Implications of Gender on the Outcome in Patients With Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is uncommon and predominantly affects females. Data on AIH from India are scanty. We retrospectively analyzed the spectrum and outcome of adults with AIH and compared it between male and female patients. METHODS: AIH was diagnosed using a simplified AIH score. For suspected seronegative AIH, the revised score was used. Standard therapies for AIH and portal hypertension were administered and response was assessed at six months. Relapse rates and five-year mortality were also evaluated. RESULTS: Of the 157 patients with AIH, 85 (male: female 25: 60) were included in the study. The median age at diagnosis was 46 (interquartile range (IQR) 32-55.5) years in males vs 45 (IQR 34.2-54) years in females (p=0.91). A similar proportion of male and female patients presented with cirrhosis, acute severe AIH, or AIH-related acute on chronic liver failure (ACLF); Extra-hepatic autoimmune diseases were less common in male patients (16% vs 35.5% p=0.02). Other laboratory and histological features were comparable in both groups. During the median follow-up period of 51 months (IQR 45-67 months). The biochemical and clinical response at six months were seen in 64% of male patients and 63.3% of female patients (p= 0.57). Of patients, 75% relapsed in the male AIH group (12 of 16 patients) after initial remission compared to 42% in the female group (p=0.02). Five-year mortality was 14.1%, and no patient developed hepatocellular carcinoma. CONCLUSION: Male and female patients with AIH have similar clinical, biochemical, and histological profiles. More male patients relapsed after an initial response to therapy.

The contribution of network elasticity to electro-optic response in polymer stabilized cholesteric liquid crystals.

Polymer stabilization of cholesteric liquid crystals can enable dynamic reconfiguration of the selective reflection of the CLC phase. Here, we explore how the contribution of the elasticity of the polymer stabilizing network affects the ion-mediated, electromechanical deformation and associated electro-optic response in PSCLCs. We utilize a free-radical chain transfer reaction between acrylate and thiol monomers that has been used to prepare elastomeric networks. This work maps the compositional contributions of total concentration and crosslink density to tuning and recovery.

Cardiovascular risks associated with Janus kinase inhibitors: peering outside the black box.

Considerable controversy related to the cardiovascular safety of Janus kinase inhibitors (JAKinibs) has arisen following the results of the ORAL Surveillance trial. In this trial of rheumatoid arthritis (RA) ≥ 50 years with at least one prevalent cardiovascular disease (CVD) risk factor, tofacitinib was not found to be non-inferior to tumour necrosis factor-alpha inhibitors (TNFi) with regards to the risk for major adverse cardiovascular events (MACE), venous thromboembolism (VTE) or malignancy. Following the results of ORAL Surveillance, the United States Food and Drug Administration (US FDA) issued a boxed warning regarding increased risks of MACE, VTE and malignancy with tofacitinib, baricitinib or upadacitinib in inflammatory arthritis or ulcerative colitis. Analysis of data from other trials (including long-term follow-up studies) of tofacitinib in RA, psoriasis, psoriatic arthritis, spondyloarthritis and inflammatory bowel diseases suggests an overall similar risk of MACE or VTE with tofacitinib when compared with TNFi. In specific patient populations with risk factors for or prior history of MACE or VTE, the risk of subsequent MACE or VTE with tofacitinib use is considerably heightened. Post-hoc analyses from ORAL Surveillance presented at the recent EULAR meeting further help to delineate patients with RA at increased risk of MACE/VTE with tofacitinib. Based on the available literature from trials and long-term follow-up studies of baricitinib and upadacitinib, there exists insufficient evidence to extend the warning of MACE/VTE with tofacitinib to these drugs. Ongoing post-marketing surveillance studies of JAKinibs in immune-mediated inflammatory diseases should help clarify CVD risk with JAKinibs.

Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute on Chronic Liver Failure: A Proof-of-Concept Study.

Background and Aims: Acute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival. Methods: In the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium >80mmol/day) slow albumin-furosemide infusion ±â€…terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated. Results: Age, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = <0.001). All those who were unable to reach urine sodium >80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations. Conclusion: Ascitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.

Does Treatment of Erectile Dysfunction With PDE 5 Inhibitor Tadalafil Improve Quality of Life in Male Patients With Compensated Chronic Liver Disease? A Prospective Pilot Study.

