Publications by authors named "Subhashis Banerjee"

57 Publications

Functional outcome of supracondylar humerus fracture in children with the use of pin configuration as per Bahk classification.

J Clin Orthop Trauma 2021 Feb 21;13:78-81. Epub 2020 Aug 21.

Department of Orthopaedics, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India.

Introduction: A variety of fracture patterns are seen in supracondylar humerus fractures in children and these are well described by Bahk et al. Currently followed treatment protocol doesn't recognize these common fracture patterns and pin placement is done at the discretion of the treating surgeon. The aim of the study is to evaluate the usefulness of Bahk classification system in deciding the pin configuration for the specific fracture patterns and thereby assess the functional outcome in the management of supracondylar fractures in children.

Method: The study was done on 100 children of 2-12 years of age from February 2019 to January 2020. After closed reduction under general anesthesia, fractures were classified and pin configuration was decided according to Bahk classification. In the follow-up, patients were assessed for clinicoradiological outcomes based on Modified Flynn's criteria, Baumann angle, and anterior humeral line.

Results: In our study Typical transverse and low sagittal fracture were the most common fracture patterns. In the final follow up as per Flynn's criteria, 93% of the patients showed excellent results. Mean Baumann's angle was not significantly different from the uninjured side and anterior humeral line passed through anterior or middle third of the capitulum in 95% patients.

Conclusion: Using pin configuration suitable to fracture pattern as per Bahk classification improves functional outcome in supracondylar humerus fractures in children and minimizes complications.
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http://dx.doi.org/10.1016/j.jcot.2020.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920002PMC
February 2021

Artificial Intelligence-assisted chest X-ray assessment scheme for COVID-19.

Eur Radiol 2021 Jan 20. Epub 2021 Jan 20.

Indian Institute of Technology, Delhi, New Delhi, India.

Objectives: To study whether a trained convolutional neural network (CNN) can be of assistance to radiologists in differentiating Coronavirus disease (COVID)-positive from COVID-negative patients using chest X-ray (CXR) through an ambispective clinical study. To identify subgroups of patients where artificial intelligence (AI) can be of particular value and analyse what imaging features may have contributed to the performance of AI by means of visualisation techniques.

Methods: CXR of 487 patients were classified into [4] categories-normal, classical COVID, indeterminate, and non-COVID by consensus opinion of 2 radiologists. CXR which were classified as "normal" and "indeterminate" were then subjected to analysis by AI, and final categorisation provided as guided by prediction of the network. Precision and recall of the radiologist alone and radiologist assisted by AI were calculated in comparison to reverse transcriptase-polymerase chain reaction (RT-PCR) as the gold standard. Attention maps of the CNN were analysed to understand regions in the CXR important to the AI algorithm in making a prediction.

Results: The precision of radiologists improved from 65.9 to 81.9% and recall improved from 17.5 to 71.75 when assistance with AI was provided. AI showed 92% accuracy in classifying "normal" CXR into COVID or non-COVID. Analysis of attention maps revealed attention on the cardiac shadow in these "normal" radiographs.

Conclusion: This study shows how deployment of an AI algorithm can complement a human expert in the determination of COVID status. Analysis of the detected features suggests possible subtle cardiac changes, laying ground for further investigative studies into possible cardiac changes.

Key Points: • Through an ambispective clinical study, we show how assistance with an AI algorithm can improve recall (sensitivity) and precision (positive predictive value) of radiologists in assessing CXR for possible COVID in comparison to RT-PCR. • We show that AI achieves the best results in images classified as "normal" by radiologists. We conjecture that possible subtle cardiac in the CXR, imperceptible to the human eye, may have contributed to this prediction. • The reported results may pave the way for a human computer collaboration whereby the expert with some help from the AI algorithm achieves higher accuracy in predicting COVID status on CXR than previously thought possible when considering either alone.
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http://dx.doi.org/10.1007/s00330-020-07628-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816060PMC
January 2021

An audit of admissions and mortality of orthopedic indoor patients in a tertiary care hospital of India.

J Clin Orthop Trauma 2020 Jul 14;11(Suppl 4):S518-S521. Epub 2020 Apr 14.

Department of Orthopaedics, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai, India.

Introduction: Mortality in orthopaedics is different in underdeveloped, developing and developed countries depending on the health, orthopaedic and trauma care services, education status and social awareness. Analysis of mortality and causes of death is an important step to identify the risk factor. Such study is invaluable for epidemiological monitoring and health care planning.

Methods: Between September 2015 to August 2018 demographic data, timing and primary diagnosis of both mortality and admission were collected retrospectively in a leading tertiary care hospital in the city of Mumbai, India.

Results: Total admissions of 10,937 in the 3-year period with increased average monthly admission in the month of June, July and August. Trauma to be most common cause of admission and death and Road traffic accident to be the most common cause of trauma followed by slip and fall. The death rate was 0.55 per 100 admissions per year. In males most common age group was 18-60 years and in females above 60 years of age.

