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Intracellular adhesion molecule 1 (ICAM-1) is one of the most extensively studied inducible cell adhesion molecules which is responsible for several immune functions like T cell activation, extravasation, inflammation, etc. The molecule is constitutively expressed over the cell surface and is regulated up / down in response to inflammatory mediators like cellular stress, proinflammatory cytokines, viral infection. These stimuli modulate the expression of ICAM-1 primarily through regulating the ICAM-1 gene transcription. On account of the presence of various binding sites for NF-κB, AP-1, SP-1, and many other transcription factors, the architecture of the ICAM-1 promoter become complex. Transcription factors in union with other transcription factors, coactivators, and suppressors promote their assembly in a stereospecific manner on ICAM-1 promoter which mediates ICAM-1 regulation in response to different stimuli. Along with transcriptional regulation, epigenetic modifications also play a pivotal role in controlling ICAM-1 expression on different cell types. In this review, we summarize the regulation of ICAM-1 expression both at the transcriptional as well as post-transcriptional level with an emphasis on transcription factors and signaling pathways involved.

The purpose of this research is to identify and characterize deleterious genetic variants in the co-stimulatory ligand B7-1, also known as the human cluster of differentiation CD80 marker. The B7-1 ligand and the major histocompatibility complex class II (MHC II) molecules are the main determinants that provide B-cells the required competency to act as antigen presenting cells. For this, participation of both MHC class II molecules and CD80 is required. The interaction of the CD80 ligand with CD28 on the surface 7 of TH cells plays a key role in the activation of TH cells and progression of B cells through the S phase, hence, leading to their proliferation in mitosis. A set of 2313 genetic variants in the B7-1 ligand have been mapped and retrieved from dbSNP database. Subsequently, 150 non-synonymous single nucleotide polymorphisms (nsSNPs) were mapped and subjected to the sequence and structural homology based predictions, which were further analyzed for protein stability and the disease phenotypes. Finally, we identified 7 potentially damaging nsSNPs in the B7-1 ligand that may affect its interaction with the cognitive receptor CD28, hence, may also interfere with TH cell activation and B cell proliferation. We propose that subsequent experimental analyses (stability, expression and interactions) on these proteins can provide a deep understanding about the effect of these variants on the structure and function of CD80.

Rotational Moulding (RM) is a versatile plastic processing method for the production of hollow products. Since the life expectancy of RM products are over several decades, prediction of mechanical properties like creep will be useful during the design phase of a product. In this research, an analytical model based on time hardening model was developed to predict and compare the creep behaviour of linear low-density polyethylene (LLDPE) and PP at 40 °C. The model uses some constants obtained from the experimental findings of a typical accelerated creep test using stepped isothermal method- time-temperature superposition (SIM-TTS). Based on the creep performance, the comparison of the two materials (LLDPE and PP) has been carried out and inferences have been made about their long term performance under constant stress.

In a country like India which has a long history of human occupancy and rich cultural heritage, identification of potential archaeological sites is essential before they get fully obliterated due to rapid urbanization, large-scale infrastructure development and mechanised agriculture activities. In this study, an important Buddhist site Sannati (which dates back to Maurya period, 3rd century BCE) and its surrounding, is investigated. Earlier investigations have uncovered a fortified mound, Vihara complex, habitation site and 3 stupa mounds in this region. The present study develops simple and cost-effective ways to identify potential buried archaeological sites and mounds using the knowledge of known sites and visual interpretation of remote sensing images of the region. This study has successfully located several archaeologically potential sites in the study area that now require archaeological investigation on ground. The developed approach can be applied to investigate other similar buried/undiscovered potential archaeological sites.

