Miracle-dz/UniFAR-FTUs huggingface dataset:
Induction of Tolerance Towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models.

Background The application of hematopoietic cell transplantation for induction of immune tolerance has been limited by toxicities associated with conditioning regimens and to graft-versus-host disease (GVHD). Decades of animal studies have culminated into sufficient control of these two problems, making immune tolerance a viable alternative to life-long application of immunosuppressive drugs to prevent allograft rejection. Methods Studies in mice have paved the way for the application of HCT with limited toxicity in large animal models. Resultant studies in the pig, dog, and ultimately the nonhuman primate have led to appropriate methods for achieving nonmyeloablative irradiation protocols, dose, and timing of post-grafting immunosuppressive drugs, monoclonal antibody therapy, and biologicals for costimulatory molecule blockade. The genetics field has been extensively evaluated in appreciation of the ultimate need to obtain organs from MHC-mismatched unrelated donors. Results Nonmyeloablative conditioning regimens have been shown to be successful in inducing immune tolerance across all three animal models. Postgrafting immunosuppression is also important in assuring sustained donor hematopoiesis for tolerance. Donor chimerism need not be permanent to establish stable engraftment of donor organs, thereby essentially eliminating the risk of GVHD. Using nonmyeloablative HCT with monoclonal antibody immunosuppression, the kidney has been successfully transplanted in MHC-mismatched nonhuman primates. Conclusions Nonmyeloablative HCT for the establishment of temporary mixed chimerism has led to the establishment of stable tolerance against solid organ allografts in large animal models. The kidney, considered a tolerogenic organ, has been successfully transplanted in the clinic. Other organs such as heart, lung, and vascularized composite allografts (face and hands), remain distant possibilities. Further study in large animal models will be required to improve tolerance against these organs before success can be attained in the clinic.
Smoking alters the evolutionary trajectory of non-small cell lung cancer

Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin α erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes.
Anthropometric variables as cardiovascular risk predictors in a cohort of adult subjects with Turner syndrome

Background and purpose Excessive adiposity is associated with cardiometabolic complications in Turner syndrome (TS) subjects. Reference data for predictive anthropometric indices of overweight/obesity and metabolic syndrome (MetS) are lacking for subjects with TS. The purpose of this study was to identify the best anthropometric predictor of cardiometabolic risk in a Latin-American cohort of TS subjects. Patients and methods This was a cross-sectional correlational study conducted in adult TS subjects (n=88) over the past seven years. Anthropometric parameters, body composition and biochemical variables were evaluated in a study and in a reference (n=57) group. Overweight/obesity and MetS were diagnosed using international consensus. The area under the ROC curve (AUC-ROC) was then used to determine the value of each anthropometric variable in predicting MetS or overweight/obesity. Results The prevalence of MetS and overweight/obesity in TS subjects was 40% and 48%, respectively. All anthropometric and cardiometabolic variables were significantly increased in TS subjects when compared to the reference group, except for body mass index (BMI) and HDL-c. To detect MetS and overweight/obesity, waist to height ratio (WHtR) was found to have a higher correlation with cardiometabolic variables (TC, LDL-c, HDL-c levels and the LDL-c/HDL-c ratio), and to have a higher AUC-ROC and odds ratio than BMI, waist circumference (WC) and the waist to hip ratio (WHR). Conclusion The prevalence of MetS and overweight/obesity is elevated in TS subjects. WHtR was the most useful variable in predicting the presence of MetS and overweight and obesity in this TS cohort. A combination of WHtR with BMI or with WC could have the best clinical utility in identifying adult TS subjects with overweight/obesity and MetS, respectively.
Prediction modeling and distributed learning for radiotherapy outcomes in lung cancer patients