Conclusion: There is a link of increased admission rate in the monsoon months (rainy season) in India and road traffic accident and slip and fall. So accident prevention and health care planning and management of trauma victim, improvement of quality of life of general population will reduce trauma and related complications.
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http://dx.doi.org/10.1016/j.jcot.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394819PMC
July 2020

Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction.

J Biol Chem 2020 10 29;295(40):13753-13768. Epub 2020 Jul 29.

Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA; Department of Metabolism and Aging, Scripps Research Institute, Jupiter, Florida, USA; Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, USA. Electronic address:

The micropeptide adropin encoded by the clock-controlled energy homeostasis-associated gene is implicated in the regulation of glucose metabolism. However, its links to rhythms of nutrient intake, energy balance, and metabolic control remain poorly defined. Using surveys of Gene Expression Omnibus data sets, we confirm that fasting suppresses liver adropin expression in lean C57BL/6J (B6) mice. However, circadian rhythm data are inconsistent. In lean mice, caloric restriction (CR) induces bouts of compulsive binge feeding separated by prolonged fasting intervals, increasing NAD-dependent deacetylase sirtuin-1 signaling important for glucose and lipid metabolism regulation. CR up-regulates adropin expression and induces rhythms correlating with cellular stress-response pathways. Furthermore, adropin expression correlates positively with phosphoenolpyruvate carboxokinase-1 () expression, suggesting a link with gluconeogenesis. Our previous data suggest that adropin suppresses gluconeogenesis in hepatocytes. Liver-specific adropin knockout (LAdrKO) mice exhibit increased glucose excursions following pyruvate injections, indicating increased gluconeogenesis. Gluconeogenesis is also increased in primary cultured hepatocytes derived from LAdrKO mice. Analysis of circulating insulin levels and liver expression of fasting-responsive cAMP-dependent protein kinase A (PKA) signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 µg/kg intraperitoneally). Fasting-associated changes in PKA signaling are attenuated in transgenic mice constitutively expressing adropin and in fasting mice treated acutely with adropin peptide. In summary, hepatic adropin expression is regulated by nutrient- and clock-dependent extrahepatic signals. CR induces pronounced postprandial peaks in hepatic adropin expression. Rhythms of hepatic adropin expression appear to link energy balance and cellular stress to the intracellular signal transduction pathways that drive the liver fasting response.
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http://dx.doi.org/10.1074/jbc.RA120.014381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535914PMC
October 2020

Poor prognostic factors in predicting abatacept response in a phase III randomized controlled trial in psoriatic arthritis.

Rheumatol Int 2020 Jul 30;40(7):1021-1028. Epub 2020 Apr 30.

Bristol-Myers Squibb, Princeton, NJ, USA.

In ASTRAEA (NCT01860976), abatacept significantly increased American College of Rheumatology criteria 20% (ACR20) responses at Week 24 versus placebo in patients with psoriatic arthritis (PsA). This post hoc analysis explored relationships between prospectively identified baseline characteristics [poor prognostic factors (PPFs) ] and response to abatacept. Patients were randomized (1:1) to receive subcutaneous abatacept 125 mg weekly or placebo for 24 weeks; those without ≥ 20% improvement in joint counts at Week 16 switched to open-label abatacept. Potential predictors of ACR20 response were identified by treatment arm using multivariate analyses. Likelihood of ACR20 response to abatacept versus placebo was compared in univariate and multivariate analyses in subgroups stratified by the PPF, as defined by EULAR and/or GRAPPA treatment guidelines. Odds ratios (ORs) were generated using logistic regression to identify meaningful differences (OR cut-off: 1.2). 424 patients were randomized and treated (abatacept n = 213; placebo n = 211). In abatacept-treated patients, elevated C-reactive protein (CRP), high Disease Activity Score based on 28 joints (CRP), presence of dactylitis, and ≥ 3 joint erosions were identified as predictors of response (OR > 1.2). In placebo-treated patients, only dactylitis was a potential predictor of response. In the univariate analysis stratified by PPF, ACR20 response was more likely (OR > 1.2) with abatacept versus placebo in patients with baseline PPFs than in those without; multivariate analysis confirmed this finding. Response to abatacept versus placebo is more likely in patients with features indicative of high disease activity and progressive disease; these characteristics are recognized as PPFs in treatment guidelines for PsA.
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http://dx.doi.org/10.1007/s00296-020-04564-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256096PMC
July 2020

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon-γ-Induced Protein 10, BMS-986184, in Healthy Participants to Guide Therapeutic Dosing.

Clin Pharmacol Drug Dev 2020 08 18;9(6):689-698. Epub 2020 Feb 18.

Bristol-Myers Squibb, Princeton, New Jersey, USA.

BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials. Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.
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http://dx.doi.org/10.1002/cpdd.784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496395PMC
August 2020

Novel Volumetric Sub-region Segmentation in Brain Tumors.

Front Comput Neurosci 2020 24;14. Epub 2020 Jan 24.

Machine Intelligence Unit, Indian Statistical Institute, Kolkata, India.

