Miracle-dz/UniFAR-FTUs huggingface dataset:
Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade

Background Immune checkpoint inhibitors are poised to revolutionize the management of a growing number of malignancies. Unfortunately, the management of steroid-refractory immune mediated adverse events is based on a paucity of randomized data and limited to single center experiences. Our initial experience with the IL-6 receptor antagonist tocilizumab showed clinical improvement in a wide variety of irAEs. As a result, we adopted the use of tocilizumab for the management of steroid refractory irAEs. Methods The character and clinical course of irAEs were abstracted from the medical record and analyzed. The dose of tocilizumab was 4 mg/kg given IV over one hour. C-reactive protein was drawn at first nivolumab infusion and at q two weeks (and with irAEs) thereafter. Clinical improvement was defined as either: documentation of resolution of symptoms or hospital discharge within seven days. Results Of the initial 87 patients that were treated with nivolumab, 34 required tocilizumab (39.1%). All patients were on corticosteroids. The majority (88.2%) were lung cancer patients. The index grade 3/4 irAE was pneumonitis in 35.3%, serum sickness/SIRS in 35.3%, cerebritis in 14.7% and one case each of hypophysitis, colitis, pancreatitis, hepatitis and immune mediated coagulopathy. Median time between first nivolumab and initiation of tocilizumab was 76 days (range 1–429). There was a statistically significant increase in C-reactive protein from a median of 23 mg/L (range 0.1–238.5) at baseline to 109.3 mg/L (21.5–350.4) at the time of index irAE, followed by a decrease to 19.2 mg/L (0.25–149) after tocilizumab (p < 0.00001). Clinical improvement was noted in 27/34 patients (79.4%). Some patients (52.9%) required a single dose, while 38.2% required two, 8.8% required three and 1 patient required four doses. Twenty-seven doses were given in the inpatient setting (49.1%). Median time to discharge was four days (range 1–27). Seventy-four percent of patients were discharged home. For the 53 doses of tocilizumab that were delivered when infliximab was an option, there was a cost savings of $141,048.72 (WAC) during the 18 month study period. Conclusions Tocilizumab may be a therapeutic option for the management of steroid refractory irAEs secondary to immune checkpoint blockade. However, randomized trials are needed to better elucidate the relative efficacy and safety of these agents.
Effects of gait training using the Hybrid Assistive Limb® in recovery-phase stroke patients: A 2-month follow-up, randomized, controlled study.

BACKGROUND Gait training using the Hybrid Assistive Limb® (HAL®) may have beneficial effects on post-stroke gait function and independent walking. However, the long-term and medium-term efficacies of gait training using HAL® in stroke patients remain unclear. OBJECTIVE To compare the medium-term efficacy of gait training using a single-leg version of the Hybrid Assistive Limb® (HAL®) on the paretic side with conventional gait training (CGT) in recovery-phase stroke patients. METHODS Twenty-four post-stroke participants (HAL® group: n = 12, CGT group: n = 12) completed the trial. Over 4 weeks, all participants received twelve 20-min sessions of either HAL® (using the single-leg version of HAL® on the paretic side) or conventional (performed by skilled and experienced physical therapists) gait training. Outcome measures were evaluated prior to training, after 12 sessions, and at 8 and 12 weeks after intervention initiation. Functional Ambulation Category (FAC) was the primary outcome measure. RESULTS The HAL® group showed significant improvement in FAC after 12 sessions, and at 8 and 12 weeks compared to the conventional group (P = 0.02). CONCLUSIONS The results suggested that a gait training program based on HAL® may improve independent walking more efficiently than CGT at 1 and 2 months after intervention.
Is the 135S Poliovirus Particle an Intermediate during Cell Entry?