Prior research on IS mandates (MdIS) has mainly focused on the organization as a monolith in responding to mandates. However, companies often compete across multiple business lines and prior research has not fully examined how companies derive value from MdIS when competing across different business segments where they face different levels of customer bargaining power. Evidence of deriving value is discernible in endogenous price and demand changes as the company adheres to the mandate. Under the Medical Loss Ratio clause of the Patient Privacy and Affordable Care Act of 2010, health insurance companies were mandated to invest in information systems and associated quality improvement processes that improve the health of insurance buyers. Health insurance companies in the US operate as one or more of the three business lines serving the individual, small group/employer with less 500 employees, and the large group/employer with more than 500 employees in each state in the US. The standard and alternate translog profit functions for the financial data of US health insurance companies from 2011-2017 shed light on the impact of MdIS on price and demand decisions. The results show that the demand and prices charged across the individual and small group business lines increased with MdIS and did not change for large group business line, providing evidence of differential implementation to derive value from customers rather than passively implementing MdIS as the cost of doing business.

The treatment of critical sized bone defect remains a significant challenge in orthopedics. The objective of the study is to evaluate the effect of the combination of bone morphogenetic protein 2 (BMP2) expressing genetically engineered mesenchymal stem cells (MSCs) [MSCs engineered using a multimam vector, pAceMam1, an emerging gene delivery vector] and an osteoconductive scaffold [silica coated nanohydroxyapatite-gelatin reinforced with fibers] in enhancing bone regeneration in critical sized segmental defects. The scaffold with transfected MSCs showed significantly higher viability, proliferation and osteogenic differentiation in vitro. Further, this group augmented union and new bone formation in critical sized rat femoral segmental defect at 12 weeks when compared to control groups (scaffold with MSCs and scaffold alone). These data demonstrated that the MSCs engineered for transient expression of BMP2 can improve the repair of segmental defects, which paves an avenue for using pAceMam1 as a vector for bone tissue regeneration.

We evaluated the performance of an early prototype core molecular mirroring nuclear magnetic resonance detection platform (Mentor-100) to detect toxigenic Clostridium difficile from stool. This technology uses customized nanoparticles bound to target specific oligonucleotide probes that form binaries in the presence of nucleic acid from the target microorganism. Liquid patient stool specimens were seeded with C. difficile or other Clostridium species to determine the analytical sensitivity and specificity. Samples underwent nucleic acid extraction and target amplification with probes conjugated with iron nanoparticles. Signal from nuclear magnetic resonance spin–spin relaxation time was measured to detect the presence or absence of toxigenic C. difficile. The limit of detection was

Context: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia, hypercellular bone marrow, and dysplastic hematopoietic progenitors. Death is commonly caused by the effects of cytopenia, leading to infections or bleeding [1]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias. Objective: The objective was to develop a semi-mechanistic model of disease progression in MDS based on clinical data, involving relevant hematopoietic cells that can describe the effect of drug intervention with venetoclax azacitidine combination therapy. The model was subsequently used to simulate different treatment regimens (with respect to dose, dosing duration in a cycle, and number of cycles) and compare the outcomes. Study Design and Data: Data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax (400 mg or 800 mg for 28 days or 100 mg to 400 mg for 14 days in each 28-day cycle) with azacitidine (75 mg/m2 on days 1-7 of each cycle) in treatment-naive patients with higher-risk MDS were used for the analysis. The data contained venetoclax concentrations, neutrophil, red blood cell, and platelet count in the blood and blasts in the bone marrow. Methods: An integrated semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accounted for venetoclax PK and azacitidine treatment to describe time dynamics of neutrophils, red blood cells, and platelets. The model also included crowding in the bone marrow due to excess stem cells, MDS blasts, and progenitor cells, and its effect on hematopoiesis. Results: The model described the observed clinical data well and showed predictive ability across considered cell types. Complete remission (CR) and marrow complete remission (mCR) rates were predicted close to observed rates in the study. Simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are comparable to the expected outcomes from various dosing regimens. Conclusions: A model describing drug-disease interactions in MDS was developed that integrates multiple end points and differentiates disease driven from drug-induced cytopenia. Reference: [1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179. Disclosures: The analysis presented was funded by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. NT, JZ, RM, BE, JW, SM, and SG are employees of AbbVie and may hold stock. AHW receives honoraria from Novartis, Astellas, Pfizer, Macrogenics, Abbvie, Genentech, Servier, Celgene, Amgen, Astra Zeneca and Janssen. AHW also receives research funding from Novartis, Celgene, Abbvie, Servier, Astra Zeneca and Amgen. AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. G-GM is an investigator in AbbVie funded Clinical Trials. DM is a Genentech employee and may own stock. C.M. performed the analysis at AbbVie during an internship. C.M. also receives research funding from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grunenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and Sanofi) for the PharMetrX program