Background and aims: Erectile dysfunction (ED) is common in patients with compensated cirrhosis but its impact on the quality of life (QOL) is usually overlooked. This study aimed at determining the frequency of ED in male patients with compensated chronic liver disease (CLD), assessing their QOL and the response to treatment with tadalafil. A secondary aim was to assess the effect of the tadalafil therapy on liver fibrosis, if any. Methods: Consecutive patients with compensated CLD and advanced liver fibrosis were screened at the baseline with the International Index of Erectile Function-5 (IIEF-5), QOL questionnaire (WHOQOL-BREF), liver stiffness measurements (LSM) made with Fibroscan™ (Echosens, France), and fibrosis index based on 4 factors (FIB-4) scores. Patients with ED meeting eligibility criteria were prescribed PDE5 inhibitor tadalafil 20 mg on alternate days. During the follow-up, IIEF-5, LSM, and FIB-4 were monitored after 3 and 6 months while the WHOQOL-BREF questionnaire was administered at the baseline and at 6 months. Results: Among 89 patients with CLD and advanced liver fibrosis, ED was present in 43 (48%) and tadalafil was prescribed to 34 patients (38%) meeting exclusion and inclusion criteria. At 3 months follow-up, the mean IIEF 5 score increased from 15.57 ± 4 to 20.78 ± 3.6, (P = 0.0001) and the improvement persisted at 6 months (IIEF-5 score 21.87 ± 2.2; P = 0.12). The physical, social relationships, and environment domains in the WHOQOL-BREF questionnaire showed significant improvement at six months (P < 0.05) but not the psychological domain (P = ns). From a baseline value of 12.69 ± 3.1 kPa, the mean LSM decreased to 11.37 ± 3.9 kPa, (P = 0.02) after 3 months on tadalafil. After 6 months, the LSM further decreased from 11 ± 0.9 to 8.2 ± 3.2 kPa (P = 0.034). FIB-4 values showed a decline from the baseline at 3 months, from 1.52 ± 0.58 to 1.32 ± 0.55, P < 0.05 and at 6 months, from 1.25 ± 0.53 to 0.97 ± 0.36, P > 0.05. The CAP values did not show any significant change. There was an insignificant decline in the SGOT and SGPT levels (P > 0.05) with no significant change in CTP or MELD scores. Conclusions: In the short term, tadalafil improves ED and QOL in patients with CLD and advanced liver fibrosis. It may also reduce liver fibrosis in them. Further studies that include liver histology are needed to confirm this preliminary observation of a possible antifibrotic effect.

Influence of ITO electrode on the electrochromic performance outcomes of viologen-functionalized polyhedral oligomeric silsesquioxanes.

Electrochromic devices (ECDs) exhibit reversible optical changes under applied electrical stimuli. Transparent conducting electrodes (TCOs), generally constructed with indium tin oxide (ITO), are a vital component determining transparency and switching behaviors. ITO specifications for TCO materials have not drawn much attention despite the critical role of these materials. Herein we investigate the influence of ITO electrodes in achieving high-performance ECDs containing viologen-functionalized polyhedral oligomeric silsesquioxane (POSS-viologen). Indeed, ITO electrodes exert significant effects on the electrochromic characteristics. A high ITO thickness shows superior color-switching with high optical density and coloration efficiency levels. Enhanced electrical conductivity facilitates diffusion behaviors, an outcome beneficial for electrochromic switching. The surface-charge capacity ratio values are measured and found to be close to one, indicating that no residual current remains, and the prepared devices provide good reversibility during the coloring and bleaching process. Furthermore, with an increase in the ITO thickness, the current required for the coloring and bleaching processes decreases, and the power consumption needed for the operation of the device becomes low. The superiority of POSS-viologen should also be noted, especially when compared to normal viologens, in terms of the electrochromic properties and long-term operational stability. These results demonstrate the critical role of electrical conductivity in ITO electrodes, providing a valuable guideline for TCO specifications for ECD fabrication using viologen derivatives.

Novel Th17 Lymphocyte Populations, Th17.1 and PD1+Th17, are Increased in Takayasu Arteritis, and Both Th17 and Th17.1 Sub-Populations Associate with Active Disease.