A novel deep learning based model called Multi-Planar Spatial Convolutional Neural Network (MPS-CNN) is proposed for effective, automated segmentation of different sub-regions . peritumoral edema (), necrotic core (), enhancing and non-enhancing tumor core (/), from multi-modal MR images of the brain. An encoder-decoder type CNN model is designed for pixel-wise segmentation of the tumor along three anatomical planes (axial, sagittal, and coronal) at the slice level. These are then combined, by incorporating a consensus fusion strategy with a fully connected Conditional Random Field (CRF) based post-refinement, to produce the final volumetric segmentation of the tumor and its constituent sub-regions. Concepts, such as spatial-pooling and unpooling are used to preserve the spatial locations of the edge pixels, for reducing segmentation error around the boundaries. A new aggregated loss function is also developed for effectively handling data imbalance. The MPS-CNN is trained and validated on the recent Multimodal Brain Tumor Segmentation Challenge (BraTS) 2018 dataset. The Dice scores obtained for the validation set for whole tumor ( :/ + +), tumor core (:/ +), and enhancing tumor () are 0.90216, 0.87247, and 0.82445. The proposed MPS-CNN is found to perform the best (based on leaderboard scores) for and segmentation tasks, in terms of both the quantitative measures (viz. Dice and Hausdorff). In case of the segmentation it also achieved the second highest accuracy, with a score which was only 1% less than that of the best performing method.
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http://dx.doi.org/10.3389/fncom.2020.00003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993215PMC
January 2020

A Review of Physical Simulators for Neuroendoscopy Skills Training.

World Neurosurg 2020 05 31;137:398-407. Epub 2020 Jan 31.

Department of Computer Science Engineering, Indian Institute of Technology-Delhi, New Delhi, India.

Background: Minimally invasive neurosurgical approaches reduce patient morbidity by providing the surgeon with better visualization and access to complex lesions, with minimal disruption to normal anatomy. The use of rigid or flexible neuroendoscopes, supplemented with a conventional stereoscopic operating microscope, has been integral to the adoption of these techniques. Neurosurgeons commonly use neuroendoscopes to perform the ventricular and endonasal approaches. It is challenging to learn neuroendoscopy skills from the existing apprenticeship model of surgical education. The training methods, which use simulation-based systems, have achieved wide acceptance. Physical simulators provide anatomic orientation and hands-on experience with repeatability. Our aim is to review the existing physical simulators on the basis of the skills training of neuroendoscopic procedures.

Methods: We searched Scopus, Google Scholar, PubMed, IEEE Xplore, and dblp. We used the following keywords "neuroendoscopy," "training," "simulators," "physical," and "skills evaluation." A total of 351 articles were screened based on development methods, evaluation criteria, and validation studies on physical simulators for skills training in neuroendoscopy.

Results: The screening of the articles resulted in classifying the physical training methods developed for neuroendoscopy surgical skills into synthetic simulators and box trainers. The existing simulators were compared based on their design, fidelity, trainee evaluation methods, and validation studies.

Conclusions: The state of simulation systems demands collaborative initiatives among translational research institutes. They need improved fidelity and validation studies for inclusion in the surgical educational curriculum. Learning should be imparted in stages with standardization of performance metrics for skills evaluation.
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http://dx.doi.org/10.1016/j.wneu.2020.01.183DOI Listing
May 2020

An Unusual Case of Aneurysmal Bone Cyst of Proximal Phalanx in a 2 Year Old Child.

J Hand Surg Asian Pac Vol 2020 Mar;25(1):114-118

Department of Orthopaedics, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Sion, Mumbai, India.

Aneurysmal bone cysts associated with tubular bones of the hand are rare and even rarer in the paediatric age-group. They are rapidly growing, destructive benign bone tumors. Multiple treatment modalities for aneurysmal bone cyst have been reported in the literature, but controversy exists regarding optimal treatment. We report a case of aneurysmal bone cyst of proximal phalanx of middle finger in a 2 year old child treated at our tertiary care hospital. The diagnosis was confirmed with pre-operative MRI, FNAC and post-operative histopathology. Curettage of the lesion and autologous bone grafting was performed. The hand was immobilized in a short below elbow slab for 4 weeks followed by physiotherapy. Excellent radiological and functional outcomes were obtained with no recurrence at a 5 year of follow up.
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http://dx.doi.org/10.1142/S2424835520720029DOI Listing
March 2020

Safety of Abatacept Versus Placebo in Rheumatoid Arthritis: Integrated Data Analysis of Nine Clinical Trials.

ACR Open Rheumatol 2019 Jun 29;1(4):251-257. Epub 2019 May 29.

Amsterdam University Medical Centers Vrije Universiteit Amsterdam Netherlands.

Objective: To assess the safety of abatacept treatment in rheumatoid arthritis (RA) using integrated data from multiple clinical trials.

Methods: Data from nine double-blind, placebo-controlled studies of abatacept treatment (seven intravenous, two subcutaneous) in patients with RA were pooled, focusing on safety events in the double-blind treatment period of each study. Incidence rates (IRs) of adverse events (AEs) per 100 patient-years of exposure were calculated for abatacept- and placebo-treated patients. AEs in abatacept-treated patients were combined regardless of dose and formulation.

