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Aim: Saliva play a diagnostic tool for oral and systematic diseases has multiple advantages over other body fluids especially . The aim of this study was to explore the potential of salivary glucose as a marker in diagnosis and monitoring of diabetes mellitus using glucoseoxidase method, and as a non-invasive method replacing an invasive blood glucose estimation method. Materials and methods: Fasting blood and unstimulated whole saliva were collected from 50 controls, 50 newly diagnosed diabetics, and 50 diabetics under treatment. Blood and salivary glucose were analyzed in the samples by glucose-oxidase method. Results: The mean level of salivary glucose was reported to be 0.53 ± 0.4mg/dl in controls, 1.14 ± 1.55mg/dl in newly diagnosed diabetics, and 1.22 mg/dl ± 1.99 in diabetics under treatment. Conclusion: The mean level of salivary glucose in diabetics was significantly higher than that in non-diabetics. A positive, linear and significant, yet weak correlation between salivary and blood glucose suggests some potential for saliva as a marker in diagnosis and monitoring of diabetes mellitus.

Supplementary Methods, Figure Legend from Estrogen Receptor α Inhibits p53-Mediated Transcriptional Repression: Implications for the Regulation of Apoptosis

Supplementary Figure 1 from Estrogen Receptor α Inhibits p53-Mediated Transcriptional Repression: Implications for the Regulation of Apoptosis

Estrogen receptor α (ERα) and tumor suppressor protein p53 exert opposing effects on cellular proliferation. As a transcriptional regulator, p53 is capable of activating or repressing various target genes. We have previously reported that ERα binds directly to p53, leading to down-regulation of transcriptional activation by p53. In addition to transcriptional activation, transcriptional repression of a subset of target genes by p53 plays important roles in diverse biological processes, such as apoptosis. Here, we report that ERα inhibits p53-mediated transcriptional repression. Chromatin immunoprecipitation assays reveal that ERα interacts in vivo with p53 bound to promoters of Survivin and multidrug resistance gene 1, both targets for transcriptional repression by p53. ERα binding to p53 leads to inhibition of p53-mediated transcriptional regulation of these genes in human cancer cells. Transcriptional derepression of Survivin by ERα is dependent on the p53-binding site on the Survivin promoter, consistent with our observation that p53 is necessary for ERα to access the promoters. Importantly, mutagenic conversion of this site to an activation element enabled ERα to repress p53-mediated transcriptional activation. Further, RNA interference–mediated knockdown of ERα resulted in reduced Survivin expression and enhanced the propensity of MCF-7 cells to undergo apoptosis in response to staurosporine treatment, an effect that was blocked by exogenous expression of Survivin. These results unravel a novel mechanism by which ERα opposes p53-mediated apoptosis in breast cancer cells. The findings could have translational implications in developing new therapeutic and prevention strategies against breast cancer. [Cancer Res 2007;67(16):7746–55]