Electronic Health Record (EHR) has the potential to transform the work required to create and deliver healthcare services. This has triggered large-scale adoption across hospitals. However, whether all hospitals obtain a similar effect from their EHR implementations remains an important question because there are significant differences differences in characteristics of hospitals adopting these systems. To examine differences in effects across hospitals, we examine whether the impacts of EHR applications are contingent on work domains, by assessing performance effects across hospitals with varying administrative scale and clinical complexity. Because EHRs constitute a suite of applications with different functionalities, examining the effects of different sets of applications is challenging due to nonlinear interdependencies between applications. Therefore, we use an archetype approach, identifying synergistic EHR (EHRSYN) archetype as an ideal portfolio—a conceptual anchor for a hospital’s EHR portfolio. We test contingencies by combining this technology archetype with the work domains—administrative scale and clinical complexity. We test our hypotheses using empirical data from 137 hospitals in California, hypothesizing the differences in effects of EHRs on financial, operational, and clinical performances across hospitals with different administrative scales (size) and clinical complexities (case-mix) of work. While hospitals gain the most by implementing a portfolio close to the EHRSYN archetype, our nuanced models reveal that the benefits of such portfolios increase for large hospitals and are greater for hospitals treating less complex cases. These findings underscore how variations in applications used and work domains demarcate boundaries related to the performance effects of EHRs. We present a detailed discussion of the theoretical contributions and practical implications of our findings.

Item does not contain fulltext PURPOSE: Stable fixation of distal humerus fracture fragments is necessary for adequate healing and maintenance of reduction. The purpose of this study was to measure the reliability and accuracy of interpretation of postoperative radiographs to predict which implants will loosen or break after operative treatment of bicolumnar distal humerus fractures. We also addressed agreement among surgeons regarding which fracture fixation will loosen or break and the influence of years in independent practice, location of practice, and so forth. METHODS: A total of 232 orthopedic residents and surgeons from around the world evaluated 24 anteroposterior and lateral radiographs of distal humerus fractures on a Web-based platform to predict which implants would loosen or break. Agreement among observers was measured using the multi-rater kappa measure. RESULTS: The sensitivity of prediction of failure of fixation of distal humerus fracture on radiographs was 63%, specificity was 53%, positive predictive value was 36%, the negative predictive value was 78%, and accuracy was 56%. There was fair interobserver agreement (kappa = 0.27) regarding predictions of failure of fixation of distal humerus fracture on radiographs. Interobserver variability did not change when assessed for the various subgroups. CONCLUSIONS: When experienced and skilled surgeons perform fixation of type C distal humerus fracture, the immediate postoperative radiograph is not predictive of fixation failure. Reoperation based on the probability of failure might not be advisable. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Background & Aims Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. Methods HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100mg), ombitasvir (25mg), and dasabuvir (400mg). Plasma samples were collected through 144hours after administration for pharmacokinetic assessments. Results Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C max , and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. Conclusions The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.

Background & AimsParitaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients.MethodsMechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction.ResultsCoadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