Background and purpose The majority of normal-tissue complication probability (NTCP) models for acute esophageal toxicity (AET) in advanced stage non-small cell lung cancer (AS-NSCLC) patients treated with (chemo-)radiotherapy are based on three-dimensional conformal radiotherapy (3D-CRT). Due to distinct dosimetric characteristics of intensity-modulated radiation therapy (IMRT), 3D-CRT based models need revision. We established a multivariable NTCP model for AET in 149 AS-NSCLC patients undergoing IMRT. Materials and methods An established model selection procedure was used to develop an NTCP model for Grade ≥2 AET (53 patients) including clinical and esophageal dose-volume histogram parameters. Results The NTCP model predicted an increased risk of Grade ≥2 AET in case of: concurrent chemoradiotherapy (CCR) [adjusted odds ratio (OR) 14.08, 95% confidence interval (CI) 4.70-42.19; p<0.001], increasing mean esophageal dose [Dmean; OR 1.12 per Gy increase, 95% CI 1.06-1.19; p<0.001], female patients (OR 3.33, 95% CI 1.36-8.17; p=0.008), and ≥cT3 (OR 2.7, 95% CI 1.12-6.50; p=0.026). The AUC was 0.82 and the model showed good calibration. Conclusions A multivariable NTCP model including CCR, Dmean, clinical tumor stage and gender predicts Grade ≥2 AET after IMRT for AS-NSCLC. Prior to clinical introduction, the model needs validation in an independent patient cohort.
The Utility of the Timed Up-and-Go Test in Predicting Cognitive Performance: A Cross-Sectional Study of Independent Living Adults in a Retirement Community

Physical, emotional, and cognitive changes are well documented in aging populations. We administered a comprehensive battery of mental and physical health measures and the Montreal Cognitive Assessment (MoCA; a cognitive screening tool) to 93 independently living older adults (OAs) residing in a Continuing Care Senior Housing Community. Performance on the Timed Up-and-Go (TUG) test (a measure of functional mobility) correlated more strongly with the MoCA total score than did measures of aging, psychiatric symptoms, sleep, and both self-report and objective physical health. Furthermore, it was associated with MoCA Attention, Language, Memory, and Visuospatial/Executive subscales. The MoCA-TUG relationship remained significant after controlling for demographic and physical/mental health measures. Given that the TUG explained significantly more variance in broad cognitive performance than a comprehensive battery of additional physical and mental health tests, it may function as a multimodal measure of health in OAs, capturing physical changes and correlating with cognitive measures.
ESRA19-0616 New concepts in physiopathology of the nerve lesions: intraneural injection microanatomy in humans and animal models