Results: In total, 2653 patients received abatacept and 1485 received placebo, with 2357 and 1254 patient-years of exposure, respectively. The mean (SD) durations of exposure in the abatacept and placebo groups were 10.8 (3.3) and 10.3 (3.5) months, respectively. The IRs (95% confidence interval [CI]) for serious AEs were 14.8 (13.3, 16.5) and 14.6 (12.5, 17.0) in the abatacept and placebo groups, respectively. Death occurred in 12 (0.5%) and 12 (0.8%) patients in the abatacept and placebo groups, respectively, and was most commonly caused by cardiac disorders. Malignancies were observed in 31 patients (1.2%) treated with abatacept (IR: 1.32 [95% CI: 0.90, 1.87]) versus 14 (0.9%; IR: 1.12 [0.61, 1.88]) who received placebo. Solid organ tumor was the most frequent malignancy reported in both groups (abatacept: 1.0%; IR: 1.11 [95% CI: 0.72, 1.62]; placebo: 0.8%; 0.96 [0.50, 1.67]).

Conclusion: In this integrated analysis, the IRs of safety events in the abatacept and placebo groups were similar with no new safety concerns identified.
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http://dx.doi.org/10.1002/acr2.1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858048PMC
June 2019

Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension.

Circulation 2019 12 10;140(24):2005-2018. Epub 2019 Oct 10.

University of Texas Southwestern Medical Center, Dallas (J.P., W.V., S.B., I.S.Y., K.T., A.S., H.C., N.C.S., A.R., K.L.C., C.M., P.W.S.).

Background: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension.

Methods: Involvement of IgG was studied using IgG μ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc).

Results: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension.

Conclusions: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027951PMC
December 2019

Baseline Objective Inflammation by Magnetic Resonance Imaging as a Predictor of Therapeutic Benefit in Early Rheumatoid Arthritis With Poor Prognosis.

Arthritis Care Res (Hoboken) 2020 07 26;72(7):959-964. Epub 2020 May 26.

University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK.

Objective: High magnetic resonance imaging (MRI)-detected inflammation is associated with greater progression and poorer outcomes in rheumatoid arthritis (RA). This analysis aimed to determine if baseline MRI inflammation was related to clinical response and remission in the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) study.

Methods: AVERT was a phase IIIb, randomized, controlled trial with a 12-month, double-blind treatment period enrolling patients with early (≤2 years' duration), anti-citrullinated peptide-positive methotrexate (MTX)-naive RA. In this post hoc analysis, patients in the abatacept plus MTX (n = 114) and MTX (n = 111) arms with available MRI results were stratified into low and high baseline MRI inflammation groups based on previously developed cutoffs of synovitis and osteitis on unilateral hand-wrist contrast-enhanced MRI. Simplified Disease Activity Index (SDAI) remission (≤3.3), Clinical Disease Activity Index (CDAI) remission (≤2.8), Boolean remission, and Disease Activity Score in 28 joints using the C-reactive protein level (<2.6) were assessed.

Results: Overall, 100 of 225 patients (44.4%) had high baseline MRI inflammation. In patients with high baseline MRI inflammation, a significantly greater proportion achieved remission at 12 months with abatacept plus MTX versus MTX across SDAI (45.1% versus 16.3%; P = 0.0022), CDAI (47.1% versus 20.4%; P = 0.0065), and Boolean indices (39.2% versus 16.3%; P = 0.0156). In patients with low baseline MRI inflammation, remission rates were not significantly different with abatacept plus MTX versus MTX (SDAI: 39.7% versus 32.3%; P = 0.4961).

Conclusion: In seropositive, MTX-naive patients with early RA and presence of objectively measured high inflammation by MRI, indicating poor prognosis, remission rates were higher with abatacept plus MTX treatment versus MTX.
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http://dx.doi.org/10.1002/acr.24072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383909PMC
July 2020

A review of virtual reality simulators for neuroendoscopy.

Neurosurg Rev 2020 Oct 23;43(5):1255-1272. Epub 2019 Aug 23.

Department of Computer Science Engineering, Indian Institute of Technology Delhi, New Delhi, India.

Neurosurgery is a challenging surgical specialty that demands many technical and cognitive skills. The traditional surgical training approach of having a trainee coached in the operating room by the faculty is time-consuming, costly, and involves patient risk factors. Simulation-based training methods are suitable to impart the surgical skills outside the operating room. Virtual simulators allow high-fidelity repeatable environment for surgical training. Neuroendoscopy, a minimally invasive neurosurgical technique, demands additional skills for limited maneuverability and eye-hand coordination. This study provides a review of the existing virtual reality simulators for training neuroendoscopic skills. Based on the screening, the virtual training methods developed for neuroendoscopy surgical skills were classified into endoscopic third ventriculostomy and endonasal transsphenoidal surgery trainers. The study revealed that a variety of virtual reality simulators have been developed by various institutions. Although virtual reality simulators are effective for procedure-based skills training, the simulators need to include anatomical variations and variety of cases for improved fidelity. The review reveals that there should be multi-centric prospective and retrospective cohort studies to establish concurrent and predictive validation for their incorporation in the surgical educational curriculum.
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http://dx.doi.org/10.1007/s10143-019-01164-7DOI Listing
October 2020

Body mass index and treatment response to subcutaneous abatacept in patients with psoriatic arthritis: a analysis of a phase III trial.

