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Background and Aims: Whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) differentially affect relapse and outcomes following treatment discontinuation across different patient subpopulations remains unclear. We aimed to compare rates of off-therapy hepatitis B surface antigen (HBsAg) loss, virological and clinical relapse, and retreatment between chronic hepatitis B (CHB) patients who discontinued TDF or ETV therapy. Methods: This study included 1402 virally suppressed CHB patients who stopped either ETV (n = 981) or TDF (n = 421) therapy between 2001 and 2020 from 13 participating centers across North America, Europe, and Asia. All patients were hepatitis B e antigen–negative at treatment discontinuation. Inverse probability of treatment weighting was used to balance the treatment groups. Outcomes were analyzed using survival methods. Results: During a median off-treatment follow-up of 18 months, HBsAg loss occurred in 96 (6.8%) patients overall. Compared with ETV, TDF was associated with a higher rate of HBsAg loss (P = .03); however, the association was no longer significant after statistical adjustment (P = .61). Virological relapse occurred earlier among TDF-treated patients (P < .01); nonetheless, rates became comparable after the first year off therapy (P = .49). TDF was significantly associated with a higher clinical relapse rate than ETV throughout follow-up (P < .01). The development of a virological or clinical relapse did not affect the rate of HBsAg loss. Retreatment rates were not significantly different between the treatment groups. Conclusions: TDF and ETV have differential relapse patterns but are associated with similar rates of HBsAg loss and retreatment following discontinuation. Finite therapy can be considered for CHB patients on either TDF or ETV therapy.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4–12], 7.6 × ULN [IQR 6.2–10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p 10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

Background & Aims: Patients with chronic hepatitis B (CHB) are at increased risk of hepatocellular carcinoma and (liver-related) mortality. In addition to hepatitis B–related factors, metabolic comorbidities may contribute to the progression of fibrosis. Therefore, we studied the association between metabolic comorbidities and adverse clinical outcomes in patients with CHB. Methods: We conducted a retrospective cohort study of CHB patients attending the Erasmus MC University Medical Center (Rotterdam, The Netherlands) and CHB patients who underwent liver biopsy at the Toronto General Hospital (Toronto, Canada). The presence of metabolic comorbidities (ie, overweight, diabetes mellitus, hypertension, and dyslipidemia) was assessed based on chart review. The primary end point was liver-related events, defined as the first composite of hepatocellular carcinoma, liver transplantation, or liver-related mortality. Results: We analyzed 1850 patients, of whom 926 (50.1%) were overweight, 161 (8.7%) had hypertension, 116 (6.3%) had dyslipidemia, and 82 (4.4%) had diabetes. During a median follow-up period of 7.3 years (interquartile range, 2.9–11.5 y), a total of 111 first events were recorded. Hypertension (hazard ratio [HR], 8.3; 95% CI, 5.5–12.7), diabetes (HR, 5.4; 95% CI, 3.2–9.1), dyslipidemia (HR, 2.8; 95% CI, 1.6–4.8), and overweight (HR, 1.7; 95% CI, 1.1–2.5) were associated with an increased risk for liver-related events. The presence of multiple comorbidities further increased the risk. Findings were consistent for patients with and without cirrhosis, among noncirrhotic hepatitis B e antigen–negative patients with hepatitis B virus DNA less than 2000 IU/mL and in multivariable analysis adjusting for age, sex, ethnicity, hepatitis B e antigen status, hepatitis B virus DNA, use of antiviral therapy, and the presence of cirrhosis. Conclusions: Metabolic comorbidities in CHB patients are associated with an increased risk for liver-related events, with the highest risk observed in patients with multiple comorbidities. Findings were consistent in various clinically relevant subgroups, underscoring the need for thorough metabolic assessment in patients with CHB.

