A retrospective case-control cohort analysis of comorbidity and health expenditure in hospitalized adults diagnosed with obesity utilizing ICD-10 diagnostic coding.

The cost and comorbidity of obesity in hospitalized inpatients, is less known. A retrospective study of patients presenting to a large district hospital in Western Sydney (April 2016-February 2017) using clinical, pathological as well as diagnostic coding data for obesity as per ICD-10. Of 43 212 consecutive hospital presentations, 390 had an obesity-coded diagnosis (Ob, 0.90%), of which 244 were gender and age-matched to a non-obesity coded cohort (NOb). Weight and BMI were higher in the Ob vs NOb group (126 ± 37 vs 82 ± 25 kg; BMI 46 ± 12 vs 29 ± 8 kg/m2 , P < .001) with a medical record documentation rate of 62% for obesity among Ob. The Ob cohort had 2-5× higher rates of cardiopulmonary and metabolic complications (P < .001), greater pharmacologic burden, length of stay (LOS, 225 vs 89 hours, P < .001) and stay in intensive care but no differences in the prevalence of mental disorders. Compared with BMI <35 kg/m2 , inpatients with BMI >35 kg/m2 were 5× more likely to require intensive care (OR 5.08 [1.43-27.3, 95% CI], P = .0047). The initiation of obesity-specific interventions by clinical teams was very low. People with obesity who are admitted to hospital carry significant cost and complications, yet obesity is seldom recognized as a clinical entity or contributor.

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

The antiviral role of zinc and metallothioneins in hepatitis C infection.

Metallothioneins (MTs) are small, cysteine-rich proteins characterized by a high affinity for monovalent and divalent cations, such as copper and zinc. Of the four known MT isoforms, only, members of the MT 1 and 2 subfamilies are widely expressed, acting as metal chaperones whose primary role is to mediate intracellular zinc homoeostasis. Metallothioneins are potently induced by heavy metals and other sources of oxidative stress where they facilitate metal binding and detoxification as well as free radical scavenging. Metallothionein expression is well documented in the context of viral infection; however, it remains uncertain whether MTs possess specific antiviral roles or whether induction is merely a consequence of cellular stress. To better understand the role of MTs following hepatitis C virus (HCV) infection, we examined MT expression and localization in vitro and in vivo and used a siRNA knockdown approach to ascertain their antiviral efficacy. We confirmed HCV-driven MT induction in vitro and demonstrated MT accumulation in the nucleus of HCV-infected hepatocytes by immunofluorescence. Using a pan-MT siRNA to knock down all members of the MT1 and MT2 subfamilies, we demonstrate that they are mildly antiviral against the JFH1 strain of HCV in vitro (~1.4 fold increase in viral RNA, P < .05). Furthermore, the antiviral effect of zinc treatment against HCV in vitro was mediated through MT induction (P < .05). Our data suggest a potential benefit of using zinc as a low-cost adjunct to current HCV antiviral therapies and suggest that zinc may facilitate the antiviral role of MTs against other viruses.

IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection.

Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.

Hepatic metallothionein expression in chronic hepatitis C virus infection is IFNL3 genotype-dependent.

The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype (P=2.38 × 10(-7)). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype (P=1.00 × 10(-4)). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection.

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

The influence of HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV-positive Individuals.

OBJECTIVE: This study was performed to investigate the impact of HAART versus no HAART and nucleoside free versus nucleoside containing HAART on the efficacy and safety of pegylated interferon and ribavirin therapy for the treatment of chronic HCV infection in HIV/HCV co-infected patients. In addition a control group of HCV mono-infected patients undergoing anti-HCV therapy was evaluated. METHODS: Multicenter, partially randomized, controlled clinical trial. HIV-negative and -positive patients with chronic HCV infection were treated with pegylated interferon alfa-2a and ribavirin (800 - 1200 mg/day) for 24 - 48 weeks in one of four treatment arms: HIV-negative (A), HIV-positive without HAART (B) and HIV-positive on HAART (C). Patients within arm C were randomized to receive open label either a nucleoside containing (C1) or a nucleoside free HAART (C2). RESULTS: 168 patients were available for analysis. By intent-to-treat analysis similar sustained virological response rates (SVR, negative HCV-RNA 24 weeks after the end of therapy) were observed comparing HIV-negative and -positive patients (54% vs. 54%, p = 1.000). Among HIV-positive patients SVR rates were similar between patients off and on HAART (57% vs. 52%, p = 0.708). Higher SVR rates were observed in patients on a nucleoside free HAART compared to patients on a nucleoside containing HAART, though confounding could not be ruled out and in the intent-to-treat analysis the difference was not statistically significant (64% vs. 46%, p = 0.209). CONCLUSIONS: Similar response rates for HCV therapy can be achieved in HIV-positive and -negative patients. Patients on nucleoside free HAART reached at least equal rates of sustained virological response compared to patients on standard HAART.