Purpose A high recurrence rate following ablative therapy of hepatocellular carcinoma (HCC) necessitates routine follow-up imaging (secondary surveillance) to facilitate early re-treatment. We evaluate our unique secondary surveillance algorithm (with use of alternating MRI and CEUS) by assessment of the relative diagnostic accuracy of MRI and CEUS in detection of residual/recurrent tumor. Potential benefits of alternating surveillance are compared to the use of MRI alone. Materials and methods This prospective observational IRB approved study included 231 patients with 354 treated tumors between January 2017 and June 2020. Treated lesions underwent secondary surveillance for a minimum of 7 months and up to 3 years, median follow-up 14 months. Secondary surveillance involved MRI performed at 1 month after treatment, followed by CEUS and MRI at alternate 3-month intervals (i.e., CEUS at month 4, MRI at month 7, etc.), for a total of 2 years. An equivocal finding on one imaging modality triggered expeditious evaluation with the alternate modality. Arterial phase hyperenhancement and washout comprise the classic features of recurrent tumor on both modalities. Results A total of 746 MRI and 712 CEUS examinations were performed, and a total of 184 tumor recurrences detected, MRI (n = 82) and CEUS (n = 102) (p = 0.19). There was no difference in the sensitivity (71.0–85.0% and 80.9–92.0%), specificity (97.4–99.2% and 98.5–99.9%), and area under the ROC curve (0.85–0.92 and 0.91–0.96) between MRI and CEUS, respectively. 23 of 82 recurrent tumors identified on MRI were equivocal and confirmed with expedited CEUS. 9 equivocal cases on MRI were disproved by expedited CEUS. On CEUS, 1 of the 102 recurrent tumors was equivocal and confirmed on MRI, and 2 equivocal CEUS cases were disproved by MRI. Conclusion MRI and CEUS performed similarly in our secondary surveillance algorithm for HCC in their ability to detect tumor recurrence, and showed no significant difference in their relative diagnostic test accuracy measures. Of greater interest, equivocal results on MRI (typically due to difficulty in distinguishing tumor recurrence from post-treatment change/shunting) were either confirmed or disproven by CEUS in all cases. Secondary surveillance of treated HCC with alternating MRI and CEUS shows equivalent performance of each modality. CEUS resolves equivocal MRI and optimally demonstrates APHE and washout in tumor recurrence. Graphic abstract

Objective To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology. Study design We identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made. Results Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively. Conclusions NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

Background and aims: genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. Approach and results: we studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. Conclusions: unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course., Fifth Medical Center of PLA General Hospital; Roger Dobson Funds; King's College Hospital Charity; Medical Research Council Clinician Scientist Fellowship; Medical Research Council PhD Studentship; Alex Mowat PhD Studentship; King's College Hospital Charity; National Institute for Health Research University College London Hospital/University College London Biomedical Research Centre

The present paper reports an experimental and theoretical investigation on performance behaviour of twin-groove elliptical (two-lobe) white metal hydrodynamic journal bearing used in steam turbines. The experiments are performed on a fully automatic journal bearing test rig with provisions to various operating conditions (i.e. load, speed, and lubricant temperature). The performance behaviour in terms of coefficient of friction, lubricant inlet temperature, load carrying capacity, journal displacement, weight loss etc. has been presented. In addition to this, numerical investigations have also been performed with the numerical solution of governing Reynolds equation using FEM (finite element method) technique and Jakobsson-Floberg-Olsson (JFO) boundary condition. The experimentally obtained and theoretical results have been correlated.

Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children.