It has generally been accepted that intrafascicular spread of local anesthetic solution is the major cause of severe and devastating neurological complications after intraneural local anesthetic injection.1 Furthermore, the validity of the human extrapolation of animal experiment conclusions has been recently disputed.2 After performing deliberate intraneural injections using StimuPlex D, 22-guage (15° bevel) needles with a new marker (heparinized erythrocytes)3 under ultrasound guidance mimicking clinical practice, and creating the worst possible conditions for regional block, we microscopically analyzed the longitudinal and circumferential spread in the extrafascicular and intrafascicular compartments in human sciatic and median nerves. This was also done in sciatic nerves of dogs, pigs and sheep. Swelling of the nerves confirmed intraneural injection. Extrafascicular spread was seen in all human and animal samples outside the perineurium, intermingled between the interfascicular adipocytes except in extrafascicular compartments where adipocytes were absent. Intrafascicular spread was absent in almost all samples. the marker was also observed filling the entire thickness of perineurium between the perineurium cellular layers. Erythrocytes were not found inside the endoneurium of most of the fascicles examined. Intrafascicular intraneural injection has been entertained as possible option in a few cases, but we were surprises to find no evidence of intrafascicular spreading in the vast majority of fascicles. the compact endoneural structure and the absence of endoneural spaces4–5 probably explain our findings and may help to understand the relatively low number of neurological complications caused by peripheral regional anesthesia considering the high number of blocks that are performed and the high number of intraneural injections that may be done intentionally or unintentionally. References Brull R, Hadzic A, Reina MA, Barrington MJ: Pathophysiology and etiology of nerve injury following peripheral nerve blockade. Reg Anesth Pain Med 2015;40:479–90. Server A, Reina MA, Boezaart AP, Prats-Galino A, Esteves Coelho M, Sala-Blanch X. Microanatomical nerve architecture of six mammalian species: Is trans-species translational anatomic extrapolation valid? Reg Anesth Pain Med 2018;43:496–501. Reina MA, Boezaart AP, Sala-Blanch X, Monzó E, Tubbs S, Server A, Bigeleisen P. A novel marker for studying nerves. Clin Anat 2018; In Press. doi:10.1002/ca.23253 Reina MA, Machés F, De Diego-Isasa P, Del Olmo C. Ultrastructure of endoneurium, Atlas of Functional Anatomy of Regional Anesthesia and Pain Medicine. Edited by Reina MA. New York, Springer, 2015, pp 37–58. Reina MA, Sala Blanch X, Arriazu R, Machés F. Microscopic morphology and ultrastructure of human peripheral nerves, Nerves and Nerve Injuries, Vol. 1: History, Embryology, Anatomy, Imaging, and Diagnostics. Edited by Tubbs RS, Rizk E, Shoja M, Loukas M. Cambridge, MA, Elsevier, 2015, pp. 91–106.
IL-17 Modulation of Rhinovirus-Induced Allergic Airways Disease

Asthma is a chronic inflammatory disease of the airways, resulting in significant morbidity and premature deaths. Rhinoviruses, agents of the common cold, have been identified as the most frequent viruses inducing asthma exacerbations. However the mechanisms involved in this process, especially in moderate-to-severe asthmatics, are not clear. IL-17, a protein secreted by Th17 and IL-17γδ T cells, is found to be up-regulated in asthmatics and correlates with severity of disease. Observations from a clinical study of rhinovirus infection showed increased induction of IL-17 in nasal lavage fluid from asthmatics following experimental rhinovirus infection compared to healthy controls. Using mouse models, this thesis addresses the interactions of rhinovirus with IL-17 in the context of allergic airways disease. Primary infection of C57BL/6 mice did not induce IL-17 responses as seen in human subjects; this may be explained by the apparent lack of induction of IL-23 following primary infection in mice. Supplementation of rhinovirus infection with recombinant IL-17 showed significant, selective increases in neutrophil chemokines with subsequent increases in both neutrophil recruitment and activation, as defined by myeloperoxidase activity. In an existing Th2-driven model of allergic airways disease, rhinovirus was seen to selectively expand Th2 responses while not increasing allergen-induced Th17, IL-17γδ T cells or IL-17. However, rhinovirus infection in a Th17-driven model of allergic airways disease showed a significant increase of neutrophil numbers with a concomitant increase in airway hyperresponsiveness. This work augments existing knowledge on rhinovirus exacerbation of Th2mediated asthma with the interactions between Th17 and rhinovirus, which may play a significant role in moderate-to-severe asthma exacerbations. This supports current research on therapeutic targeting of the IL-17 pathway in asthmatics.
The correlations among pain, disability, lumbar muscle endurance and fear-avoidance behaviour in patients with chronic low back pain