While the incorporation of pendant Bronsted acid/base sites in the secondary coordination sphere is a promising and effective strategy to increase the catalytic performance and product selectivity in organometallic catalysis for CO2 reduction, the control of product selectivity still faces a great challenge. Herein, we report two new trans(Cl)-[Ru(6-X-bpy)(CO)2Cl2] complexes functionalized with a saturated ethylene-linked functional group (bpy = 2,2'-bipyridine; X = -(CH2)2-OH or -(CH2)2-N(CH3)2) at the ortho(6)-position of bpy ligand, which are named Ru-bpyOH and Ru-bpydiMeN, respectively. In the series of photolysis experiments, compared to nontethered case, the asymmetric attachment of tethering ligand to the bpy ligand led to less efficient but more selective formate production with inactivation of CO2-to-CO conversion route during photoreaction. From a series of in situ FTIR analyses, it was found that the Ru-formate intermediates are stabilized by a highly probable hydrogen bonding between pendent proton donors (-diMeN+H or -OH) and the oxygen atom of metal-bound formate (RuI-OCHO···H-E-(CH2)2-, E = O or diMeN+). Under such conformation, the liberation of formate from the stabilized RuI-formate becomes less efficient compared to the nontethered case, consequently lowering the CO2-to-formate conversion activities during photoreaction. At the same time, such stabilization of Ru-formate species prevents the dehydration reaction route (η1-OCHO → η1-COOH on Ru metal) which leads toward the generation of Ru-CO species (key intermediate for CO production), eventually leading to the reduction of CO2-to-CO conversion activity.

Herein, we employed a molecular Ru(II) catalyst immobilized onto TiO2 particulates of (4,4'-Y2-bpy)RuII(CO)2Cl2 (RuP; Y = CH2PO(OH)2), as a hybrid catalyst system to secure the efficient and steady catalytic activity of a molecular bipyridyl Ru(II)-complex-based photocatalytic system for CO2 reduction. From a series of operando FTIR spectrochemical analyses, it was found that the TiO2-fixed molecular Ru(II) complex leads to efficient stabilization of the key monomeric intermediate, RuII-hydride (LRuII(H)(CO)2Cl), and suppresses the formation of polymeric Ru(II) complex (-(L(CO)2Ru-Ru(CO)2L)n-), which is a major deactivation product produced during photoreaction via the Ru-Ru dimeric route. Active promotion of the monomeric catalytic route in a hetero-binary system (IrPS + TiO2/RuP) that uses TiO2-bound Ru(II) complex as reduction catalyst led to highly increased activity as well as durability of photocatalytic behavior with respect to the homogeneous catalysis of free Ru(II) catalyst (IrPS + Ru(II) catalyst). This catalytic strategy produced maximal turnover numbers (TONs) of >4816 and >2228, respectively, for CO and HCOO- production in CO2-saturated N,N-dimethylformamide (DMF)/TEOA (16.7 vol % TEOA) solution containing a 0.1 M sacrificial electron donor.

We now report full details of the collisional ET process at the interface between the solvated porphyrin dye (a representative molecular dye) and heterogeneous TiO2 particles (a well-defined n-type...

Objective: It is of critical importance to develop socially sensitive vehicles that will enhance pedestrians’ sense of comfort and safety. The current study is the first to extend these effects to ...

A porphyrinic metal-organic framework (PMOF) known as PCN-222(Zn) was chemically doped with a molecular Re(I) catalyst-bearing carboxylate anchoring group to form a new type of metal-organic framework (MOF)-Re(I) hybrid photocatalyst. The porphyrinic MOF-sensitized hybrid (PMOF/Re) was prepared with an archetypical CO2 reduction catalyst, (L)ReI(CO)3Cl (Re(I); L = 4,4'-dicarboxylic-2,2'-bipyridine), in the presence of 3 vol % water produced CO with no leveling-off tendency for 59 h to give a turnover number of ≥1893 [1070 ± 80 μmol h-1 (g MOF)-1]. The high catalytic activity arises mainly from efficient exciton migration and funneling from photoexcited porphyrin linkers to the peripheral Re(I) catalytic sites, which is in accordance with the observed fast exciton (energy) migration (≈1 ps) in highly ordered porphyrin photoreceptors and the effective funneling into Re(I) catalytic centers in the Re(I)-doped PMOF sample. Enhanced catalytic performance is convincingly supported by serial photophysical measurements including decisive Stern-Volmer interpretation.

To evaluate the efficacy of ortho-arylation in the second coordination sphere of octahedral iridium complex, a series of homoleptic N-heterocyclic carbene (NHC)-based Ir(C∧CR)3-type complexes were ...

Dye detachment issue in the TiO2-mediated dye-sensitized photocatalytic system engenders an electron injection route based on collisional quenching between the detached solution-phase dye and dispe...