Whether estrogen receptor beta (ERβ/ESR2) is a pro- or anti-oncogenic protein in breast cancer has been controversial. ERβ levels are generally high in triple-negative breast cancer (TNBC). Reports including the Cancer Genome Atlas (TCGA) show that about 80% of TNBC express mutant p53 and it is a major driver of these cancers. We tested the hypothesis that WT versus mutant status of p53 will have an important role in determining the duality of ERβ functions. We showed that ERβ directly binds to TP53 in human breast cancer cells. Using glutathione-S-transferase (GST)-pull down and co-imunoprecipitation assays, we have delineated the DNA binding domain (DBD) along with the hinge domain of ERβ and the C-terminal regulatory domain of p53 to be essential for the interaction. The highly sensitive in situ proximity ligation assay (PLA) showed that ERβ is capable of interacting with both wild type (WT) and mutant p53 in breast cancer cells and tumor tissues. ERβ and p53 antibodies validated for specificity were used for all experiments. Combination of proliferation, cell cycle, and apoptosis assays, RNAi technology, quantitative ChIP (qChIP), and real-time PCR (qRT-PCR) showed that ERβ is pro-proliferative in the context of WTp53, whereas it is anti-proliferative in the context of mutant p53 in multiple breast cancer cell lines. The p53-dependent diametrically opposite functions of ERβ were recapitulated in isogenic MDA-MB-231 TNBC cells (generated by CRISPR) that differ only in the presence of WT versus mutant p53. A major gain-of-function of mutant p53 is its ability to bind and inactivate tumor suppressor p73. We show that ERβ binds and sequesters mutant p53 from mutant p53−p73 complex leading to reactivation of p73. Consistent with these observations, immunohistochemistry (IHC) in TNBC patient tumor tissue microarray (TMA) showed that patients with tumors expressing mutant p53 along with high levels of ERβ were of smaller size and lower stage. Complementing these findings, our analysis of the subgroup of the basal-like/TNBC tumors expressing mutant p53 (but not WTp53) in the METABRIC dataset showed that patients with tumors expressing higher levels of ERβ RNA (ESR2) had significantly better breast cancer-specific survival. The finding that ERβ–mutant p53 combination prognosticates survival in TNBC is important as to date there are no effective prognostic markers for TNBC and suggest the potential for using ERβ−mutant p53 combination in stratification of TNBC into therapeutically actionable subgroups.Furthermore, our findings provide a mechanistic explanation for the functional duality of ERβ and the controversy over its pro-versus anti-tumorigenic role.Surprisingly, Tamoxifen (Tam) increased ERβ-mut-p53 interaction in TNBC cells leading to increased transcription of anti-proliferation genes and knockdown experiments showed that the effect on transcription was dependent on both p73 and ERβ. Importantly, when combined with doxorubicin (Adriamycin) Tam decreased several fold the IC50 of doxorubicin resulting in increased apoptosis. The combination was more effective in inhibiting TNBC xenograft tumor growth in vivo compared to either treatment alone. Significant clinical implications of these findings include the potential for treating patients with doxorubicin at much lower dose than what is currently used in the management of TNBC, thereby reducing its major cumulative dose side effects. Importantly, although at present Tam is not indicated for TNBC, our data suggest the possibility for repurposing Tam therapy alone or in combination with chemotherapy to treat TNBC stratified based on ERβ and p53 status. If validated in a clinical trial, our findings could lead to a therapy that is fundamentally better in terms of effectiveness, cost and time needed to reach the TNBC patients. Citation Format: Gokul M Das, Utpal K Mukhopadhyay, Chetan C Oturkar, Christina Adams, Nadi Wickramasekera, Sanjay Bansal, Rajesh Medisetty, Austin Miller, Wendy M Swetzig, Laxmi Silwal-Pandit, Anne-Lise Borresen-Dale, Creighton J Creighton, Jun Hyoung Park, Santhi D Konduri, Alka Mukhopadhyay, Alexander Caradori, Benny Abraham Kaipparettu. Exploiting p53-dependent functional duality of estrogen receptor-beta to repurpose tamoxifen for triple negative breast cancer therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-03.

Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype.In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients.All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults.The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.

Background HCV-specific DAAs have transformed treatment of chronic HCV, but few studies have evaluated these therapies in children. Methods Patients aged 12–17 years old with chronic GT1 HCV were enrolled into an open-label study to receive 12 weeks of LDV/SOF 90 mg/400 mg once daily, and those with HCV GT2 or GT3 to receive SOF (400 mg once daily) + RBV (15 mg/kg/day) for 12 (GT2) or 24 weeks (GT3), respectively. Primary efficacy endpoint was SVR12. Safety was assessed by adverse events and clinical/laboratory data. Pharmacokinetic (PK) sampling was conducted to confirm the appropriateness of the doses. Results 150 adolescents (100 GT1, 13 GT2 and 37 GT3) were enrolled and treated. The majority were female (56%), white (90%), treatment naive (81%), and vertically infected (80%). The mean age was 15 years (range 12–17). LDV, SOF and GS-331007 (primary metabolite) exposures were within the range of adult exposures observed in the SOF and LDV/SOF phase 2/3 studies. The SVR12 rate was 98% in GT1, 100% in GT2 and 97% in GT3; all 3 patients who were considered not to have achieved SVR12 were lost to follow-up. No adverse event (AE) leading to study drug discontinuation or serious AEs have been reported. Conclusion In adolescents, LDV/SOF for 12 weeks and SOF + RBV for 12 or 24 weeks, resulted in a SVR12 rate of 97–100% with no virologic failures. These regimens were well tolerated, demonstrating their potential as an important treatment option for children with HCV infection.