ABSTRACT Poliovirus binding to its receptor (PVR) on the cell surface induces a conformational transition which generates an altered particle with a sedimentation value of 135S versus the 160S of the native virion. A number of lines of evidence suggest that the 135S particle is a cell entry intermediate. However, the low infection efficiencies of the 135S particle and the absence of detectable 135S particles during infection at 26°C by the cold-adapted mutants argue against a role for the 135S particle during the cell entry process. We show here that binding of 135S-antibody complexes to the Fc receptor (CDw32) increases the infectivity of these particles by 2 to 3 orders of magnitude. Thus, the low efficiency of infection by 135S particles is due in part to the low binding affinity of these particles. In addition, we show that there is an additional stage in the entry process that is associated with RNA release. This stage occurs after formation of the 135S particle, is rate limiting during infection at 37°C, but not at 26°C, and is PVR independent. The data also demonstrate that during infection at 26°C, the rate-limiting step is the PVR-mediated conversion of wild-type 160S particles to 135S particles. This suggests that during infection at 26°C by the cold-adapted viruses, 135S particles are formed, but they fail to accumulate to detectable levels because the subsequent post-135S particle events occur at a significantly faster rate than the initial conversion of 160S to 135S particles. These data support a model in which the 135S particle is an intermediate during poliovirus entry.
Pharmacokinetics and in vivo potency of soluble epoxide hydrolase inhibitors in cynomolgus monkeys

BACKGROUND AND PURPOSE Soluble epoxide hydrolase inhibitors (sEHIs) possess anti‐inflammatory, antiatherosclerotic, antihypertensive and analgesic properties. The pharmacokinetics (PK) and pharmacodynamics in terms of inhibitory potency of sEHIs were assessed in non‐human primates (NHPs). Development of a sEHI for use in NHPs will facilitate investigations on the role of sEH in numerous chronic inflammatory conditions.
A Bio-Inspired Early-Level Image Representation and Its Contribution to Object Recognition

A visual stimulus is represented by the biological visual system at several levels, from low to high levels they are, photoreceptor cells, GCs, LGN cells and visual cortical neurons. Retinal ganglion cells (GCs) at the early level need to represent raw data only once, but meet a wide number of diverse requests from different vision-based tasks. This means the information representation at this level is general and not task-specific. Neurobiological findings have attributed this universal adaptation to GCs' RF mechanisms. For the purposes of developing a highly efficient image representation method that can facilitate information processing and interpretation at later stages, here we design a computational model to simulate the GC's non-classical RF. This new image presentation method can extract major structural features from raw data, and is consistent with other statistical measures of the image. Based on the new representation, the performances of other state-of-the-art algorithms in segmentation can be upgraded remarkably. This work concludes that applying sophisticated representation schema at early state is an efficient and promising strategy in visual information processing.
Examining discriminant validity issues of the Sport Motivation Scale-6

Abstract The current study was conducted to re-assess the factor structure of the 24-item Sport Motivation Scale-6 (SMS-6; Mallett, Kawabata, Newcombe, Otero-Forero, & Jackson, 2007) with an independent sample. A total of 437 participants completed the SMS-6, and their responses were examined with confirmatory factor analysis and recent exploratory structural equation modelling (Asparouhov & Muthén, 2009). A six-factor confirmatory-factor-analysis model did not fit to the sample data adequately. Through examination of the corresponding exploratory-structural-equation-modelling solution, it was found that two items loaded on non-target factors poorly. This result was replicated by a published data set (Mallett, Kawabata, Newcombe, et al., 2007). The modified confirmatory-factor-analysis model with these two items removed fit to the present study’s data satisfactorily and all six factors were adequately diferentiated. These results generally validate the SMS-6 responses. Furthermore, this study demonstrated the usefulness of a comparison of confirmatory-factor-analysis and exploratory-structural-equation-modelling solutions for an accurate interpretation of individual parameters.
Association of Serotonin Transporter Gene Polymorphism with Obstructive Sleep Apnea Syndrome

Background and Objective: Obstructive sleep apnea syndrome (OSAS) is a common condition characterized by repetitive pharyngeal collapse during sleep and daytime sleepiness. There is genetic predisposition to sleep disorders. Serotonin is involved in the regulation of sleep. The synaptic 5‐hydroxytryptamine (HT) is inactivated by presynaptic reuptake, which is mediated by the serotonin transporter. Blockage of the serotonin transporter leads to increased extracellular 5‐HT. Polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level and may be important in OSAS. In this study, we aimed to assess the role of STG polymorphism in OSAS.
Medical Management of Sinusitis: Educational Goals and Management Guidelines