Purpose: We evaluated T helper lymphocyte profile, including novel Th17 subsets Th17.1 (secrete IFN-γ, associate with corticosteroid resistance) and PD1+Th17 (secrete TGF-ß1, implicated in fibrosis), and related cytokines in peripheral blood of Takayasu arteritis (TAK). Materials and Methods: We evaluated circulating Th1, Th2, Th17, Th17.1, PD1+CD4+ T lymphocytes, PD1+Th17, and Treg lymphocytes, inflammatory (IFN-γ, IL-4, IL-6, IL-17A, IL-23, IL-1ß, TNF-α) and regulatory (IL-10, TGF-ß1) cytokines in peripheral blood of TAK (n = 57; median age 35 (interquartile range 26-45) years; 40 females) in a cross-sectional design. We studied inflammatory and regulatory cytokines in culture supernatant of peripheral blood mononuclear cells (PBMCs) from TAK following stimulation with anti-CD3/anti-CD28 and their modulation by tacrolimus (immunosuppressive) with/without tadalafil (anti-fibrotic). Furthermore, we followed up immunosuppressive-naïve active TAK (n = 16) and compared T helper lymphocyte populations and cytokines before and after immunosuppressive therapy. Healthy controls (HC, n = 21) and sarcoidosis (disease control, n = 11) were compared against TAK. Results: TAK had higher Th17, Th17.1 and PD1+Th17 lymphocytes than HC (p < 0.001), and higher PD1+CD4+ T lymphocytes than sarcoidosis (p < 0.001). Th17 lymphocytes associated with active TAK after multivariable-adjusted logistic regression (p = 0.008). TAK had greater cytokine secretion from PBMCs (IFN-γ, IL-17A, IL-10 versus HC; IL-6, TNF-α, IL-1ß versus HC or sarcoidosis) (p < 0.05). In-vitro, PBMCs from TAK showed reduced secretion of all inflammatory cytokines with tacrolimus, with synergistic reduction in IL-17A, IL-6, IL-1ß and IL-10 following addition of tadalafil to tacrolimus. Serial follow-up of immunosuppressive-naïve TAK (n = 16) showed reduction in serum IL-6 and TGF-ß1 (p < 0.05) and IL-6 in culture supernatant (p < 0.05) following immunosuppressive therapy. Conclusion: Novel Th17 sub-populations (Th17.1 and PD1+Th17) are elevated in TAK. Th17 lymphocytes associate with active TAK. In-vitro experiments on cultured PBMCs suggest promise for further evaluation of a combination of immunosuppressive tacrolimus with anti-fibrotic tadalafil (or other anti-fibrotic therapies) in clinical trials of TAK.

Serum Metabolic Disturbances Associated with Acute-on-chronic Liver Failure in Patients with Underlying Alcoholic Liver Diseases: An Elaborative NMR-based Metabolomics Study.

OBJECTIVES: Acute-on-chronic liver failure (ACLF), which develops in patients with underlying alcoholic liver disease (ALD), is characterized by acute deterioration of liver function and organ failures are secondary to that. The clear understanding of metabolic pathways perturbed in ALD-ACLF patients can greatly decrease the mortality and morbidity of patients through predicting outcome, guiding treatment, and monitoring response to treatment. The purpose of this study was to investigate the metabolic disturbances associated with ACLF using nuclear magnetic resonance (NMR)-based serum metabolomics approach and further to assess if the serum metabolic alterations are affected by the severity of hepatic impairment. MATERIALS AND METHODS: The serum-metabolic profiles of 40 ALD-ACLF patients were compared to those of 49 age and sex-matched normal-control (NC) subjects making composite use of both multivariate and univariate statistical tests. RESULTS: Compared to NC, the sera of ACLF patients were characterized by significantly decreased serum levels of several amino acids (except methionine and tyrosine), lipid, and membrane metabolites suggesting a kind of nutritional deficiency and disturbed metabolic homeostasis in ACLF. Twelve serum metabolic entities (including BCAA, histidine, alanine, threonine, and glutamine) were found with AUROC (i.e., area under ROC curve) value >0.9 suggesting their potential in clinical diagnosis and surveillance. CONCLUSION: Overall, the study revealed important metabolic changes underlying the pathophysiology of ACLF and those related to disease progression would add value to standard clinical scores of severity to predict outcome and may serve as surrogate endpoints for evaluating treatment response.

Epigallocatechin Gallate with Potent Anti-Helicobacter pylori Activity Binds Efficiently to Its Histone-like DNA Binding Protein.

Helicobacter pylori (H. pylori)-a human gastric pathogen-forms a major risk factor for the development of various gastric pathologies such as chronic inflammatory gastritis, peptic ulcer, lymphomas of mucosa-associated lymphoid tissues, and gastric carcinoma. The complete eradication of infection is the primary objective of treating any H. pylori-associated gastric condition. However, declining eradication efficiencies, off-target effects, and patient noncompliance to prolong and broad-spectrum antibiotic treatments has spurred the clinical interest to search for alternative effective and safer therapeutic options. As natural compounds are safe and privileged with high levels of antibacterial-activity, previous studies have tested and reported a plethora of such compounds with potential in vitro/in vivo anti-H. pylori activity. However, the mode of action of majority of these natural compounds is unclear. The present study has been envisaged to compile the information of various such natural compounds and to evaluate their binding with histone-like DNA-binding proteins of H. pylori (referred here as Hup) using in silico molecular docking-based virtual screening experiments. Hup-being a major nucleoid-associated protein expressed by H. pylori-plays a strategic role in its survival and persistent colonization under hostile stress conditions. The ligand with highest binding energy with Hup-that is, epigallocatechin-(-)gallate (EGCG)-was rationally selected for further computational and experimental testing. The best docking poses of EGCG with Hup were first evaluated for their solution stability using long run molecular dynamics simulations and then using fluorescence and nuclear magnetic resonance titration experiments which demonstrated that the binding of EGCG with Hup is fairly strong (the resultant apparent dissociation constant (k D) values were equal to 2.61 and 3.29 ± 0.42 µM, respectively).