A high recurrence rate following ablative therapy of hepatocellular carcinoma (HCC) necessitates routine follow-up imaging (secondary surveillance) to facilitate early re-treatment. We evaluate our unique secondary surveillance algorithm (with use of alternating MRI and CEUS) by assessment of the relative diagnostic accuracy of MRI and CEUS in detection of residual/recurrent tumor. Potential benefits of alternating surveillance are compared to the use of MRI alone.This prospective observational IRB approved study included 231 patients with 354 treated tumors between January 2017 and June 2020. Treated lesions underwent secondary surveillance for a minimum of 7 months and up to 3 years, median follow-up 14 months. Secondary surveillance involved MRI performed at 1 month after treatment, followed by CEUS and MRI at alternate 3-month intervals (i.e., CEUS at month 4, MRI at month 7, etc.), for a total of 2 years. An equivocal finding on one imaging modality triggered expeditious evaluation with the alternate modality. Arterial phase hyperenhancement and washout comprise the classic features of recurrent tumor on both modalities.A total of 746 MRI and 712 CEUS examinations were performed, and a total of 184 tumor recurrences detected, MRI (n = 82) and CEUS (n = 102) (p = 0.19). There was no difference in the sensitivity (71.0-85.0% and 80.9-92.0%), specificity (97.4-99.2% and 98.5-99.9%), and area under the ROC curve (0.85-0.92 and 0.91-0.96) between MRI and CEUS, respectively. 23 of 82 recurrent tumors identified on MRI were equivocal and confirmed with expedited CEUS. 9 equivocal cases on MRI were disproved by expedited CEUS. On CEUS, 1 of the 102 recurrent tumors was equivocal and confirmed on MRI, and 2 equivocal CEUS cases were disproved by MRI.MRI and CEUS performed similarly in our secondary surveillance algorithm for HCC in their ability to detect tumor recurrence, and showed no significant difference in their relative diagnostic test accuracy measures. Of greater interest, equivocal results on MRI (typically due to difficulty in distinguishing tumor recurrence from post-treatment change/shunting) were either confirmed or disproven by CEUS in all cases. Secondary surveillance of treated HCC with alternating MRI and CEUS shows equivalent performance of each modality. CEUS resolves equivocal MRI and optimally demonstrates APHE and washout in tumor recurrence.

Hepatocellular carcinoma (HCC) has a high incidence of recurrence following therapy. Therefore, secondary surveillance (scheduled follow-up imaging after treatment) is an important part of disease management. The recent approval in the United States for use of a microbubble-based contrast agent for US liver imaging promotes the increased use of contrast-enhanced US (CEUS) in patients with HCC. Although the criteria for the diagnosis of HCC at CEUS are well described, there is a paucity of published literature describing the role of CEUS in ablative therapy and secondary surveillance. In the setting of ablative therapy, CEUS can have vital roles, including patient selection, intraprocedural guidance, and immediate postprocedural assessment. Although CEUS is not widely used, the authors found that it can be used to accurately detect residual or recurrent tumor, characterize the geographic pattern of recurrence (intrazonal, extrazonal, segmental, or remote), and assess for tumor in vein. In addition, similar to primary surveillance, secondary surveillance includes assessment of the entire liver for evaluation of new nodules. Arterial phase hyperenhancement is the reference standard characteristic of disease recurrence at secondary surveillance with CEUS. ©RSNA, 2019 See discussion on this article by Rodgers.

