children

Summary A global phase 3 study evaluated the pharmacokinetics, efficacy and safety of a recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 27 previously treated male children (1–11 years) with severe and moderately severe haemophilia B (factor IX [FIX] activity ≤2 IU/dl). All patients received routine prophylaxis once every seven days for up to 77 weeks, and treated any bleeding episodes on-demand. The mean terminal half-life of rIX-FP was 91.4 hours (h), 4.3-fold longer than previous FIX treatment and clearance was 1.11 ml/h/kg, 6.4-fold slower than previous FIX treatment. The median (Q1, Q3) annualised spontaneous bleeding rate was 0.00 (0.00, 0.91) and was similar between the <6 years and ≥6 years age groups, with a weekly median prophylactic dose of 46 IU/kg. In addition, patients maintained a median trough level of 13.4 IU/dl FIX activity on weekly prophylaxis. Overall, 97.2 % of bleeding episodes were successfully treated with one or two injections of rIX-FP (95 % CI: 92 % to 99 %), 88.7 % with one injection, and 96 % of the treatments were rated effective (excellent or good) by the Investigator. No patient developed FIX inhibitors and no safety concerns were identified. These results indicate that rIX-FP is safe and effective for preventing and treating bleeding episodes in children with haemophilia B with weekly prophylaxis. Routine prophylaxis with rIX-FP at treatment intervals of up to 14 days are currently being investigated in children with severe and moderately severe haemophilia B. Clinicaltrials.gov (NCT01662531)
Docosahexaenoic acid biostatus is associated with event-related functional connectivity in cortical attention networks of typically developing children

Objective: Although extant preclinical evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) is important for neurodevelopment, little is known about its role in human cortical structural and functional maturation. In the present cross-sectional study, we investigated the relationship between DHA biostatus and functional connectivity in cortical attention networks of typically developing children. Methods: Male children (aged 8–10 years, n = 36) were divided into ‘low-DHA’ (n = 18) and ‘high-DHA’ (n = 18) biostatus groups by a median split of erythrocyte DHA levels. Event-related functional connectivity during the performance of a sustained attention task (identical pairs continuous performance task (CPT-IP)) was conducted using functional magnetic resonance imaging. A voxelwise approach used the anterior cingulate cortex (ACC) as the seed-region. Results: Erythrocyte DHA composition in the low-DHA group (2.6 ± 0.9%) was significantly lower than the high-DHA group (4.1 ± 1.1%, P ≤ 0.0001). Fish intake frequency was greater in the high-DHA group (P = 0.003) and was positively correlated with DHA levels among all subjects. The low-DHA group exhibited reduced functional connectivity between the ACC and the ventrolateral prefrontal cortex, insula, precuneus, superior parietal lobule, middle occipital gyrus, inferior temporal gyrus, and lingual gyrus compared with the high-DHA group (P < 0.05; corrected). The low-DHA group did not exhibit greater ACC functional connectivity with any region compared with the high-DHA group. On the CPT-IP task, the low-DHA group had slower reaction time (P = 0.03) which was inversely correlated with erythrocyte DHA among all subjects. Discussion: These data suggest that low-DHA biostatus is associated with reduced event-related functional connectivity in cortical attention networks of typically developing children.
Response of periodontium to mineral trioxide aggregate and Biodentine: a pilot histological study on humans

BACKGROUND The aim of this study was to investigate for the first time the histological response of human periodontium to mineral trioxide aggregate (MTA) and Biodentine. METHODS Six patients scheduled for implant full-arch rehabilitation were randomly assigned to one of the two test groups: MTA or Biodentine treatment. For each patient, two teeth scheduled for strategic extraction were randomly assigned either to the test or to the control treatment. A lateral perforation was drilled on the root and either repaired with MTA/Biodentine or filled with gutta-percha(control). Three months later, the teeth were extracted along with the coronal third of the alveolar bone and a portion of gingival tissue, while performing implant placement, and processed for histological analysis. RESULTS Biodentine resulted in less extrusion into the periodontal environment. All the materials showed good biocompatibility. A new mineralized cementum-like tissue incorporating periodontal fibres was visible in all cases treated with MTA. A small amount of new mineralized tissue was found in two Biodentine cases but not in control cases. Biodentine resulted in less damage to the periodontal ligament. CONCLUSIONS Bioactivity and biocompatibility of MTA were confirmed in human models. Biodentine proved to be biocompatible, but it seems not to induce cementum regeneration.
Ethnic density and cancer: A review of the evidence