RMD Open 2019 30;5(1):e000934. Epub 2019 May 30.

Swedish Medical Center and University of Washington, Seattle, Washington, USA.

Objective: This analysis of the phase III Active PSoriaTic Arthritis RAndomizEd TriAl (ASTRAEA) evaluated the effect of baseline body mass index (BMI) on subsequent response to subcutaneous (SC) abatacept in patients with psoriatic arthritis (PsA).

Methods: In ASTRAEA, patients with active PsA were randomised (1:1) to receive blinded weekly SC abatacept 125 mg or placebo for 24 weeks. Treatment response at week 24 was assessed by the proportions of patients achieving American College of Rheumatology 20% improvement response, Disease Activity Score in 28 joints (DAS28 (C reactive protein (CRP))) ≤3.6 and <2.6, Health Assessment Questionnaire-Disability Index reduction from baseline ≥0.35 and radiographic non-progression (defined as change from baseline ≤0 in PsA-modified total Sharp/van der Heijde score). Responses were stratified by baseline BMI (underweight/normal, <25 kg/m; overweight, 25-30 kg/m; obese, >30 kg/m) and compared in univariate and multivariate models.

Results: Of 212/213 and 210/211 patients with baseline BMI data in the abatacept and placebo groups, respectively, 15% and 19% were underweight/normal, 36% and 27% were overweight, and 49% and 54% were obese. After adjusting for baseline characteristics, there were no significant differences for any outcome measure at week 24 with abatacept in the overweight or obese versus underweight/normal subgroup. In the placebo group, patients in the obese versus underweight/normal subgroup were significantly less likely to achieve DAS28 (CRP) <2.6 at week 24 (OR 0.26; 95% CI 0.08 to 0.87; p=0.03).

Conclusion: BMI does not impact clinical or radiographic response to SC abatacept in patients with PsA.

Trial Registration Number: NCT01860976.
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http://dx.doi.org/10.1136/rmdopen-2019-000934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560664PMC
April 2020

Development of novel liver X receptor modulators based on a 1,2,4-triazole scaffold.

Bioorg Med Chem Lett 2019 02 15;29(3):449-453. Epub 2018 Dec 15.

Chemistry Department, Faculty of Science, Benha University, Benha 13518, Egypt; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63110, USA. Electronic address:

Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer's disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility.
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http://dx.doi.org/10.1016/j.bmcl.2018.12.025DOI Listing
February 2019

Improved patient-reported outcomes in patients with psoriatic arthritis treated with abatacept: results from a phase 3 trial.

Arthritis Res Ther 2018 12 6;20(1):269. Epub 2018 Dec 6.

Swedish Medical Center and University of Washington, Seattle, WA, USA.

Background: To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA).

Methods: Patients with PsA were randomised (1:1) to subcutaneous abatacept 125 mg weekly/placebo for 24 weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs ≤ upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and ≥ normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed.

Results: In total population, numerically higher improvements in most PROs were reported with abatacept (n = 213) versus placebo (n = 211) at both time points (P > 0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and ≥ NV at week 16. At week 16, all PRO improvements were numerically greater (P > 0.05) in patients with baseline CRP > ULN versus CRP ≤ ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers.

Conclusions: Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations.

Trial Registration: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013.
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http://dx.doi.org/10.1186/s13075-018-1769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282264PMC
December 2018

Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.

N Engl J Med 2018 10 11;379(14):1313-1321. Epub 2018 Sep 11.

From K. Papp Clinical Research and Probity Medical Research, Waterloo (K.P.), the SKiN Centre for Dermatology and Probity Medical Research, Peterborough (M.G.), and Queen's University, Kingston (M.G.) - all in Ontario, Canada; Medical College of Wisconsin, Milwaukee (K.G.); the University of Luebeck, Luebeck, Germany (D.T.); Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan (A.M.); the University of Melbourne, St. Vincent's Hospital Melbourne, Skin and Cancer Foundation, and Probity Medical Research, Melbourne, VIC, Australia (P.F.); and Bristol-Myers Squibb, Princeton, NJ (I.G.G., S.K., S.B.).

Background: Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis.

Methods: We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis).

Results: A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P=0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment.

Conclusions: Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838 .).
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http://dx.doi.org/10.1056/NEJMoa1806382DOI Listing
October 2018

Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics.

Biomedicines 2018 May 5;6(2). Epub 2018 May 5.

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.