For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct‐acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir‐sofosbuvir in HCV‐infected children aged 3 to

Currently, the only approved hepatitis C virus (HCV) treatment for children aged

BackgroundAnti-tumorigenic vs pro-tumorigenic roles of estrogen receptor-beta (ESR2) in breast cancer remain unsettled. We investigated the potential of TP53 status to be a determinant of the bi-faceted role of ESR2 and associated therapeutic implications for triple negative breast cancer (TNBC).MethodsESR2-TP53 interaction was analyzed with multiple assays including the in situ proximity ligation assay. Transcriptional effects on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2 were determined. Patient survival according to ESR2 expression levels and TP53 mutation status was analyzed in the basal-like TNBC subgroup in the Molecular Taxonomy of Breast Cancer International Consortium (n = 308) and Roswell Park Comprehensive Cancer Center (n = 46) patient cohorts by univariate Cox regression and log-rank test. All statistical tests are two-sided.ResultsESR2 interaction with wild-type and mutant TP53 caused pro-proliferative and anti-proliferative effects, respectively. Depleting ESR2 in cells expressing wild-type TP53 resulted in increased expression of TP53-target genes CDKN1A (control group mean [SD] = 1 [0.13] vs ESR2 depletion group mean [SD] = 2.08 [0.24], P = .003) and BBC3 (control group mean [SD] = 1 [0.06] vs ESR2 depleted group mean [SD] = 1.92 [0.25], P = .003); however, expression of CDKN1A (control group mean [SD] = 1 [0.21] vs ESR2 depleted group mean [SD] = 0.56 [0.12], P = .02) and BBC3 (control group mean [SD] = 1 [0.03] vs ESR2 depleted group mean [SD] = 0.55 [0.09], P = .008) was decreased in cells expressing mutant TP53. Overexpressing ESR2 had opposite effects. Tamoxifen increased ESR2-mutant TP53 interaction, leading to reactivation of TP73 and apoptosis. High levels of ESR2 expression in mutant TP53-expressing basal-like tumors is associated with better prognosis (Molecular Taxonomy of Breast Cancer International Consortium cohort: log-rank P = .001; hazard ratio = 0.26, 95% confidence interval = 0.08 to 0.84, univariate Cox P = .02).ConclusionsTP53 status is a determinant of the functional duality of ESR2. Our study suggests that ESR2-mutant TP53 combination prognosticates survival in TNBC revealing a novel strategy to stratify TNBC for therapeutic intervention potentially by repurposing tamoxifen.

Treatment guidelines for chronic hepatitis B (CHB) do not recommend antiviral therapy for patients in the immune-tolerant phase of the disease, which generally occurs in children who acquire hepatitis B virus (HBV) vertically and may last for decades. On the basis of promising results of a pilot study, we conducted a randomized, controlled, multicenter study to evaluate the efficacy and safety of antiviral therapy in children and adolescents with immune-tolerant CHB.Fifty-nine children aged 3 to18 years hepatitis B e antigen-positive with an HBV DNA titer20,000 IU/mL and persistently normal alanine aminotransferase levels were randomized to 56 weeks of antiviral therapy with an oral nucleoside analogue [entecavir or lamivudine], combined with subcutaneous peginterferon alfa-2a from week 8, or 80 weeks of untreated observation. The primary efficacy outcome was hepatitis B surface antigen loss 24 weeks post-treatment in the antiviral therapy group or at the end of observation in the control group.Enrollment was terminated after the results of two similar studies showed that similar antiviral regimens were ineffective in children and adults with immune-tolerant CHB. At 24 weeks post-treatment, 1 of 26 patients in the antiviral treatment group experienced HBsAg loss (vs none of 33 patients in the control group). No serious treatment-related adverse events were reported, and no patients discontinued treatment because of adverse events.The antiviral regimen evaluated in this trial had an acceptable tolerability profile, but was ineffective in children and adolescents with immune-tolerant CHB.