The primary goal of sinusitis management is resolution of infection, leading to patency of the ostiomeatal complex. Antibiotics and decongestants are the cornerstones of therapy for acute sinusitis. Diagnosis of acute sinusitis is based on the history and physical findings. Sinusitis is considered to be acute or recurrent acute if infection resolves without residual mucosal damage. Choices for first-line antibiotic therapy include adequate dosages of trimethoprim-sulfamethoxazole, loracarbef, and amoxicillin-clavulanate. Decongestants and mucoevacuants may reduce tissue edema, facilitate drainage, and maintain ostial patency. Topical corticosteroids are useful additional therapy in allergic rhinosinusitis and as an aid in the long-term management of chronic sinusitis. Parenteral corticosteroids have no role in first-line management of acute or recurrent acute sinusitis.
Prognosis of patients with gastric cancer and solitary lymph node metastasis.

AIM To investigate the relationship of solitary lymph node metastasis (SLNM) and age with patient survival in gastric cancer (GC). METHODS The medical records databases of China's Beijing Cancer Hospital at the Peking University School of Oncology and Shanghai Tenth People's Hospital affiliated to Tongji University were searched retrospectively to identify patients with histologically proven GC and SLNM who underwent surgical resection between October 2003 and December 2012. Patients with distant metastasis or gastric stump carcinoma following resection for benign disease were excluded from the analysis. In total, 936 patients with GC + SLNM were selected for analysis and the recorded parameters of clinicopathological disease and follow-up (range: 13-2925 d) were collected. The Kaplan-Meier method was used to stratify patients by age (≤ 50 years-old, n = 198; 50-64 years-old, n = 321; ≥ 65 years-old, n = 446) and by metastatic lymph node ratio [MLR < 0.04 (1/25), n = 180; 0.04-0.06 (1/25-1/15), n = 687; ≥ 0.06 (1/15), n = 98] for 5-year survival analysis. The significance of intergroup differences between the survival curves was assessed by a log-rank test. RESULTS The 5-year survival rate of the entire GC + SLNM patient population was 49.9%. Stratification analysis showed significant differences in survival time (post-operative days) according to age: ≤ 50 years-old: 950.7 ± 79.0 vs 50-64 years-old: 1697.8 ± 65.9 vs ≥ 65 years-old: 1996.2 ± 57.6, all P < 0.05. In addition, younger age (≤ 50 years-old) correlated significantly with mean survival time (r = 0.367, P < 0.001). Stratification analysis also indicated an inverse relationship between increasing MLR and shorter survival time: < 0.04: 52.8% and 0.04-0.06: 51.1% vs ≥ 0.06: 40.5%, P < 0.05. The patients with the shortest survival times and rates were younger and had a high MLR (≥ 0.06): ≤ 50 years-old: 496.4 ± 133.0 and 0.0% vs 50-65 years-old: 1180.9 ± 201.8 and 21.4% vs ≥ 65 years-old: 1538.4 ± 72.4 and 37.3%, all P < 0.05. The same significant trend in shorter survival times and rates for younger patients was seen with the mid-range MLR group (0.04-0.06), but the difference between the two older groups was not significant. No significant differences were found between the age groups of patients with MLR < 0.04. Assessment of clinicopathological parameters identified age group, Borrmann type, histological type and tumor depth as the most important predictors of the survival rates and times observed for this study population. CONCLUSION GC patients below 51 years of age with MLR of SLNM above 0.06 have shorter life expectancy than their older counterparts.
Genetic divergence in the small Indian mongoose (Herpestes auropunctatus), a widely distributed invasive species

The combination of founder events, random drift and new selective forces experienced by introduced species typically lowers genetic variation and induces differentiation from the ancestral population. Here, we investigate microsatellite differentiation between introduced and native populations of the small Indian mongoose (Herpestes auropunctatus). Many expectations based on introduction history, such as loss of alleles and relationships among populations, are confirmed. Nevertheless, when applying population assignment methods to our data, we observe a few specimens that are incorrectly assigned and/or appear to have a mixed ancestry, despite estimates of substantial population differentiation. Thus, we suggest that population assignments of individuals should be viewed as tentative and that there should be agreement among different algorithms before assignments are applied in conservation or management. Further, we find no congruence between previously reported morphological differentiation and the sorting of microsatellite variation. Some introduced populations have retained much genetic variation while others have not, irrespective of morphology. Finally, we find alleles from the sympatric grey mongoose (Herpestes edwardsii) in one small Indian mongoose within the native range, suggesting an alternative explanation for morphological differentiation involving a shift in female preferences in allopatry.
Immunoglobulin class‐switch recombination occurs in mantle cell lymphomas