Herein, we report the synthesis, and photochemical and -physical properties, as well as the catalytic performance, of a series of heteroleptic IrIII photosensitizers (IrPSs), [Ir(C^N)2 (N^NAryl )]+ , possessing ancillary ligands that are varied with aryl-substituents on bipyridyl unit [C^N=(2-pyridyl)benzo[b]thiophen-3-yl (btp); N^NAryl =4,4'-Y2 -bpy (Y=-Ph or -PhSi(Ph)3 ]. We found that the π-extension of bipyridyl ligand by aryl-substitution put bipyridyl ligand in use as an electron relay unit that performed charge accumulation before delivering to the catalytic center, greatly improving the overall CO2 -to-CO conversion activities. In a typical run, the aryl-substituted IrPS (tBu IrP-PhSi )-sensitized homogeneous systems (IrPS+ReI catalyst) gave a turnover number of 1340 (ΦCO =24.2 %) at the early stage of photolysis (

Chronic hepatitis B virus (HBV) infection remains difficult to cure due to the persistent, self-replenishing nature of the viral genome and impaired host immune responses. Current treatment goals for chronic hepatitis B (CHB) are to prevent or significantly delay liver-related adverse outcomes and death, and two types of treatments are available: nucleos(t)ide analogues (NAs) and interferons (IFNs). NAs effectively suppress HBV replication, and IFNs improve serological response rates, thereby decreasing the risk of adverse outcomes. However, their efficacy in attaining serological responses, especially functional cure (i.e., loss of serum hepatitis B surface antigen), is very limited. Various strategies such as stopping antiviral therapy or combining therapies have been investigated to enhance response, but efficacy is only modestly improved. Importantly, the development of novel direct-acting antivirals and immunomodulators is underway to improve treatment efficacy and enhance rates of functional cure. The present review provides an overview of the treatment goals and indications, the possibility of expanding indications, and the safety and efficacy of different treatment strategies involving established and/or novel therapies as we continue our search for a cure.

Background & Aims A recent consensus document has defined metabolic dysfunction-associated fatty liver disease (MAFLD) as hepatic steatosis together with overweight, diabetes, and/or a combination of other metabolic risk factors. The clinical relevance of this novel diagnosis is unknown among patients with chronic hepatitis B (CHB). We studied the association between MAFLD (with or without steatohepatitis) and adverse clinical outcomes in patients with CHB. Methods We performed a retrospective long-term follow-up cohort study at 2 tertiary hospitals in patients with CHB who underwent liver biopsy. Biopsies were reassessed for steatosis, degree of fibrosis, and presence of steatohepatitis. Associations with event-free hepatocellular carcinoma (HCC)-free and transplant-free survival were explored. Results In our cohort, 1076 patients were included, median follow-up was 9.8 years (25th–75th percentile: 6.6−14.0), and 107 events occurred in 78 patients, comprising death (n = 43), HCC (n = 36), liver decompensation (n = 21), and/or liver transplantation (n = 7). MAFLD was present in 296 (27.5%) patients and was associated with reduced event-free (adjusted hazard ratio [aHR] 2.00, 95% CI 1.26–3.19), HCC-free (aHR 1.93, 95% CI 1.17–3.21), and transplant-free survival (aHR 1.80, 95% CI 0.98–3.29) in multivariable analysis. Among patients with MAFLD, the presence of steatohepatitis (p = 0.95, log-rank test) was not associated with adverse outcomes. Conclusions The presence of MAFLD in patients with CHB was associated with an increased risk for liver-related clinical events and death. Among patients with MAFLD, steatohepatitis did not increase the risk of adverse outcomes. Our findings highlight the importance of metabolic dysfunction in patients with CHB. Lay summary Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been defined as fatty liver disease with signs of metabolic dysfunction. Among patients with chronic hepatitis B, MAFLD was associated with liver-related events and death. Metabolic health assessment should be encouraged among patients with chronic hepatitis B, especially in those with fatty liver disease., Graphical abstract, Highlights • Recently, MAFLD was defined as hepatic steatosis in the presence of metabolic dysfunction (e.g. overweight, diabetes). • In patients with chronic hepatitis, MAFLD was associated with reduced event-free (p