Background DAA regimens have been approved for CHC treatment in 12 to Methods Patients 6 to Results 102 patients 12 to 15%) were headache, fatigue, and nausea in adolescents and vomiting, cough and headache in 6 to Conclusions In patients 6 to

The first clinical case of persistent HEV infection in England was reported in 2009. We describe the demography, virology and outcomes of patients identified with persistent HEV infection in England and Wales between 2009 and 2017. A series of 94 patients with persistent HEV infection, defined by HEV viraemia of more than 12 weeks, was identified through routine reference laboratory testing. Virology, serology and clinical data were recorded through an approved PHE Enhanced Surveillance System. Sixty-six cases (70.2%) were transplant recipients, 16 (17.0%) had an underlying haematological malignancy without stem cell transplantation, six (6.4%) had advanced HIV infection, five (5.3%) were otherwise immunosuppressed, and one patient (1.1%) had no identified immunosuppression. Retrospective analysis of 46 patients demonstrated a median 38 weeks of viraemia before diagnostic HEV testing. At initial diagnosis, 16 patients (17.0%) had no detectable anti-HEV serological response. Of 65 patients treated with ribavirin monotherapy, 11 (16.9%) suffered virological relapse despite undetectable RNA in plasma or stool at treatment cessation. Persistent HEV infection remains a rare diagnosis, but we demonstrate that a broad range of immunocompromised patients are susceptible. Both lack of awareness and the pauci-symptomatic nature of persistent HEV infection likely contribute to significant delays in diagnosis. Diagnosis should rely on molecular testing since anti-HEV serology is insufficient to exclude persistent HEV infection. Finally, despite treatment with ribavirin, relapses occur even after cessation of detectable faecal shedding of HEV RNA, further emphasising the requirement to demonstrate sustained virological responses to treatment.

Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is pro-apoptotic protein Bcl-2-related Ovarian Killer (BOK). Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p regulates BOK expression by binding to its 3'-UTR in breast cancers. Interestingly, miR-296-5p also regulates the expression of anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1), which is highly expressed in breast cancers. Our results reveal that Mcl-1 and BOK constitute a regulatory feedback loop as ectopic BOK expression induces Mcl-1, whereas silencing of Mcl-1 results in reduced BOK levels in breast cancer cells. In addition, we show that silencing of Mcl-1 but not BOK reduced the long-term growth of breast cancer cells. Silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1. Depletion of BOK suppressed caspase-3 activation in the presence of paclitaxel and in turn protected cells from paclitaxel-induced apoptosis. Furthermore, we demonstrate that glycogen synthase kinase (GSK3) α/β interacts with BOK and regulates its level post-translationally in breast cancer cells. Taken together, our results suggest that fine tuning of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 may decide the fate of cancer cells to either undergo apoptosis or proliferation.

Hepatitis E virus (HEV) is a zoonotic infection, with consumption of processed pork products thought to be the major route of transmission in England. The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure. Persistent, chronic hepatitis is increasingly recognized in immunocompromised patients. Infection via HEV-containing blood components and organs has been reported and measures to reduce this transmission risk were introduced into the blood service in England in 2016. We report here the sequence and phylogenetic findings from investigations into a transmission event from an HEV-infected donor to two recipients. Phylogenetic analysis of HEV genome sequence fragments obtained by Sanger sequencing showed that, whilst most of the sequences from both recipients' samples grouped with the sequence from the blood donor sample, the relationship of five sequences from recipient 2 were unresolved. Analysis of Illumina short-read deep sequence data demonstrated the presence of two divergent viral populations in the donor's sample that were also present in samples from both recipients. A clear phylogenetic relationship was established, indicating a probable transmission of both populations from the donor to each of the immunocompromised recipients. This study demonstrates the value of the application of new sequencing technologies combined with bioinformatic data analysis when Sanger sequencing is not able to clarify a proper phylogenetic relationship in the investigation of transmission events.