Objectives: To determine the correlations among pain, disability, lumbar muscle endurance and fear-avoidance behaviour in patients with chronic low back pain and to investigate the predictive power of fear-avoidance behaviour on improvement in treatment outcomes. Design: Longitudinal retrospective correlation study. Participants: 178 patients with chronic low back pain. Intervention: Back reconditioning exercises using standardized protocol. Outcome measures: Pain, disability and lumbar muscle endurance were measured at week 0, 6 and 12. Fear-avoidance behaviour was measured at week 0. Changes in pain and disability were measured at week 6 and 12. Results: Fair to moderate correlation was found between pain and disability (r = 0.35-0.62, p< 0.01). Fear Avoidance Behaviour Questionaire (FABQ) correlated with pain at a weak degree (r = 0.23, p< 0.01). FABQ correlated with disability at a fair degree (r = 0.30-0.42, p< 0.05). FABQ correlated inversely with long-term improvement in disability at a fair degree (r = �0.35, p< 0.05). FABQ significantly predicted long-term reduction in disability, accounting for 12% of the variance in outcome. Conclusions: No strong correlations were found among pain, disability, lumbar muscle endurance and fear-avoidance behaviour in patients with chronic low back pain. Treatment, therefore, should aim to address as many related aspects including physical, psychosocial and behavioural aspects, as possible, in order to enhance treatment success. Fear avoidance behaviour significantly predicted long-term reduction in disability, accounting for 12% of the variance in outcome.
Classification of H&E Stained Breast Cancer Histopathology Images Based on Convolutional Neural Network

Automatic classification of H&E breast cancer histopathology images is a challenging task. Computer-aided diagnostic systems help reduce costs and increase the efficiency of the process. Although the existing research on breast cancer histopathology image classification is higher than 90% accurate in the binary classifications (non-carcinoma/carcinoma), the classification accuracy of four classifications (normal, benign, in situ, invasive) is less than 80%. This paper proposes a framework for the classification of H&E stained breast cancer histopathological images, which includes two methods based on convolutional neural network. The first method is based on the convolutional neural network structure of the SE-ResNet module, and the second method is based on the transfer learning hybrid model structure, which achieves the accuracy of 80.33% and 86.11% respectively. Compared with the state-of-the-art method, the accuracy is improved by 2.56% and 8.33% respectively. The proposed framework achieves 91.67% accuracy in binary classification and is competitive with state-of-the-art methods.
Evaluation of Right Ventricular Systolic Function in Patients with Right Bundle Branch Block Using Two-Dimensional Speckle Tracking Echocardiography

Background: the prevalence of right bundle branch block (RBBB) is estimated to be 0.2-2.3% in healthy individuals in many previous studies. The prevalence of RBBB increases with age, higher in men, diabetics and in patients with hypertension. Objectives: the purpose of this study was to evaluate the right ventricular systolic function in patients with right bundle branch block with structurally normal heart disease using conventional and speckle tracking 2D echocardiography. Subjects and Methods: forty patients with right bundle branch block (RBBB) were classified into 2 groups each of 20 patients; complete right bundle branch block (CRBBB) and incomplete RBBB (IRBBB), beside 20 normal individuals matched in age and sex served as controls. Results: Tricuspid annular plane systolic excursion (TAPSE) and right ventricle free wall longitudinal strain (RV FWLS) were not statistically significant in patients with RBBB, there was decrease in CRBBB than normal individuals. In right ventricle global longitudinal strain (RV GLS), tricuspid lateral annular systolic velocity (S’), Tei index by both tissue and pulsed Doppler assessment, fractional area change (RV FAC%) and RV basal diameter; and in incomplete right bundle branch block in the mean of RV STE GLS%, S’, Tei index by both tissue and pulsed Doppler. Conclusion: Isolated right bundle branch block has an effect on the RV morphologic characteristics, systolic function compared with healthy individuals by 2D, M-mode, Doppler and speckle tracking echocardiographic assessment.
Evaluating optic nerve diameter as a possible biomarker for disability in patients with multiple sclerosis