Accumulating data suggest that factors in the social environment may be associated with cancer‐related outcomes. Ethnic density, defined as the proportion of racial/ethnic minority individuals residing in a given geographic area, is 1 of the most frequently studied social environment factors, but studies on ethnic density and cancer have yielded inconsistent findings. Thus, the objective of the current review was to summarize the extant data on ethnic density and cancer‐related outcomes (cancer risk, stage at diagnosis, and mortality) with the aim of identifying pathways by which ethnic density may contribute to outcomes across populations. In general, the findings indicated an association between ethnic density and increased risk for cancers of infectious origin (eg, liver, cervical) but lower risk for breast and colorectal cancers, particularly among Hispanic and Asian Americans. Hispanic ethnic density was associated with greater odds of late‐stage cancer diagnosis, whereas black ethnic density was associated with greater mortality. In addition, this review highlights several methodological and conceptual issues surrounding the measurement of ethnic neighborhoods and their available resources. Clarifying the role of neighborhood ethnic density is critical to developing a greater understanding of the health risks and benefits accompanying these environments and how they may affect racial and ethnic disparities in cancer‐related outcomes. Cancer 2018;124:1877‐903. © 2018 American Cancer Society.
Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress-induced degradation products and in biological matrix employing analytical quality by design approach.

The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor-three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C18 column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H2 O2 showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method.
Sprint performance and propulsion asymmetries on an ergometer in trained high‐ and low‐point wheelchair rugby players

The purpose of this study was to examine the propulsion asymmetries of wheelchair athletes while sprinting on an instrumented, dual‐roller ergometer system. Eighteen experienced wheelchair rugby players (8 low point (LP) (class ≤1.5) and 10 high point (HP) (class ≥2.0)) performed a 15‐second sprint in their sports wheelchair on the instrumented ergometer. Asymmetry was defined as the difference in distance and power output (PO) between left and right sides when the best side reached 28 m. Propulsion techniques were quantified based on torque and velocity data. HP players covered an average 3 m further than the LP players (P = .002) and achieved faster sprint times than LP players (6.95 ± 0.89 vs 8.03 ± 0.68 seconds, P = .005) and at the time the best player finished (5.96 seconds). Higher peak POs (667 ± 108 vs 357 ± 78 W, P = .0001) and greater peak speeds that were also evident were for HP players (4.80 ± 0.71 vs 4.09 ± 0.45 m/s, P = .011). Greater asymmetries were found in HP players for distance (1.86 ± 1.43 vs 0.70 ± 0.65 m, P = .016), absolute peak PO (P = .049), and speed (0.35 ± 0.25 vs 0.11 ± 0.10 m/s, P = .009). Although HP players had faster sprint times over 28 m (achieved by a higher PO), high standard deviations show the heterogeneity within the two groups (eg, some LP players were better than HP players). Quantification of asymmetries is important not only for classifiers but also for sports practitioners wishing to improve performance as they could be addressed through training and/or wheelchair configuration.
A novel online model-based wind estimation approach for quadrotor micro air vehicles using low cost MEMS IMUs

This work extends the drag-force enhanced quadrotor model by denoting the free stream air velocity as the difference between the ground speed and the wind speed. It is demonstrated that a relatively simple nonlinear observer is capable of estimating the local wind components, provided accelerometer and GPS-velocity measurements are available. We perform a wind tunnel experiment at various wind speeds using a quadrotor vehicle with a low-cost Inertial Measurement Unit (IMU) and a motion tracking system to provide accurate ground speed measurements. It is shown that the onboard Extended Kalman Filter (EKF) accurately estimates the wind components.
On Interval Soft Sets with Applications

AbstractInterval set theory and soft set theory are mathematical tools for dealing with uncertainty information. As a combination of interval set and soft set, recently, we introduced the new notion of interval soft sets. In this paper we further research interval soft sets and its application. We investigate the tabular representation of interval soft sets, introduce the new concepts of interval choice values, and apply the theory of interval soft sets to solve a decision making problem by using two methods. We discuss some operations of interval soft sets, and construct some lattice structures. Moreover, we introduce the notion of soft equality in interval soft set theory, establish quotient algebra by soft equality relation, and discuss the application of soft equality relations in preconditioning of decision making.
National Trends in Extended Procedures for Ovarian Cancer Debulking Surgery