The impact of preoperative stable angina pectoris on postoperative cardiovascular outcomes in patients with previous myocardial infarction (MI) who underwent major noncardiac surgery is not well studied. We studied patients with previous MI who underwent elective major noncardiac surgeries within the American College of Surgeons-National Surgical Quality Improvement Program (2005 to 2011). Primary outcome was occurrence of an adverse cardiac event (MI and/or cardiac arrest). Multivariable logistic regression models evaluated the impact of stable angina on outcomes. Of 1,568 patients (median age 70 years; 35% women) with previous MI who underwent major noncardiac surgery, 5.5% had postoperative MI and/or cardiac arrest. Patients with history of preoperative angina had significantly greater incidence of primary outcome compared to those without anginal symptoms (8.4% vs 5%, p = 0.035). In secondary outcomes, reintervention rates (22.5% vs 11%, p0.001) and length of stay (median 6-days vs 5-days; p0.001) were also higher in patients with preoperative angina. In multivariable analyses, preoperative angina was a significant predictor for postoperative MI (odds ratio 2.49 [1.20 to 5.58]) and reintervention (odds ratio 2.40 [1.44 to 3.82]). In conclusion, our study indicates that preoperative angina is an independent predictor for adverse outcomes in patients with previous MI who underwent major noncardiac surgery, and cautions against overreliance on predictive tools, for example, the Revised Cardiac Risk Index, in these patients, which does not treat stable angina and previous MI as independent risk factors during risk prognostication.

Ever increasing need of electricity has paved the need for Smart Grids. Smart Meters, digitalized networks and fault tolerant systems are the basic infrastructure which supports Smart Grid. Security in Smart Grid has become a major concern in the present scenario. In this paper we have proposed security architecture at the last mile distribution in Home Area Networks. A Secure communication architecture has been modeled which focuses on secure data transmission between the Smart Meters at home and Central Gateway at the utility centre. Hybrid Encryption algorithms and Digital Signature has been used to provide data integrity. The strength of the model has been verified with the help of an attacker and the model is found to resist attacks. The Encryption time and Decryption time of the cyptostack is lower when compared with other encryption algorithms.

Innovation contest platforms are often organized around specific fields of interest and involve contests that span a variety of interdependent problem domains. While specialization in contests within a problem domain can improve a contestant’s performance in a future contest in the same domain, prior research on individual learning also suggests that a contestant can benefit from her related experience—i.e., experience in contests whose problem domains share an interdependency with the focal problem domain. It is, however, unclear whether the benefits of related experience arise symmetrically from upstream related problem domains (i.e., upstream experience) and downstream related problem domains (i.e., downstream experience) or differ among them. Given that an innovation contest platform serves to provide an effective match between contest problem requirements and contestants’ skills, it is important to understand how a contestant’s prior experience on such a platform contributes to her problem-solving performance. To address the research question, we collect detailed archival data from TopCoder, a leading platform for software development contests, from its launch in 2001 to September 2013. Our dataset comprises detailed participation history of 821 contestants in 3,274 contests across eight interdependent problem domains involving 8,985 observations. We find that while a contestant’s related experience on the innovation contest platform has a stronger positive association with her focal contest performance compared to unrelated experience on the platform, the benefits of related experience arise only from downstream experience. No significant performance benefits of upstream experience are observed. We also find that the performance benefits of downstream experience are more salient when the contest duration is shorter. Contrary to the notion of “hyper-specialization” that has been emphasized in previous research, our findings highlight the importance of targeted diversification of experience for participants on innovation platforms. They also shed light on the effective design of innovation contest platforms and resource allocation decisions in complex new product development projects involving interdependent problem domains.

Summary Introduction Crohn's disease is increasing in incidence worldwide. It is associated with many complications including fistulae, which may require surgical intervention. Occasionally, formal perineal reconstruction is needed for extensive or definitive fistula surgery. Reconstruction for inflammatory disease presents unique challenges and often calls for innovative solutions. Gluteal fold flaps (GFFs), which have been widely used in vulvo-vaginal malignancy and anorectal cancer surgery, have not hitherto been reported for Crohn's disease-associated fistulae. Case presentation A 30-year-old female presented with a 5-year history of Crohn's-associated perianal and rectovaginal fistulae. She had a previous small bowel resection and ileostomy. A laparascopic pan-proctocolectomy was carried out followed by perineal reconstruction in a single stage procedure using a pedicled fasciocutaneous GFF. Seven months postoperatively, revisional surgery was carried out using the contralateral GFF due to two areas of persistent wound dehiscence. The outcome was complete resolution of the fistulae, stable wound closure and good cosmesis. Discussion & conclusion This case demonstrates that it is practical to use the GFF for perineal reconstruction following excision of complex Crohn's-associated fistulae. The flap avoids the sequelae associated with sacrifice of regional muscle flaps and specifically circumvents the unavailability of the rectus abdominis flap in slim patients or those with in-situ ileostomies. It is easy and quick to raise and does not require an intra-operative change in the patient's position. The GFF ensured well vascularised skin cover, adequate flap volume with no loss of function and low donor site morbidity.