A series of heteroleptic iridium(III) complexes functionalized with two phosphonic acid (-PO3 H2 ) groups (dfppy IrP, ppy IrP, btp IrP, and piq IrP) were prepared and anchored onto rhenium(I) catalyst (ReP)-loaded TiO2 particles (TiO2 /ReP) to build up a new IrP-sensitized TiO2 photocatalyst system (IrP/TiO2 /ReP). The photosensitizing behavior of the IrP series was examined within the IrP/TiO2 /ReP platform for the photocatalytic conversion of CO2 into CO. The four IrP-based ternary hybrids showed increased conversion activity and durability than that of the corresponding homo- (IrP+ReP) and heterogeneous (IrP+TiO2 /ReP) mixed systems. Among the four IrP/TiO2 /ReP photocatalysts, the low-energy-light (>500 nm) activated piq IrP immobilized ternary system (piq IrP/TiO2 /ReP) exhibited the most durable conversion activity, giving a turnover number of ≥730 for 170 h. A similar kinetic feature observed through time-resolved photoluminescence measurements of both btp IrP/TiO2 and TiO2 -free btp IrP films suggests that the net electron flow in the ternary hybrid proceeds dominantly through a reductive quenching mechanism, unlike the oxidative quenching route of typical dye/TiO2 -based photolysis.

Red light-sensitized squaraine (SQ) dyes were developed and incorporated into dye-sensitized catalysts (DSCs) with the formula of SQ/TiO2/Cat, and their efficacies were evaluated in terms of performance on either water or carbon dioxide reduction. Pt nanoparticles or fac-[Re(4,4′-bis-(diethoxyphosphorylmethyl)-2,2′-bipyridine)(CO)3Cl] were used as each catalytic center within the DSC frame of SQ/TiO2/Pt (Type I) or SQ/TiO2/Re(I) (Type II). In order to convey the potential utility of SQ in low energy sensitization, the following catalytic reductions were carried out under selective lower energy irradiation (>500 nm). Type I and II showed different catalytic performances, primarily due to the choice of solvent for each catalytic condition: hydrogenation was carried out in H2O, but CO2 reduction in dimethylformamide (DMF), and SQ was more stable in aqueous acid conditions for hydrogen generation than CO2 reduction in DMF. A suspension of Type I in 3 mL water containing 0.1 M ascorbic acid (pH = 2.66) resulted in efficient photocatalytic hydrogen evolution, producing 37 μmol of H2 for 4 h. However, in photocatalysis of Type II (SQ/TiO2/Re(I)) in 3 mL DMF containing 0.1 M 1,3-dimethyl-2-phenyl-1,3-dihydrobenzimidazole, the TiO2-bound SQ dyes were not capable of working as a low energy sensitizer because SQ was susceptible to dye decomposition in nucleophilic DMF conditions, resulting in DSC deactivation for the CO2 reduction. Even with the limitation of solvent, the DSC conditions for the utility of SQ have been established: the anchoring group effect of SQ with either phosphonic acid or carboxylic acid onto the TiO2 surface; energy alignment of SQ with the flat band potentials (Efb) of TiO2 semiconductors and the reduction power of electron donors; and the wavelength range of the light source used, particularly when >500 nm.

Background Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. Patients and methods We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. Results A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440] and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. Conclusion HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

A Mn(I)-based hybrid system (OrgD-|TiO2|-MnP) for photocatalytic CO2 reduction is designed to be a coassembly of Mn(4,4′-Y2-bpy)(CO)3Br (MnP; Y = CH2PO(OH)2) and (E)-3-[5-(4-(diphenylamino)phenyl)-...

While passive social information (e.g. pictures of people) routinely draws one's eyes, our willingness to look at live others is more nuanced. People tend not to stare at strangers and will modify their gaze behaviour to avoid sending undesirable social signals; yet they often continue to monitor others covertly “out of the corner of their eyes.” What this means for looks that are being made near to live others is unknown. Will the eyes be drawn towards the other person, or pushed away? We evaluate changes in two elements of gaze control: image-independent principles guiding how people look (e.g. biases to make eye movements along the cardinal directions) and image-dependent principles guiding what people look at (e.g. a preference for meaningful content within a scene). Participants were asked to freely view semantically unstructured (fractals) and semantically structured (rotated landscape) images, half of which were located in the space near to a live other. We found that eye movements were horizontally displaced away from a visible other starting at 1032 ms after stimulus onset when fractals but not landscapes were viewed. We suggest that the avoidance of looking towards live others extends to the near space around them, at least in the absence of semantically meaningful gaze targets.