The promise of nucleic acid based oligonucleotides as effective genetic therapies has been held back by their low bioavailability and poor cellular uptake to target tissues upon systemic administration. One such strategy to improve upon delivery is the use of short cell-penetrating peptides (CPPs) that can be either directly attached to their cargo through covalent linkages or through the formation of noncovalent nanoparticle complexes that can facilitate cellular uptake. In this review, we will highlight recent proof-of-principle studies that have utilized both of these strategies to improve nucleic acid delivery and discuss the prospects for translation of this approach for clinical application.
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http://dx.doi.org/10.3390/biomedicines6020051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027240PMC
May 2018

Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthritis: 5-year Results from a Phase IIIb Trial.

J Rheumatol 2018 08 15;45(8):1085-1092. Epub 2018 Apr 15.

From Stanford University, Palo Alto, California; Arthritis Center of Nebraska, Lincoln, Nebraska; Box Arthritis and Rheumatology of the Carolinas, Charlotte, North Carolina; Low Country Rheumatology, Charleston, South Carolina; Bristol-Myers Squibb, Princeton, New Jersey, USA; Universidad Autónoma de Chihuahua, Chihuahua; Unidad Reumatológica Las Américas S.C.P., Mérida; Köhler & Milstein Research, Mérida, Mexico; Instituto De Ginecología Y Reproducción, Lima, Peru; Organización Médica de Investigación, Buenos Aires, Argentina; Pontifical Catholic University, Porto Alegre, Brazil; University of Queensland, Brisbane, Australia; Russian Academy of Medical Sciences, Moscow, Russia; Cliniques Universitaires Saint-Luc; Université Catholique de Louvain, Brussels, Belgium; Schlosspark-Klinik University Medicine, Berlin, Germany.

Objective: To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA).

Methods: The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported.

Results: Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96-8.58), infection 38.60 (36.24-41.12), serious infection 1.68 (1.35-2.07), malignancies 1.09 (0.84-1.42), and autoimmune disorders 1.33 (1.05-1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study.

Conclusion: These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.
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http://dx.doi.org/10.3899/jrheum.170344DOI Listing
August 2018

Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: Results From a Phase III Open-Label Study.

Arthritis Rheumatol 2018 07 20;70(7):1144-1154. Epub 2018 May 20.

Istituto Giannina Gaslini, Genoa, Italy.

Objective: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA).

Methods: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (C ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity.

Results: The median abatacept C at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 μg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects.

Conclusion: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.
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http://dx.doi.org/10.1002/art.40466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032847PMC
July 2018

Volumetric brain tumour detection from MRI using visual saliency.

PLoS One 2017 2;12(11):e0187209. Epub 2017 Nov 2.

Dept. of Computer Science, Meiji University, Tama-ku, Kawasaki 214-8571, Japan.

Medical image processing has become a major player in the world of automatic tumour region detection and is tantamount to the incipient stages of computer aided design. Saliency detection is a crucial application of medical image processing, and serves in its potential aid to medical practitioners by making the affected area stand out in the foreground from the rest of the background image. The algorithm developed here is a new approach to the detection of saliency in a three dimensional multi channel MR image sequence for the glioblastoma multiforme (a form of malignant brain tumour). First we enhance the three channels, FLAIR (Fluid Attenuated Inversion Recovery), T2 and T1C (contrast enhanced with gadolinium) to generate a pseudo coloured RGB image. This is then converted to the CIE L*a*b* color space. Processing on cubes of sizes k = 4, 8, 16, the L*a*b* 3D image is then compressed into volumetric units; each representing the neighbourhood information of the surrounding 64 voxels for k = 4, 512 voxels for k = 8 and 4096 voxels for k = 16, respectively. The spatial distance of these voxels are then compared along the three major axes to generate the novel 3D saliency map of a 3D image, which unambiguously highlights the tumour region. The algorithm operates along the three major axes to maximise the computation efficiency while minimising loss of valuable 3D information. Thus the 3D multichannel MR image saliency detection algorithm is useful in generating a uniform and logistically correct 3D saliency map with pragmatic applicability in Computer Aided Detection (CADe). Assignment of uniform importance to all three axes proves to be an important factor in volumetric processing, which helps in noise reduction and reduces the possibility of compromising essential information. The effectiveness of the algorithm was evaluated over the BRATS MICCAI 2015 dataset having 274 glioma cases, consisting both of high grade and low grade GBM. The results were compared with that of the 2D saliency detection algorithm taken over the entire sequence of brain data. For all comparisons, the Area Under the receiver operator characteristic (ROC) Curve (AUC) has been found to be more than 0.99 ± 0.01 over various tumour types, structures and locations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187209PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667735PMC
December 2017

Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis.

Ann Rheum Dis 2017 Sep 4;76(9):1550-1558. Epub 2017 May 4.

University of Toronto and Toronto Western Hospital, Toronto, Canada.

Objectives: To assess the efficacy and safety of abatacept, a selective T-cell costimulation modulator, in a phase III study in psoriatic arthritis (PsA).

Methods: This study randomised patients (1:1) with active PsA (~60% with prior exposure to a tumour necrosis factor inhibitor) to blinded weekly subcutaneous abatacept 125 mg (n=213) or placebo (n=211) for 24 weeks, followed by open-label subcutaneous abatacept. Patients without ≥20% improvement in joint counts at week 16 were switched to open-label abatacept. The primary end point was the proportion of patients with ≥20% improvement in the American College of Rheumatology (ACR20) criteria at week 24.