Mantle cell lymphoma (MCL) is an IgM‐expressing B cell lymphoma that originates from naive B cells and responds poorly to chemotherapy. We show here that several MCLs harbour isotype‐switched subclones. Similar to the situation in normal B cells, in vitro stimulation of MCL cell lines with CD40 ligand (CD40L) and interleukin‐4 induced expression of activation‐induced cytidine deaminase (AID) and germline transcription at the immunoglobulin heavy chain gene locus. Additionally, the occurrence of switch‐circle transcripts and mature IgG transcripts after stimulation indicated ongoing class‐switch recombination in mantle cell lymphoma cell lines. Furthermore, stimulation of primary MCL cells in vitro induced expression of class‐switched IgG mRNA in the tumour cells. Our data indicate that mantle cell lymphomas have retained the ability to undergo class‐switch recombination if appropriate stimuli, such as the CD40 ligand, are provided. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Ca2+ influx in human T lymphocytes is induced independently of inositol phosphate production by mobilization of intracellular Ca2+ stores. A study with the Ca2+ endoplasmic reticulum‐ATPase inhibitor thapsigargin

Thapsigargin (TG), a sesquiterpene lactone and non‐phorbol 12‐myristate 13‐acetate tumor promoter, stimulates a rapid increase in intracellular free Ca2+ ([Ca2+]i) in human T lymphocytes clone P28. The [Ca2+]i response to TG is sustained in the presence of 1 mM extracellular Ca2+, while it becomes transient in Ca2+‐free medium suggesting that TG activates both the release of Ca2+ from intracellular stores and the entry of Ca2+ from extracellular spaces. TG‐induced Ca2+ influx is completely abolished after cell depolarization caused by increased extracellular concentrations of K+. The rise in [Ca2+]i stimulated by TG occurs in the absence of detectable production of inositol phosphates. Moreover, TG does not alter the early biochemical events of T cell activation triggered through the CD2 or the CD3 T cell antigens. Indeed, both inositol phosphate production and intracellular pH increase induced by specific monoclonal antibodies (mAb) remain unchanged after TG treatment. These data suggest that in human T lymphocytes TG releases Ca2+ from an intracellular pool by a mechanism which is independent of the phospholipase C metabolic pathway. Preincubation with TG of T cell clone P28 empties both the CD2 and the CD3‐sensitive intracellular Ca2+ pool(s). Conversely, prestimulation of T cell clone P28 by CD3 or CD2‐specific mAb inhibits the Ca2+‐mobilizing effect of TG. Thus it appears that TG and CD2‐or CD3‐specific mAb mobilize Ca2+ from common Ca2+ pool(s). Taken together, these results demonstrate that Ca2+ influx in human T cells may be linked to mobilization of intracellular Ca2+ pools and by a mechanism independent of phosphoinositide hydrolysis. They further indicate that the release of intracellular Ca2+ pool(s) may play a major role in the opening of cell membrane Ca2+ channels observed during the CD2‐ or CD3‐induced stimulation of human T lymphocytes.
Trade Liberalization and Regional Dynamics

We study the evolution of trade liberalizationâ€™s effects on local labor markets, following Brazilâ€™s early 1990s trade liberalization. Regions that initially specialized in industries facing larger tariff cuts experienced prolonged declines in formal sector employment and earnings relative to other regions. The impact of tariff changes on regional earnings 20 years after liberalization was three times the size of the effect 10 years after liberalization. These findings are robust to a variety of alternative specifications and to controlling for a wide array of postliberalization shocks. The pattern of increasing effects on regional earnings is not consistent with conventional spatial equilibrium models, which predict that effect magnitudes decline over time due to spatial arbitrage. We investigate potential mechanisms, finding empirical support for a mechanism involving imperfect interregional labor mobility and dynamics in labor demand, driven by slow capital adjustment and agglomeration economies. This mechanism gradually amplifies the initial labor demand shock resulting from liberalization. We show that the mechanism explains the slow adjustment path of regional earnings and quantitatively accounts for the magnitude of the long-run effects. [Working Paper No. 488].
Person-Centered Care for Mental Illness: The Evolution of Adherence and Self-Determination