Objective Primary cytoreduction for ovarian cancer often requires extended radical procedures and is associated with significant morbidity. In 2010, neoadjuvant chemotherapy was shown to have similar survival to primary cytoreduction but with less need for radical surgery. We hypothesized that the increased use of neoadjuvant chemotherapy would decrease the use of radical cytoreductive procedures and thus examined trends in the performance of radical cytoreductive procedures. Methods We used the Nationwide Inpatient Sample to determine the annual number of extended procedures (colon, small intestine, liver, diaphragm, spleen, and gastric resection, ileostomy, colostomy) performed in women undergoing surgery for ovarian cancer from 1998 to 2013. Estimates were weighted to provide national averages. To account for changes in incidence over time, we used national incidence rates and report procedures performed per 1000 new cases of ovarian cancer. Trends were assessed using Cochrane-Armitage tests. Results We identified 274,639 ovarian cancer patients who underwent surgery, ranging from 15,720 to 18,714 procedures performed each year. We identified a significant increase in the use of extended procedures over this period. These differences were significant for absolute numbers of procedures, rate per 1000 new ovarian cancer cases, and percent per hysterectomy/bilateral salpingoophorectomy for rectosigmoid resection, diaphragm resection, splenectomy, ileostomy, and liver resection. Specifically, the use of these procedures rose from 1998 to 2010, declined in 2011, and rose again in 2012 and 2013. Conclusions Although there was a transient decrease in the use of extended cytoreductive procedures from 2010 to 2011 after the publication of randomized neoadjuvant trial data, use of these procedures again rose in 2012 and 2013.
Transfusion of red blood cells in coronary surgery: is there an effect on long-term mortality when adjusting for risk factors and postoperative complications?

OBJECTIVES The aim of this study was to compare long-term mortality in patients undergoing primary isolated coronary artery bypass grafting who received ≥1 units of red blood cells (RBCs) or no RBCs. We hypothesized that a possible difference in long-term mortality was due to preoperative morbidity and/or postoperative morbidity. METHODS This prospective cohort study, part of the Cardiac Surgery Outcome Study (CaSOS) at St. Olavs University Hospital, Trondheim, Norway, included patients operated on from 2000 through 2014 (n = 4014) and excluded those with large intra- or postoperative blood loss or 30-day mortality. Observed mortality from 30 days to 15 years postoperatively was compared between patients who received RBC transfusion and those who did not. Cox regression analysis was performed with unadjusted models, adjusting for pre- and intraoperative covariates, and with further adjustment for postoperative complications. Sensitivity analyses were performed with propensity score matching or including 30-day mortality. RESULTS The unadjusted hazard ratio (HR) for long-term mortality was 2.10 (1.81-2.43; P < 0.01) for transfused patients. After adjusting for pre- and intraoperative variables, the HR was 1.26 (1.04-1.53; P = 0.02). With further adjustment for postoperative complications, RBC transfusion was no longer significant and the HR was 1.19 (0.98-1.44; P = 0.08). These results were supported by the sensitivity analyses. CONCLUSIONS The study indicated that most of the association between RBC transfusion and long-term mortality following primary isolated coronary artery bypass grafting was due to confounders, especially from postoperative complications.
Design principles for robust vesiculation in clathrin-mediated endocytosis