Results: Abatacept significantly increased ACR20 response versus placebo at week 24 (39.4% vs 22.3%; p<0.001). Although abatacept numerically increased Health Assessment Questionnaire-Disability Index response rates (reduction from baseline ≥0.35) at week 24, this was not statistically significant (31.0% vs 23.7%; p=0.097). The benefits of abatacept were seen in ACR20 responses regardless of tumour necrosis factor inhibitor exposure and in other musculoskeletal manifestations, but significance could not be attributed due to ranking below Health Assessment Questionnaire-Disability Index response in hierarchical testing. However, the benefit on psoriasis lesions was modest. Efficacy was maintained or improved up to week 52. Abatacept was well tolerated with no new safety signals.

Conclusions: Abatacept treatment of PsA in this phase III study achieved its primary end point, ACR20 response, showed beneficial trends overall in musculoskeletal manifestations and was well tolerated. There was only a modest impact on psoriasis lesions.

Trial Registration Number: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb).
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http://dx.doi.org/10.1136/annrheumdis-2016-210724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561378PMC
September 2017

The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6 Monoclonal Antibody, in a Phase IIb Study of Adults With Active Psoriatic Arthritis.

Arthritis Rheumatol 2016 09;68(9):2163-73

Bristol-Myers Squibb, Princeton, New Jersey.

Objective: To evaluate the efficacy of clazakizumab, a monoclonal antibody with high affinity and specificity for the interleukin-6 (IL-6) cytokine, in psoriatic arthritis (PsA).

Methods: In this randomized, double-blind, placebo-controlled, dose-ranging study (ClinicalTrials. gov identifier: NCT01490450), patients with active PsA and an inadequate response to nonsteroidal antiinflammatory drugs were randomized (1:1:1:1) to receive subcutaneous placebo or clazakizumab 25 mg, 100 mg, or 200 mg every 4 weeks, with or without methotrexate. The primary end point was the response rate according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 16, with secondary efficacy end points at weeks 16 and 24.

Results: A total of 165 patients were randomized. At week 16, the ACR20 response rate was significantly higher with clazakizumab 100 mg versus placebo (52.4% versus 29.3%; P = 0.039). ACR20 response rates at week 16 were 46.3% with clazakizumab 25 mg (P = 0.101 versus placebo) and 39.0% with clazakizumab 200 mg (P = 0.178 versus placebo). ACR50/ACR70 response rates were numerically higher with clazakizumab versus placebo at weeks 16 and 24. Compared with placebo, clazakizumab treatment significantly improved musculoskeletal manifestations (joint signs and symptoms, enthesitis, and dactylitis), with minimal improvements in skin disease, without clear evidence of a dose response. Clazakizumab was well tolerated.

Conclusion: This is the first clinical trial of an IL-6-targeted therapy in PsA. Clazakizumab may be an effective treatment option for musculoskeletal aspects of PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose. The safety profile is consistent with the pharmacology of IL-6 blockade and prior clinical experience with this antibody in rheumatoid arthritis.
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http://dx.doi.org/10.1002/art.39700DOI Listing
September 2016

Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression.

PLoS One 2016 10;11(3):e0151014. Epub 2016 Mar 10.

Department of Pharmacology and Physiology, Saint Louis University, Saint Louis, Missouri, United States of America.

The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151014PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786293PMC
July 2016

A Novel GBM Saliency Detection Model Using Multi-Channel MRI.

PLoS One 2016 11;11(1):e0146388. Epub 2016 Jan 11.

Department of Computer Science, Meiji University, Kawasaki, Japan.

The automatic computerized detection of regions of interest (ROI) is an important step in the process of medical image processing and analysis. The reasons are many, and include an increasing amount of available medical imaging data, existence of inter-observer and inter-scanner variability, and to improve the accuracy in automatic detection in order to assist doctors in diagnosing faster and on time. A novel algorithm, based on visual saliency, is developed here for the identification of tumor regions from MR images of the brain. The GBM saliency detection model is designed by taking cue from the concept of visual saliency in natural scenes. A visually salient region is typically rare in an image, and contains highly discriminating information, with attention getting immediately focused upon it. Although color is typically considered as the most important feature in a bottom-up saliency detection model, we circumvent this issue in the inherently gray scale MR framework. We develop a novel pseudo-coloring scheme, based on the three MRI sequences, viz. FLAIR, T2 and T1C (contrast enhanced with Gadolinium). A bottom-up strategy, based on a new pseudo-color distance and spatial distance between image patches, is defined for highlighting the salient regions in the image. This multi-channel representation of the image and saliency detection model help in automatically and quickly isolating the tumor region, for subsequent delineation, as is necessary in medical diagnosis. The effectiveness of the proposed model is evaluated on MRI of 80 subjects from the BRATS database in terms of the saliency map values. Using ground truth of the tumor regions for both high- and low- grade gliomas, the results are compared with four highly referred saliency detection models from literature. In all cases the AUC scores from the ROC analysis are found to be more than 0.999 ± 0.001 over different tumor grades, sizes and positions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709039PMC
July 2016

Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phase II Study in Biologic-naive and TNF-IR Patients with Rheumatoid Arthritis.