Objectives No randomized controlled trials have evaluated the comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Methods A prospective observational cohort study including all S. aureus bacteraemia was conducted at 10 hospitals. Patients (≥15 years) with MSSA bacteraemia who received cefazolin or nafcillin as definitive antibiotics were included. The rates of treatment failure (premature discontinuation of antibiotics because of adverse effects, switching of antibiotics because of clinical failure, all-cause mortality within 1 month, or recurrence) were compared between the cefazolin and nafcillin groups. Propensity score matching analyses were performed to balance the factors influencing the selection of antibiotics. Results Among the 242 included cases, the bones and joints (36.8%) were the most common sites of infection and 60.7% of the patients had sepsis. The overall treatment failure rate was 43.8% (106/242). All-cause mortality within 1 month was 6.2% (15/242). After propensity score matching, the treatment failure rate of cefazolin was lower than that of nafcillin (30.4% (24/79) vs. 49.4% (39/79), p 0.015) because of a higher rate of discontinuation caused by adverse events. When the data were limited to patients with sepsis, the treatment failure rates of both groups were not significantly different. Approximately 22% (24/110) of MSSA isolates exhibited a cefazolin-inoculum effect (CIE) that had significant impact on the failure rate and mortality of the cefazolin group. Conclusions Cefazolin might be recommended as an adequate and better-tolerated treatment for MSSA bacteraemia in the absence of CIE.

A series of Zn–porphyrin dyes was prepared and anchored onto a TiO2 surface to complete a dye-sensitized photocatalyst system, Zn–porphyrin-|TiO2|-Cat, and tested as lower energy photosensitizers for photocatalytic CO2 reduction. Three major synthetic modifications were performed on the Zn–porphyrin dye to obtain a lower energy sensitization and improve the catalyst lifetime. We found that incorporating acetylene and linear hexyl groups into the Zn–porphyrin core allowed facile lower energy sensitization, and the addition of the cyanophosphonic acid as an anchoring group gave the long-term dye stability on the TiO2 surface. Under irradiation with red light of >550 nm and a light intensity of 207 mW/cm2, the hybrid ZnPCNPA catalyst showed a TONRe of ∼800 over an extended time period of 90 h. The photocatalytic activities of porphyrin hybrids differ greatly with the binding strength of the anchoring groups of dye and spectral range of the irradiated light and its intensity.

Background and Aims Interferon-alpha (IFN-α) treatment for chronic hepatitis B (CHB) virus infection is finite and leads to relatively higher functional cure rates (HBsAg loss) than nucleo(s)tide analogue (NA) therapy. Effects of pegylated (PEG)/conventional IFN-α treatment on clinical outcomes were evaluated in an ultra long-term follow-up of CHB patients. Methods HBeAg-positive patients treated with (PEG)IFN-α at a tertiary referral centre between 1977-2014 were included. We reviewed medical charts and consulted the municipal registry for patient information. Patients were invited for a single visit at the outpatient clinic in the case of missing follow-up data. The endpoints included serum HBeAg/HBsAg loss and incidence of clinical events, using life table methods and person-years to analyze the incidence of events. Patients were censored upon retreatment. Results The study cohort included 267 patients, 67% male, 58% Caucasian, with a median age of 32 years. The median follow-up duration was 11.5 years. The 5 and 10-year cumulative incidence of HBsAg loss were 14% and 32%, respectively. Baseline factors associated with a higher rate of HBsAg loss were male sex, Caucasian race, genotype A, age ≥40 years, and cirrhosis. HBsAg loss rates did not differ significantly between those who received short-term (≤24 weeks) versus long-term (>24 weeks) therapy. Both HBeAg and HBsAg loss were significantly associated with improved clinical outcomes. Early response (HBeAg loss) was associated with more HBsAg loss and better patient outcomes. Conclusions During long-term follow-up, high rates of HBsAg loss were observed from a single (PEG)IFN-α course. Its persistent effects suggest that a role for IFN-α remains, potentially in novel combination therapies in search of a functional cure.