Background & Aims Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF), but is limited by surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbead transplantation have been shown in animal models. We report our experience of this therapy in children with ALF treated on a named-patient basis. Methods Clinical grade human hepatocyte microbeads (HMBs) and empty microbeads were tested in immunocompetent healthy rats. Subsequently, 8 children with ALF, who were awaiting a suitable allograft for LT, received intraperitoneal transplantation of HMBs. We monitored complications of the procedure, assessing the host immune response and residual function of the retrieved HMBs, either after spontaneous native liver regeneration or at the time of LT. Results Intraperitoneal transplantation of HMBs in healthy rats was safe and preserved synthetic and detoxification functions, without the need for immunosuppression. Subsequently, 8 children with ALF received HMBs (4 neonatal haemochromatosis, 2 viral infections and 2 children with unknown cause at time of infusion) at a median age of 14.5 days, range 1 day to 6 years. The procedure was well tolerated without complications. Of the 8 children, 4 avoided LT while 3 were successfully bridged to LT following the intervention. HMBs retrieved after infusions (at the time of LT) were structurally intact, free of host cell adherence and contained viable hepatocytes with preserved functions. Conclusion The results demonstrate the feasibility and safety of an HMB infusion in children with ALF. Lay summary Acute liver failure in children is a rare but devastating condition. Liver transplantation is the most effective treatment, but it has several important limitations. Liver cell (hepatocyte) transplantation is an attractive option, as many patients only require short-term liver support while their own liver recovers. Human hepatocytes encapsulated in alginate beads can perform the functions of the liver while alginate coating protects the cells from immune attack. Herein, we demonstrated that transplantation of these beads was safe and feasible in children with acute liver failure.

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

The chapter on acute liver failure includes the definition, aetiology, and management of this condition. It discusses the frequently associated complications (neurological, haemodynamic, coagulopathy, infectious, and metabolic) and its prognosis, as well as the role of liver transplantation and liver support systems in its management.

The chapter on hepatitis C discusses the epidemiology, risk of transmission, and the clinical features of this infection. It explains the serology and then gives an update of treatment recommendations for children with interferon as well as directly acting antiviral agents.

Aim To study the clinical profile and site proclivity of extrapulmonary tuberculosis (EPTB) at tertiary care center of Rohilkhand region, Bareilly. Materials and methods Among 329 patients, the study was conducted on 108 patients with EPTB. The analysis included patients who were diagnosed for EPTB between May 1, 2015 and October 31, 2015 in a tertiary care hospital, Rohilkhand region, Bareilly, Uttar Pradesh. Results Among the EPTB cases studied, 62 (57.4%) were males. About 96 (88.8%) patients received Category (CAT)1 treatment and 12 (11.1%) patients received CAT2 treatment. Overall, the total number of different types of EPTB cases included lymph node (n = 44, 40.7%), human gastrointestinal tract (n = 18, 16.6%), pleura (n = 34, 31.4%), skeletal (n = 5, 4.6%), central nervous system (n = 3, 2.7%); other sites included mainly breast (n = 2, 3.2%), genitourinary (n = 1, 2.6%), and skin (n = 1, 2.6%). Conclusion Extrapulmonary tuberculosis still constitutes an important clinical problem. In this study, we assessed the site of predilection of EPTB patients, which constituted 32.8% of all tuberculosis cases presented to our center during the study period. Lymph node tuberculosis is the most common type. How to cite this article Tiwari VK, Agarwal R, Bansal S, Saini RK, Kumar A, Khan J. Study of the Clinical Profile and Site Proclivity of Extrapulmonary Tuberculosis at Tertiary Care Center of Rohilkhand Region, Bareilly. Int J Adv Integ Med Sci 2016;1(3):95-97.