J Rheumatol 2016 Feb 15;43(2):289-97. Epub 2015 Dec 15.

From the Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California; Eli Lilly and Company, Indianapolis, Indiana; Bristol-Myers Squibb, Princeton, New Jersey, USA.M.C. Genovese, MD, James W. Raitt Professor of Medicine, Co-Chief of Division of Immunology and Rheumatology, Stanford University School of Medicine; D.K. Braun, MD, Medical Fellow; Eli Lilly and Company; J.S. Erickson, PhD, Statistician, Eli Lilly and Company; P.Y. Berclaz, MD, Senior Medical Director, Eli Lilly and Company; M.P. Heffernan, MD, Senior Medical Director, Eli Lilly and Company; H. Carlier, MD, Senior Medical Advisor, Eli Lilly and Company, Indianapolis; S. Banerjee, MD, Bristol-Myers Squibb.

Objective: To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis.

Methods: Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64.

Results: A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64.

Conclusion: Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64.

Trial Registration Number: NCT00966875.
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http://dx.doi.org/10.3899/jrheum.140831DOI Listing
February 2016

Design and Validation of an Open-Source, Partial Task Trainer for Endonasal Neuro-Endoscopic Skills Development: Indian Experience.

World Neurosurg 2016 Feb 26;86:259-69. Epub 2015 Sep 26.

Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India.

Background: Box trainers are ideal simulators, given they are inexpensive, accessible, and use appropriate fidelity.

Objective: The development and validation of an open-source, partial task simulator that teaches the fundamental skills necessary for endonasal skull-base neuro-endoscopic surgery.

Methods: We defined the Neuro-Endo-Trainer (NET) SkullBase-Task-GraspPickPlace with an activity area by analyzing the computed tomography scans of 15 adult patients with sellar suprasellar parasellar tumors. Four groups of participants (Group E, n = 4: expert neuroendoscopists; Group N, n =19: novice neurosurgeons; Group R, n = 11: neurosurgery residents with multiple iterations; and Group T, n = 27: neurosurgery residents with single iteration) performed grasp, pick, and place tasks using NET and were graded on task completion time and skills assessment scale score.

Results: Group E had lower task completion times and greater skills assessment scale scores than both Group N and R (P ≤ 0.03, 0.001). The performance of Groups N and R was found to be equivalent; in self-assessing neuro-endoscopic skill, the participants in these groups were found to have equally low pretraining scores (4/10) with significant improvement shown after NET simulation (6, 7 respectively). Angled scopes resulted in decreased scores with tilted plates compared with straight plates (30° P ≤ 0.04, 45° P ≤ 0.001). With tilted plates, decreased scores were observed when we compared the 0° with 45° endoscope (right, P ≤ 0.008; left, P ≤ 0.002).

Conclusions: The NET, a face and construct valid open-source partial task neuroendoscopic trainer, was designed. Presimulation novice neurosurgeons and neurosurgical residents were described as having insufficient skills and preparation to practice neuro-endoscopy. Plate tilt and endoscope angle were shown to be important factors in participant performance. The NET was found to be a useful partial-task trainer for skill building in neuro-endoscopy.
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http://dx.doi.org/10.1016/j.wneu.2015.09.045DOI Listing
February 2016

Generalized Flows for Optimal Inference in Higher Order MRF-MAP.

IEEE Trans Pattern Anal Mach Intell 2015 Jul;37(7):1323-35

Use of higher order clique potentials in MRF-MAP problems has been limited primarily because of the inefficiencies of the existing algorithmic schemes. We propose a new combinatorial algorithm for computing optimal solutions to 2 label MRF-MAP problems with higher order clique potentials. The algorithm runs in time O(2(k)n(3)) in the worst case (k is size of clique and n is the number of pixels). A special gadget is introduced to model flows in a higher order clique and a technique for building a flow graph is specified. Based on the primal dual structure of the optimization problem, the notions of the capacity of an edge and a cut are generalized to define a flow problem. We show that in this flow graph, when the clique potentials are submodular, the max flow is equal to the min cut, which also is the optimal solution to the problem. We show experimentally that our algorithm provides significantly better solutions in practice and is hundreds of times faster than solution schemes like Dual Decomposition [1], TRWS [2] and Reduction [3], [4], [5]. The framework represents a significant advance in handling higher order problems making optimal inference practical for medium sized cliques.
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http://dx.doi.org/10.1109/TPAMI.2014.2388218DOI Listing
July 2015

The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo/active-controlled, dose-ranging study.

Arthritis Rheumatol 2015 Oct;67(10):2591-600

NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Objective: Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) once-monthly subcutaneous (SC) clazakizumab at 25, 100, or 200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24.

Results: In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus 39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade.

Conclusion: In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone.
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http://dx.doi.org/10.1002/art.39249DOI Listing
October 2015