Background and Aims: Chronic hepatitis B (CHB) and nonalcoholic fatty liver disease are increasingly observed together in clinical practice, and development of nonalcoholic steatohepatitis (NASH) represents another leading cause of liver-related morbidity and mortality. Our aims were to determine whether biopsy-proven NASH impacts clinical outcomes in CHB patients and assess prognostic risk factors. Approach and Results: CHB patients attending two tertiary centers in North America and Europe over 13 years with available clinical and biopsy data were included. Patients were categorized as no-NASH or probable/definite NASH based on standardized histological assessment. Clinical events (death, decompensation, transplant, and hepatoma) were evaluated, and Kaplan-Meier survival estimates and Cox proportional hazards regression were used to analyze the incidence of events. There were 1,089 CHB patients, classified as no-NASH (n = 904, 83%) or NASH (n = 185, 17%), with 52 (6%) versus 27 (15%) experiencing outcome events during follow-up, respectively. In the multivariable analysis adjusting for age, sex, hepatitis B e antigen serostatus, and diabetes, the presence of NASH and concomitant advanced fibrosis (AF) was significantly associated with clinical outcomes (hazard ratio [95% confidence interval], 4.8 [2.6-9.0], P

Objective The aim of this study was to determine whether polymorphisms of the Toll-like receptor ( TLR) genes are associated with susceptibility to systemic lupus erythematosus (SLE). Methods The authors conducted a meta-analysis of the relationship between 12 TLR polymorphisms and SLE susceptibility. Results In total, 26 studies that involved 11,984 patients and 14,572 controls were included in the meta-analysis. The meta-analysis showed no association between the two alleles of the rs352140, rs5743836, and rs352139 polymorphisms of TLR9 and SLE, but indicated an association between the two alleles of the rs187084 polymorphism ( TLR9) and SLE in the overall population (OR = 0.869, 95% CI = 0.762–0.992, P = 0.038). No association was detected between rs3764880 ( TLR8) and SLE; however, our meta-analysis indicated an association between rs3764879 ( TLR8) and SLE in Caucasians (OR = 1.414, 95% CI = 1.139–1.756, P = 0.002). An association between rs179008 ( TLR7) and SLE was found in the African (OR = 0.430, 95% CI = 0.238–0.775, P = 0.005), but not in the Caucasian population (OR = 1.206, 95% CI = 0.932–1.614, P = 0.145). Furthermore, our meta-analysis indicated a significant association between rs3853839 ( TLR7) and SLE in the Asian population (OR = 0.773, 95% CI = 0.735, 0.823, P −9). No associations were found between rs5744168 ( TLR5), rs4986791 ( TLR4), rs4986790 ( TLR4), and rs3775291 ( TLR3) polymorphisms and SLE susceptibility. Conclusions Our meta-analysis suggests that TLR7, TLR8, and TLR9 polymorphisms are associated with the development of SLE in Caucasian, Asian, and African populations.

Objective The aim of this study was to determine whether the functional CD40 rs4810485 G/T polymorphism is associated with susceptibility to rheumatoid arthritis (RA) or with susceptibility to systemic lupus erythematosus (SLE). Methods A series of meta-analyses were conducted to test for association between the CD40 rs4810485 G/T polymorphism and RA or SLE. Results A total of 21 comparisons involving 15,095 patients and 27,050 controls for RA, and 1353 patients and 2342 controls for SLE were considered. Meta-analysis showed a significant association between the CD40 rs4810485 T allele and RA in all subjects (odds ratio (OR) 0.890, 95% confidence interval (CI) 0.846–0.936, p = 5.5 × 10−7). After stratification by ethnicity, the CD40 T allele was found to be significantly associated with RA in Europeans (OR 0.879, 95% CI 0.848–0.901, p = 3.0 × 10−9). A similar pattern of association was observed between the CD40 T allele and RA when the analysis was performed using the recessive, dominant, and additive models. Meta-analysis also showed a significant association between the CD40 polymorphism and SLE in Europeans (OR for the T allele 0.715, 95% CI 0.641–0.832, p = 1.4 × 10−6). Conclusions Our meta-analyses confirm that the CD40 rs4810485 G/T polymorphism is associated with susceptibility to RA and SLE in Europeans.