Targeted NMR-based serum metabolic profiling of serine, glycine and methionine in acute-on-chronic liver failure patients: Possible insights into mitochondrial dysfunction.

Background: A recent study based on blood metabolomics analysis revealed inflammation-associated mitochondrial dysfunction as a potential mechanism underlying acute-on-chronic liver failure (ACLF) in cirrhotic patients. Serine, glycine, and methionine serve to maintain a healthy immune system and adequately sustain mitochondrial functionality in hepatocytes for regulating redox homeostasis through the production of antioxidant glutathione (GSH). Based on this, we hypothesized that the circulatory levels of serine, glycine and methionine will be altered in ACLF patients due to acute worsening of hepatic function and may provide novel insights into the mitochondrial dysfunction as well. Methods: The circulatory concentrations of serine, glycine, and methionine were estimated in the sera of 40 ACLF patients and 49 normal controls (NC) subject using 1D 1H-CPMG NMR spectra recorded at 800 MHz NMR spectrometer. The resulting metabolite concentrations were compared using unpaired Student t-test and p-value < 0.05 was considered as the criterion of statistical significance. The diagnostic potential and statistical correlations were established using receiver-operating-characteristic (ROC) curve analysis and Pearson-r method, respectively. Results: Circulating levels of serine and glycine were significantly decreased in ACLF patients (Ser = 23.06 ± 1.67 µM and Gly = 83.11±7.52 µM) compared to NC subjects (Ser = 55.61 ± 2.28 µM and Gly = 156.9±7.16 µM) with p-value < 0.0001, whereas those of methionine were significantly increased in ACLF (22.60 ± 2.49 µM) compared to NC subjects (=14.63 ± 0.85 µM) with p-value < 0.0015. Further, the ROC analysis yielded satisfactory sensitivity and specificity for serine, glycine, and methionine-to-glycine ratio (MGR) with area under ROC (AUROC) curve values equal to: 0.95 [95%CI = 0.91-0.99] for Ser; 0.87 [95%CI = 0.79-0.95] for Gly; and 0.90 [95%CI = 0.83-0.97] for MGR. Conclusion: Compared to NC subjects, the sera of ACLF patients were characterized by hypermethioninemia and aberrantly decreased levels of serine and glycine suggesting mitochondrial dysfunction as the possible mechanism for disturbed redox homeostasis and therefore depressed immune system in ACLF.

Ultralow Schottky Barriers in Hexagonal Boron Nitride-Encapsulated Monolayer WSe2 Tunnel Field-Effect Transistors.

To explore the potential of field-effect transistors (FETs) based on monolayers (MLs) of the two-dimensional semiconducting channel (SC) for spintronics, the two most important issues are to ensure the formation of variable low-resistive tunnel ferromagnetic contacts (FCs) and to preserve intrinsic properties of the SC during fabrication. Large Schottky barriers lead to the formation of high resistive contacts, and methods adopted to control the barriers often alter the intrinsic properties of the SC. This work aims at addressing both issues in fully encapsulated ML WSe2 FETs using bilayer hexagonal boron nitride (h-BN) as a tunnel barrier at the FC/SC interface. We investigate the electrical transport in ML WSe2 FETs with the current-in-plane geometry that yields hole mobilities of ∼38.3 cm2 V-1 s-1 at 240 K and on/off ratios of the order of 107, limited by the contact regions. We have achieved an ultralow effective Schottky barrier (∼5.34 meV) with an encapsulated tunneling device as opposed to a nonencapsulated device in which the barrier heights are considerably higher. These observations provide an insight into the electrical behavior of the FC/h-BN/SC/h-BN heterostructures, and such control over the barrier heights opens up the possibilities for WSe2-based spintronic devices.

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection in 2015.

Overall prevalence of HCV infection in India has been estimated to be approximately 1.3% in the general population. Recent introduction of sofosbuvir in India at a relatively affordable price has led to great optimism about prospects of cure for these patients. This drug is likely to form the backbone of current and future treatment regimes for HCV infection, displacing pegylated interferon. Availability of directly acting antiviral drugs (DAAs) has necessitated revision of INASL guidelines for the treatment of HCV published in 2014, as has happened across the world. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. Since only one DAA, sofosbuvir, is available in India, only two sofosbuvir-based regimes are possible: either dual drug therapy in combination with ribavirin alone for 6 months or triple drug therapy in combination with ribavirin and pegylated interferon for 3 months. The utility of these regimes in various situations has been discussed. Availability of a few other newer DAAs, expected in 2016, is expected to lead to more widespread use of these agents. Current guidance will be updated once newer DAAs, newer evidence with DAAs and 'real-life experience' with use of DAAs accumulate in India.