Contributors Acknowledgments Introduction Patrick Corrigan The Problem of Adherence and the Importance of Self-Determination Patrick W. Corrigan, Kristin Kosyluk, and Petra Kottsieper Beyond the Rational Patient: Implications for Health Decisions and Behaviors Patrick W. Corrigan, Karina J. Powell, and Patrick J. Michaels How Does Stigma Impede Adherence and Self-Determination? Patrick W. Corrigan and Andrea B. Bink Person-Centered Care Larry Davidson, Janis Tondora, Rebecca Miller, and Maria J. O'Connell Psychiatric Advance Directives Maria J. O'Connell Shared Decision Making Beth Angell, Elizabeth Matthews, Victoria Stanhope, and Michael Rowe Increasing Employment Motivation for Individuals With Psychiatric Disabilities Jonathon E. Larson Cognitive Approaches That Impact Self-Determination Patrick J. Michaels, Karina J. Powell, and Patrick W. Corrigan Self-Determination Within the Context of Legally Mandated Treatment Amy C. Watson Peer Support and Service Engagement Mark S. Salzer and Petra Kottsieper Self-Determination and Cultural Considerations: An Asian Perspective Eun-Jeong Lee, Chow Lam, and Nicole Ditchman Critical Last Thoughts About Self-Determination and Recovery Patrick W. Corrigan Index About the Editor
Epidemiology and Impact of Low-Back Pain

Disorders of the lumbar spine are among the most common medical problems in western countries, affecting up to 80% of people at some time during their lives. The epidemiology and impact of six specific disorders of the lumbar spine are reviewed. These include prolapsed discs, disc degeneration, osteoarthrosis of the apophyseal joints, fractures and dislocations of vertebrae, osteoporosis, and spondylolisthesis. Various mechanical factors contribute to the causation of most of these disorders, but other underlying pathologic mechanisms are important as well. In light of the great impact of these conditions on society and on individuals, it is concluded that there is a considerable need for a greater allocation of resources for improvement in methods of prevention, diagnosis, and treatment.
Bronchodilator use and the risk of arrhythmia in COPD: part 1: Saskatchewan cohort study.

BACKGROUND Bronchodilators are first-line therapy for COPD. There is some evidence that they may increase the risk of cardiac arrhythmias. METHODS We used the computerized health-care databases of the Province of Saskatchewan, Canada, to identify a cohort of subjects with COPD, aged ≥ 55 years, between 1990 and 1999. The subjects were followed until December 2003 for a hospital admission for, or death from, arrhythmia. A nested case-control approach was used to match each arrhythmia case on age, sex, and calendar time to 20 control subjects selected from the corresponding cohort risk set. Conditional logistic regression was used to estimate the rate ratio (RR) of arrhythmia associated with new use of bronchodilators, adjusted for disease severity and comorbidity. RESULTS The cohort included 6,018 patients with COPD in whom 469 arrhythmia cases occurred, including 56 deaths, for an overall rate of 1.37 arrhythmias per 100 per year. The rate of arrhythmia was elevated with the new use of ipratropium (RR, 2.4; 95% CI, 1.4-4.0) and of long-acting β-agonists (LABAs) (RR, 4.5; 95% CI, 1.4-14.4). It was not elevated with new use of short-acting β-agonists (RR, 0.9; 95% CI, 0.5-1.6) or methylxanthines (RR, 1.6; 95% CI, 0.7-3.7). CONCLUSIONS The new use of bronchodilators, particularly ipratropium and LABAs, may increase the risk of cardiac arrhythmias in patients with COPD. Although these results raise concerns regarding LABAs, they were based on few cases and require confirmation in larger cohorts.