A characteristic pattern of hemodynamic changes that may occur after reperfusion during liver transplantation (LT) is known as postreperfusion syndrome (PRS). We investigated the effect of prophylactic ephedrine administration on PRS and postoperative laboratory results in living donor LT. The medical records of adult recipients who underwent living donor LT were reviewed. A total of 308 recipients were divided into the prophylaxis group and the nonprophylaxis group. Graft factors, preoperative and intraoperative recipient factors, and postoperative laboratory results were compared between the 2 groups. Graft factors and preoperative and intraoperative recipient factors did not differ between the 2 groups, except the prevalence of diabetes mellitus and etiology of liver disease. After reperfusion, PRS occurred more frequently (43.2% vs 25.0%; P = .006), and mean arterial pressure was more reduced compared with prereperfusion values (33.7 ± 15.8% vs 22.3 ± 23.5%; P < .001) in the nonprophylaxis group than the prophylaxis group. Postoperative laboratory results did not differ between the 2 groups. In conclusion, prereperfusion administration of ephedrine reduced the incidence and severity of PRS. Further prospective studies on the relationship between prophylactic medication and posttransplantation outcomes are needed.

The aim of this study was to explore whether polymorphisms in miR-146a, miR-499 and IRAK1 are associated with susceptibility to inflammatory arthritis. Manual searches performed in the MEDLINE and EMBASE databases were used to identify published articles in which the roles of microRNA (miRNA) and IRAK1 polymorphisms in inflammatory arthritis were determined. A meta-analysis was conducted to investigate associations of the miR-146a rs2910164, miR-499 rs3746444, IRAK1 rs3027898 and IRAK1 rs1059703 polymorphisms with susceptibility to inflammatory arthritis. Nine studies containing 1224 patients and 1841 controls were included in the meta-analysis. The meta-analysis revealed no association between inflammatory arthritis and the rs2910164 C allele of miR-146a (odds ratio, OR = 0.974; 95 % confidence interval, CI = 0.810–1.091; p = 0.650). Stratification by ethnicity or disease type revealed no association between the miR-146a C allele and inflammatory arthritis in European, Middle Eastern or Asian patients with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA). However, the meta-analysis revealed an overall association between RA and the miR-499 rs374644 C (OR = 1.123, 95 % CI = 1.019–2.586, p = 0.041); stratification by ethnicity revealed a particular association in Middle Eastern populations (OR = 1.943, 95 % CI = 1.508–2.504, p = 2.7 × 10–8). The meta-analysis of IRAK1 polymorphisms revealed an association between inflammatory arthritis and the rs3027898 CC genotype (OR = 2.602, 95 % CI = 1.387–4.879, p = 0.003). An analysis using the homozygote contrast showed the same pattern for the rs3027898 CC genotype (OR = 2.472, 95 % CI = 1.300–4.700, p = 0.006). No association between inflammatory arthritis and the rs1059703 polymorphism was found. This meta-analysis suggests that the miR-499 rs374644 and IRAKI rs3027898 polymorphisms are associated with susceptibility to inflammatory arthritis.