Significance Plasma membrane tension plays an important role in various biological processes. In particular, recent experimental studies have shown that membrane tension inhibits membrane budding processes like clathrin-mediated endocytosis. We have identified a mathematical relationship between the curvature-generating capability of the protein coat and membrane tension that can predict whether the coat alone is sufficient to produce closed buds. Additionally, we show that a combination of increased coat rigidity and applied force from actin polymerization can produce closed buds at high membrane tensions. These findings are general to any membrane-budding process, suggesting that biology has evolved to take advantage of a set of physical design principles to ensure robust vesicle formation across a range of organisms and mechanical environments. A critical step in cellular-trafficking pathways is the budding of membranes by protein coats, which recent experiments have demonstrated can be inhibited by elevated membrane tension. The robustness of processes like clathrin-mediated endocytosis (CME) across a diverse range of organisms and mechanical environments suggests that the protein machinery in this process has evolved to take advantage of some set of physical design principles to ensure robust vesiculation against opposing forces like membrane tension. Using a theoretical model for membrane mechanics and membrane protein interaction, we have systematically investigated the influence of membrane rigidity, curvature induced by the protein coat, area covered by the protein coat, membrane tension, and force from actin polymerization on bud formation. Under low tension, the membrane smoothly evolves from a flat to budded morphology as the coat area or spontaneous curvature increases, whereas the membrane remains essentially flat at high tensions. At intermediate, physiologically relevant, tensions, the membrane undergoes a “snap-through instability” in which small changes in the coat area, spontaneous curvature or membrane tension cause the membrane to “snap” from an open, U-shape to a closed bud. This instability can be smoothed out by increasing the bending rigidity of the coat, allowing for successful budding at higher membrane tensions. Additionally, applied force from actin polymerization can bypass the instability by inducing a smooth transition from an open to a closed bud. Finally, a combination of increased coat rigidity and force from actin polymerization enables robust vesiculation even at high membrane tensions.
Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.

UNLABELLED While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials. SIGNIFICANCE DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs.
The personal financial burden of chronic rhinosinusitis: A Canadian perspective

Background Previous studies describe the financial burden of chronic rhinosinusitis (CRS) from the perspective of third-party payers, but, to our knowledge, none analyze the costs borne by patients (i.e., out-of-pocket expenses [OOPE]). Furthermore, this burden has not been previously investigated in the context of a publicly funded health care system. Objective The purpose of this study was to characterize the financial impact of CRS on patients, specifically by evaluating its associated OOPEs and the perceived financial burden. The secondary aim was to determine the factors predictive of OOPEs and perceived burden. Methods Patients with CRS at a tertiary care sinus center completed a self-administered questionnaire that assessed their socioeconomic characteristics, disease-specific quality of life (22-item Sino-Nasal Outcome Test [SNOT-22]), workdays missed due to CRS, perceived financial burden, and direct medical and nonmedical OOPEs over a 12-month period. Total OOPEs were calculated from the sum of direct medical and nonmedical OOPEs. Regression analyses determined factors predictive of OOPEs and the perceived burden. Results A total of 84 patients completed the questionnaires. After accounting for health insurance coverage and the median direct medical, direct nonmedical, and total OOPEs per patient over a 12-month period were Canadian dollars (CAD) $336.00 (2011) [U.S. $339.85], CAD $129.87 [U.S. $131.86], and CAD $607.10 [U.S. $614.06], respectively. CRS resulted in an average of 20.6 workdays missed over a 12-month period. Factors predictive of a higher financial burden included younger age, a greater number of previous sinus surgeries, <80% health insurance coverage, residing out of town, and higher SNOT-22 scores. Conclusion Total OOPEs incurred from the treatment of CRS may amount to CAD $607.10 [U.S. $614.06] per patient per year, within the context of a single-payer health care system. Managing clinicians should be aware of patient groups with a greater perceived financial burden and consider counseling them on strategies to offset expenses, including obtaining travel grants, using telemedicine for follow-up assessments, providing drug samples, and streamlining diagnostic testing with medical visits.
Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer’s disease

SummaryAlzheimer’s disease is a progressive neurodegenerative disorder and the leading cause of dementia in the Western world. Postmortem, it is characterized neuropathologically by the presence of amyloid plaques, neurofibrillary tangles, and a profound gray matter loss. Neurofibrillary tangles are composed of an abnormally hyperphosphorylated intracellular protein called tau, tightly wound into paired helical filaments and thought to impact microtubule assembly and protein trafficking, resulting in the eventual demise of neuronal viability. The extracellular amyloid plaque deposits are composed of a proteinacious core of insoluble aggregated amyloid-β (Aβ) peptide and have led to the foundation of the amyloid hypothesis. This hypothesis postulates that Aβ is one of the principal causative factors of neuronal death in the brains of Alzheimer’s patients. With multiple drugs now moving through clinical development for the treatment of Alzheimer’s disease, we will review current and future treatment strategies aimed at improving both the cognitive deficits associated with the disease, as well as more novel approaches that may potentially slow or halt the deadly neurodegenerative progression of the disease.