The aim of the study was to assess the effect of treatment with ledipasvir/sofosbuvir (LDV/SOF) on the health-related quality of life (HRQL) of pediatric patients with chronic hepatitis C virus (HCV) infection.Adolescents (12-17 years) with HCV were treated with LDV/SOF (90/400 mg daily) for 12 weeks. HRQL was assessed using the PedsQLv4.0-SF15 completed by the children and caregivers before, during, and after treatment.We included 100 adolescents with HCV genotype 1 infection (14.7 ± 2.0 years, 1% known cirrhosis, 80% treatment-naïve, 97% sustained virologic response-12). At baseline, HRQL the caregiver- perceived HRQL scores were lower than adolescents' self-reported scores (by 6.7-7.9 points, all P 0.01). At the end of 12 weeks of treatment, however, the caregiver-reported HRQL scores showed a significant improvement (+all P 0.04), whereas the adolescents' self-reported scores did not change from the baseline. HRQL scores reported by caregivers remained higher than baseline (by +4.7-+7.5, P 0.01) through 12 weeks after treatment, as did the adolescents' self-reported Emotional Functioning scores (+4.3 from baseline, P = 0.0009); observed improvements were sustained after 24 weeks of follow-up (all P 0.04). Multivariate analysis showed that, after adjustment for location, age, and sex, having a history of anxiety and panic disorders were consistent predictors of impaired HRQL in adolescents with HCV infection (P 0.05).Treatment of HCV in adolescents with LDV/SOF is associated with some improvement in HRQL. Caregivers' reports of HRQL in adolescents with HCV significantly increased with treatment and were similar to the adolescent self-reported HRQL after sustained virologic response-12.

Now in these days the social network has becomes a daily habit for all. Most of the young and teenager are consuming their time on social media. Due to frequent reachability of users the different marketing companies are also usages this platform for publishing advertises. But not only legitimate users are available in this platform, sometimes this platform is also used for abusing someone or harshen someone. Therefore, it is need to identify the sensitive contents on the social media platforms before publishing the contents. A number of different kinds of approaches are available for scanning the contents, but all these techniques are much time-consuming. Therefore, these techniques are not directly used with the social networks. In order to find an efficient technique an effort is presented in this work. The proposed technique is an enhancement over the traditional finger print scan method for sensitive content evaluation. The proposed technique incorporates the NLP (natural language processing) parsers for identifying the sensitive features. The sensitive features are considered here as the noun words in any twit, because in most of the cases the identity of person or places are used for misguiding the social network users. Additionally, in place of linear search technique, a random index scan method is introduced for improving the time consumption of the traditional approaches. Because this technique produces the results equal as the linear search in worst case. The proposed technique is evaluated over the twitter data using the Hadoop, Strom and twitter API implementation. After the successfully implementation the technique is compared with the traditional available technique over the time and space complexity. The experimental results show the performance in terms of time requirement is three times efficient than the traditional approach of sensitivity scan.

Aim: To review the efficacy and tolerability of pegylated interferon-α and ribavirin for treatment of chronic hepatitis C (CHC) in children in the UK. Methods: Retrospective review of children treated for CHC in 3 UK paediatric specialist liver centres between 2005 and 2010. Data on viral response to treatment, demographic and clinical details were collected. Treatment outcome was assessed by the absence of detectable viral RNA in blood 24 weeks after treatment - sustained viral response (SVR). Results: 75 children were included; 34 genotype 1; 39 genotypes 2 and 3; 2 genotype 4. Overall SVR was achieved in 54/71 (76%); 65% genotype 1; 89% genotypes 2 and 3; 100% genotype 4. Early response at 12 weeks was achieved in 53 and sustained in 47 (89%). Data on rapid response after 4 weeks of treatment were available in 25; 17/25 (68%) responded and 16 of these (94%) achieved SVR. IL28 T/T genotype was associated with higher SVR. There were no significant changes in weight and height z scores from baseline compared with 24 weeks post-treatment followup. No child discontinued treatment due to side effects, although 43 required dose modification. Treatment affected quality of life (QoL) in the initial 12 weeks of treatment, which improved by the end of treatment. Conclusions: Children respond well to therapy for CHC. Treatment was tolerated with minimal impact on QoL and no signi ficant effect on growth. Knowledge of viral and IL28 genotypes and early viral response is useful to plan treatment in children and provide appropriate counselling.

BACKGROUND This study aimed to estimate the prevalence of childhood chronic hepatitis B (CHB) infection diagnosed in England using capture-recapture analysis of 2 independent data sources and to describe the clinical and epidemiological characteristics, management, complications and outcome of children with CHB. METHODS Pediatric specialists were contacted to report all CHB cases in children aged