Background Advanced salivary gland neoplasm have variable natural history. The goal of systemic treatment is palliation however no clear evidence regarding when and to whom it needs to be administered.The objective of this study was to determine the molecular profile of malignant salivary gland tumors and to evaluate the impact of systemic therapy.This was a retrospective cohort study. Methods Head and Neck Medical Oncology outpatient department maintains a prospective chemotherapy database of patients planned for any form of systemic therapy. Adult patients (Age > or = 18 years) with (ECOG PS) 0-3 histologically proven salivary gland malignancy treated between January 2010- September 2018 at the host institute.Data regarding demographics, baseline characteristics, tumor details, staging details, treatment details, outcome details expression of ER, PR, AR and HER-2 Neu status was extracted.The procedure for performing IHC, interpreting, and quality assurance is already published.Molecular profilingSnapshot profiling was performed using Multiplex polymerase chain reaction (PCR) followed by multiplex base extension assay utilizing the SNaPshot TM methodology. It consists of a combination of real time PCR looking for 21 hotspot mutation sites in nine cancer genes: (EGFR, HER2, KRAS, NRAS,PIK3CA, BRAF, MEK1, PTEN,AKT1-). Results Out of the 69 evaluable patients, 55% (n = 38) had actionable target. Androgen Receptor (AR) expression was present in majority of patients (n = 23,34%), with it alone being expressed in 17% (n = 12) of patients, and along with other actionable targets in the other. 60 (87%) patients received systemic therapy either in form of chemotherapy (35,58.3%) or targeted therapy (25,41.7%). The strategy of observation in asymptomatic status lead to an median OS of 32.27 (3.03-NA) similar to patients receiving systemic therapy (p = 0.992). In patients with visceral crisis, the median OS was higher in patients receiving chemotherapy than targeted therapy (19.07 (14.20-23.8) versus 6.07 (2.23-NA), p Conclusions Actionable targets are seen in salivary gland tumors and treatment strategies should be based on these and symptomatic status. Legal entity responsible for the study Tata Memorial Hospital Mumbai. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background A novel self-expanding drug-eluting stent was designed to release everolimus 225 μg/cm 2 to prevent restenosis following peripheral arterial intervention. The purpose of this study was to measure the pharmacokinetic profile of everolimus following stent implantation. Methods One hundred four patients with symptomatic peripheral arterial disease underwent implantation of everolimus-eluting stents in the femoropopliteal arteries. In a prespecified subset of 26 patients, blood samples for assay of everolimus content were collected prior to stent implantation, at 1, 4, and 8 hours postprocedure, prior to discharge, and at 1 month postprocedure. Results A total of 39 stents, ranging from 28 mm to 100 mm in length, were implanted in 26 patients, resulting in a total delivered everolimus dose range of 3.0 to 7.6 mg. Following the procedure, the maximum observed everolimus blood concentrations ( C max ) varied from 1.83 ± 0.05 ng/mL after implantation of a single 80-mm stent to 4.66 ± 1.78 ng/mL after implantation of two 100-mm stents. The mean time to peak concentration ( T max ) varied from 6.8 hours to 35 hours. The pharmacokinetics of everolimus were dose-proportional in that dose-normalized C max and area under the curve values were constant over the studied dose range. Conclusions After implantation of everolimus-eluting self-expanding stents in the femoropopliteal arteries, systemic blood concentrations of everolimus are predictable and considerably lower than blood concentrations observed following safe oral administration of everolimus.