Identification of new major histocompatibility complex-A, -B, -C alleles in chimpanzees (Pan troglodytes).

Two new Patr-A, five new Patr-B and three new Patr-C alleles from Pan troglodytes are described.

Description of two new major histocompatibility complex (MHC) class II DRB1 [Pan troglodytes (Patr)-DRB1] alleles.

Sequence-based typing strategy is used to identify polymorphism of Patr-DRB1. Two new Patr-DRB1 are described.

Structured treatment interruptions following immediate initiation of HAART in eight patients with acute HIV-1 seroconversion.

BACKGROUND: The immunological and clinical benefits of structured treatment interruptions (STIs) during primary HIV-1 infection remain largely unclear. PATIENTS AND METHODS: Eight patients identified during primary HIV-1 infection were immediately treated with HAART and underwent subsequent STIs after reaching complete viral suppression of HIV-RNA in peripheral plasma. HAART was re-initiated if either HIV-1 RNA >5000 copies/ml, CD4-cells <200 cells/microl or symptomatic HIV-1 disease was observed. RESULTS: After treatment discontinuation, four of eight patients were able to persistently control HIV-1 viremia below 5000 copies/ml until the last time point of follow-up (median 3 years). CD4-cell counts were within the interquartile range of untreated individuals compared to historical reference data from the MACS cohort. In the remaining study subjects persistent virological control was not reached despite repeated STIs. Moreover, compared to the MACS cohort repetitive virological failures during STIs appeared to induce an accelerated decline of CD4-cells. CONCLUSION: Spontaneous HIV-1 control after treated primary HIV-1 infection was possible in four out of eight individuals, however, if STIs after treated primary infection ameliorate the overall HIV-1 disease progression remains unknown. In the absence of viral control, repetitive viral exposure during STIs might be associated with accelerated decline of CD4-cell counts.

Detection of human aspartyl (asparaginyl) beta-hydroxylase and homeobox B7 mRNA in brush cytology specimens from patients with bile duct cancer.

BACKGROUND AND STUDY AIMS: The diagnosis of bile duct cancer is hampered by the low sensitivity of intraductal brush cytology and forceps biopsy. In the present study real-time reverse transcription polymerase chain reaction (RT-PCR) assays for the detection of human aspartyl (asparaginyl) beta-hydroxylase (HAAH) and homeobox B7 (HoxB7) mRNA from intraductal brush cytology specimens were established. Both markers are overexpressed in biliary cancer cell lines and possibly involved in the pathogenesis of bile duct cancer. PATIENTS AND METHODS: RT-PCR assays were validated for detection limit, in-assay variability, and inter-assay variability. Target gene expression was determined in brush cytology specimens from 16 patients with biliary strictures (11 with histologically proven cholangiocarcinomas and five with benign biliary strictures). RESULTS: The assay was quick (about 3 h), highly sensitive (with detection limits between 3 and 106 molecules), and reproducible (maximum in-assay variability 10.3 %, maximum inter-assay variability 11.8 %). The sensitivity of routine brush cytology alone was 36 % (four of 11 cases), with 100 % specificity. A combination with detection of HoxB7 and HAAH mRNA increased the overall diagnostic sensitivity to 82 %. CONCLUSIONS: Detection of these markers using the RT-PCR assays from brush cytology specimens described here may prove to be a useful additional tool for the diagnosis of bile duct carcinoma.

Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C.

INTRODUCTION: Impaired activity of natural killer (NK) cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. As the function of NK cells is primarily regulated by NK cell receptors (NKR), we analysed whether decreased NK cell function in hepatitis C may be related to dysregulated NKR expression. PATIENTS AND METHODS: Expression of NK cell was analysed by flow cytometry on lymphocytes from HCV(+) subjects (n = 30), patients who became HCV(-) after antiviral therapy (n = 10), healthy individuals (n = 10), and hepatitis B virus (HBV) infected patients (n = 9). Cytolytic function of lymphocytes was studied in a redirected lysis assay and in a standard 51chromium release cytotoxicity assay, respectively. RESULTS: In patients with chronic hepatitis C, we found a significantly reduced proportion of NKp46 and NKp30 expressing NK cells compared with healthy and HBV infected subjects. Low expression of natural cytotoxicity receptor (NCR) was also confirmed in in vitro activated NK cell populations derived from HCV patients compared with uninfected donors. In contrast, patients who cleared HCV under antiviral therapy showed normal expression of NKp44, NKp30, and NKp46. Reduced NCR expression in chronic hepatitis C was associated with a parallel decrease in NCR mediated target cell killing. Furthermore, we found a significantly increased proportion of NKG2A expressing NK cells and CD8+ T cells in HCV positive patients, resulting in a reduced cytolytic activity against cells incubated with the HLA-E stabilising peptide HCV core35-44. CONCLUSION: The present study indicates that defective expression of NKR represents a novel mechanism contributing to impaired function of NK cells and CD8+ T cells in chronic hepatitis C.