Background and purpose The development of new biomarkers for multiple sclerosis (MS) is of paramount importance to improve our ability to predict disease progression and disability. The aim of this study was to evaluate the potential role of the optic nerve diameter (OND) measured by ultrasonography as a biomarker of early disability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods Forty-nine RRMS patients, 23 with a history of optic neuritis (MS-ON) and 26 without a history of optic neuritis (MS N-ON), and 50 age- and sex-matched healthy control subjects were included in the study. The OND and optic nerve sheath diameter (ONSD) were measured by transorbital sonography (TOS), and the retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thicknesses were measured by optical coherence tomography (OCT) using the Optovue RTVue™ system (Optovue, Inc., Fremont, CA, USA). Results There was no significant difference between the patient (whether ON or N-ON eyes) and control groups in either the OND (p=0.979) or the ONSD (p=0.911). However, patients with an expanded disability status scale (EDSS) score >2 had a significantly lower OND and RNFL thicknesses (p=0.014, p=0.010 respectively) than patients with an EDSS score ≤2. Statistical logistic regression revealed that OND was an independent predictor of EDSS>2 (p=0.044, OR =0.000, 95% CI=0.000–0.589). Conclusion The OND, as measured by ultrasonography, could be potentially used as a biomarker for the detection of early disability in RRMS patients.
Comparative analysis of classification algorithms for chronic kidney disease diagnosis

Chronic Kidney Disease (CKD) is one of the leading cause of death contributed by other illnesses such as diabetes, hypertension, lupus, anemia or weak bones that lead to bone fractures. Early prediction of CKD is important in order to contain the disesase. However, instead of predicting the severity of CKD, the objective of this paper is to predict the diagnosis of CKD based on the symptoms or attributes observed in a particular case, whether the stage is acute or chronic. To achieve this, a classification model is proposed to label stage of severity for kidney diseases patients. The experiments then investigated the performance of the proposed classification model based on eight supervised classification algorithms, which are ZeroR, Rule Induction, Support Vector Machine, Naïve Bayes, Decision Tree, Decision Stump, k-Nearest Neighbour, and Classification via Regression. The performance of the all classifiers is evaluated based on accuracy, precision, and recall. The results showed that the regression classifier perform best in the kidney diagnostic procedure.
A commentary on the efficacy of olanzapine for the treatment of schizophrenia: the past, present, and future

Abstract Olanzapine is a second-generation atypical antipsychotic with proven efficacy for the treatment of schizophrenia. Approved in 1996, olanzapine is one of the most studied antipsychotics, resulting in a considerable amount of clinical data across diverse patient populations. Despite the fact that olanzapine is associated with a known risk of metabolic side effects, including weight gain, many clinicians continue to prescribe olanzapine for the treatment of schizophrenia with the expectation of additional therapeutic antipsychotic efficacy relative to other first-line atypical antipsychotics. The goal of this narrative is to revisit the role of oral olanzapine in the management of patients with schizophrenia, including those with recently diagnosed schizophrenia (“first-episode”), those with an established schizophrenia diagnosis who experience acute exacerbations, those receiving long-term antipsychotic treatment as a maintenance intervention, and those with suboptimal response to antipsychotic treatment, including treatment resistance. Collectively, data from published literature support the favorable efficacy of olanzapine compared with other first- and second-generation antipsychotics, including lower rates of treatment discontinuation and clinically meaningful improvements in the symptoms of schizophrenia. The development of antipsychotic medications with the favorable efficacy of olanzapine, but with reduced weight gain, could address a major unmet need in the treatment of schizophrenia.
Dual mobility total hip arthroplasty: should everyone get one?

Hip instability following total hip arthroplasty (THA) remains a major challenge and is one of the main causes of revision surgery. Dual mobility (DM) implants have been introduced to try to overcome this problem. The DM design consists of a small femoral head captive and mobile within a polyethylene liner. Numerous studies have shown that DM implants reduce the rate of dislocation compared to fixed-bearing inserts. Early designs for DM implants had problems with wear and intra-prosthetic dislocations, so their use was restricted to limited indications. The results of the latest generation of DM prostheses demonstrate that these problems have been overcome. Given the results of these studies presented in this review, surgeons may now consider DM THA for a wider patient selection. Cite this article: EFORT Open Rev 2019;4:541-547. DOI: 10.1302/2058-5241.4. 180045