The tandem-repeat polymorphism of the DC-SIGNR gene in HCV infection.

The C-type lectin DC-SIGNR has been shown to bind hepatitis C virus (HCV). Here, we analysed the tandem-repeat polymorphism of the DC-SIGNR gene with respect to intraindividual HCV replication. In a cross-sectional comparison HCV-infected patients (n = 430) and healthy subjects (n = 100) were genotyped for the DC-SIGNR polymorphism using PCR. The distribution of DC-SIGNR alleles did not differ significantly between the two groups. However, HCV-infected patients with 5-, 6-, and 7-repeat alleles had higher HCV-RNA levels when compared with carriers of 4- and 9-repeat alleles (P < 0.05). Thus, the DC-SIGNR polymorphism might affect HCV loads supporting the concept that DC-SIGNR contributes to HCV replication efficacy.

Binding of HCV E2 to CD81 induces RANTES secretion and internalization of CC chemokine receptor 5.

Hepatitis C virus (HCV) infection has been shown to be associated with reduced expression of the CC chemokine receptor (CCR) 5, and reduced responsiveness of lymphocytes to chemokines. However, the mechanism by which HCV alters CCR5 expression remains unclear. Here, we investigated whether altered CCR5 expression in hepatitis C results from interactions of CD81 with the HCV E2 protein. Peripheral blood mononuclear cells (PBMC) from HCV-negative individuals were prepared by Ficoll density gradient separation. PBMC subpopulations (CD4+, CD8+ lymphocytes, CD19+ B cells, natural killer (NK) cells and monocyte-derived dendritic cells) were isolated and stimulated with immobilized HCV E2, and changes in CCR5 expression and CC-chemokine secretion were determined. Migration assays were performed using a 5-microm nitrocellulose filter microchamber system according to the manufacturer's recommendations. Exposure of PBMC to HCV E2 induced a dose-dependent release of regulated on activation normal T-cell-expressed and secreted (RANTES), down-regulation of CCR5 expression and intracellular accumulation of CCR5. This effect was blocked by preincubation of PBMC with anti-CD81. RANTES release following exposure to HCV E2 was mainly attributable to CD8+ cells. After exposure to HCV E2 markedly fewer CD8-positive lymphocytes were attracted by RANTES when compared with CD8+ cells that were studied in the absence of HCV E2. Our results suggest that interaction of HCV E2 with CD81 leads to increased RANTES secretion by CD8+ lymphocytes which induces down-regulation of CCR5 surface via receptor internalization resulting in altered lymphocyte migration.

[Do polymorphisms of the SDF1 and CCR2b genes modify the course of hepatitis C or HIV/HCV co-infection?]. / Beeinflussen Polymorphismen des SDF1- und CCR2b-Gens den Verlauf der Hepatitis C und der HIV/HCV-Koinfektion?

BACKGROUND AND OBJECTIVE: Complementary to the CCR5-Delta32 mutation polymorphisms in the genes of CCR2b (CCR2b-V64 I) and stromal derived factor (SDF)-1 (SDF-1 3'A) affect the course of the human immunodeficiency virus (HIV) infection. While the CCR5-Delta32 mutation is also increased in chronic hepatitis C virus (HCV) infection it is unclear, whether the CCR2b-V64 I and the SDF-1 3'A polymorphisms also are associated with chronic HCV infection. METHODS: We analyzed the frequencies of the CCR2b-V64I and SDF1 - 3'A mutation in patients with HIV/HCV coinfection (n = 130), HIV infection (n = 105), HCV infection (n = 153) and 112 healthy blood donors. We stratified each group into homozygous mutations, heterozygous mutations and homozygous wild types, respectively. The resulting subsets were compared with respect to HIV and HCV loads, CD4 and CD8 cell counts. RESULTS: The mutant SDF1 - 3'A allele was found at 20.3 % frequency in patients with HCV infection and at 20.4 % frequency in patients with HIV/HCV coinfection, respectively. It was present in 27.1 % of the patients with HIV infection and 27.9 % of the healthy controls (not significant). The number of SDF-1 3) A homozygous patients was highest in patients with HIV/HCV coinfection and significantly different compared to the Hardy-Weinberg equilibrium (p = 0.010, chi (2) = 9.15). However, CD4- and CD8-cell counts or viral loads were not affected by this mutation. The frequency of the CCR2b-V64 I allele was similar in all patient groups. However, CCR2b-V64 I heterozygous patients showed HIV loads that were threefold lower than in CCR2b wildtype patients (22.9 x 103 vs. 6.4 x 103 copies/ml, not significant). Furthermore, hepatitis C viral loads were reduced roughly by 30 %. CONCLUSION: These results suggest that the SDF1 - 3'A and CCR2b-V64I mutations do not affect the course of HCV and HIV/HCV infection in the same manner as does the CCR5-Delta32 mutation.