In this paper, the response characteristics of an offshore wind turbine (OWT) structure under breaking wave forces and wind forces are studied. A 3D numerical model, based on solving the viscous and incompressible Navier-Stokes equations and the volume of flmethod, is employed to estimate the breaking wave forces on an OWT structure (6.0-m diameter monopile). The calculated wave forces are then applied with the wind forces on the OWT structure modeled in the computer program HAWC2 to understand the nature of its response. The effects from the aerodynamic damping and the foundation fl exibility on the structure's response are also discussed. In recent years, a large number of fioffshore wind turbines (OWT), which are supported by monopiles, tripod structures, and jacket structures, have been planned or constructed in shallow waters to capture the abundant wind energy source. Among them, a 'monopile-transi- tion piece-tower' type of structure seems to be preferred to support an OWT in shallow waters. For the design of a monopile structure installed on a fl at bottom, the Morison equation has generally been used to estimate wave forces on the structure. Moreover, as the frequencies of the environmental loads on a structure generally stay away from the structure's natural fre- quency, the vibration of the structure is not a 'major' problem in the designing stage of the structure. However, in the case where an OWT structure is installed in a submerged shoal, the water waves may experience severely nonlinear wave deformations on their propagation, and the nonlinear waves generated toward the structure can give rise to higher local pressures and impulsive forces on the structure. Because the breaking wave impact forces normally act in a very short time, this can also cause large horizontal accelerations at the nacelle. Furthermore, the repeated occurrence of breaking waves in every season can potentially affect the fatigue life of the structure. Therefore, the accurate estimation of breaking wave impact forces and dynamic responses induced by the forces is of great importance. Several researchers have investigated breaking wave impact forces and the dynamic responses induced by the forces throughout the numerical and experimental approaches. Hu and Kashiwagi (1) applied the Constrained Interpolation Profi le (CIP) method for studying the wave impact phenomena and violent wave-structure interactions. Christiansen et al. (2) studied the wave run-up and the extreme wave forces on an OWT foundation under the plunging breaker by using Navier-Stokes solver. Marino et al. (3) presented a numerical procedure by using Boundary Element Method (BEM)-MEL (Mixed Eulerian-Lagrangian) to simulate the extreme response of an OWT structure. Bredmose et al. (4) used a focused wave technique in Open-Foam to estimate the breaking wave impact forces on a cylindrical pile. Mokrani et al. (5) used a NS-VOF approach to study the slamming forces on a vertical wall. The wave impact on a rectangular column using smoothed particle hydrodynamics (SPH) was studied by Cummins et al. (6). However, although various researchers have stud- ied the breaking wave impact forces on the structure, little information is currently available

Hypothermia (core temperature 35°C) causes multiple physiologic disturbances, including coagulopathy and cardiac dysfunction. Patients undergoing liver transplantation are at risk of inadvertent hypothermia and might be more vulnerable to its adverse effects. We sought to identify the factors contributing to hypothermia during living-donor liver transplantation (LDLT), which have not yet been studied in depth.Medical records of 134 recipients who underwent adult-to-adult LDLT were reviewed. Core temperature at the following time points were taken: anesthetic induction, skin incision, start and end of the anhepatic phase, and hourly after hepatic reperfusion.Of 134 recipients, 29 (21.6%) developed hypothermia during surgery. Four independent risk factors for hypothermia were identified: small body weight-to-body surface area ratio, acute hepatic failure, high Model for End-Stage Liver Disease (MELD) score, and low graft-to-recipient weight ratio. The amount of core temperature drop was positively correlated with the number of involved risk factors. Each risk factor had a respective contribution according to the operative phases: body weight-to-body surface area ratio and the MELD score for the preanhepatic phase, acute deterioration of hepatic failure for the anhepatic phase, and graft-to-recipient weight ratio was for the postreperfusion phase.Hypothermia was independently associated with the recipient's morphometric characteristics, emergency of end-stage liver disease, MELD score, and graft volume. These factors showed a cumulative effect, and the role of each factor was different according to the operative phase. These results should aid in the development of an optimal thermal strategy during LDLT.

Introduction Active inspired gas humidification (AH) preserves body heat and maintains normothermia intraoperatively. However, it is unclear whether AH shows comparable influences during liver transplantation (OLT), which may be affected by both large internal heat loss and external heat supply. Thus, the aim of this study was to evaluate the effect of AH compared with passive humidification (PH) on body temperature in OLT. Materials and Methods Thirty-four adult patients undergoing living donor OLT were randomly enrolled into two groups: those given AH using a heated humidifier (HH group, n = 17) and those using a heat-and-moisture exchanger (HME group, n = 17). Both core and skin temperatures (Tc and Ts), as well as respiratory parameters, including static/dynamic lung compliances and PaO2, were recorded at predetermined times. Results Both Tc and Ts were consistently higher among the HH versus the HME group after 2 hours of anesthesia. Differences in Tc and Ts between the two groups increased gradually over time. The overall Tc during surgery was higher among the HH than the HME group (P = .023). The incidences of hypothermia were lower in the HH group at 3 hours of anesthesia, 1 and 3 hours of reperfusion, and at the end of surgery (P = .037, 0.024, 0.005, and 0.010 respectively). The duration of hypothermia was lower in the HH than the HME group (3.9 ± 3.5 hours versus 6.7 ± 3.3 hours, P = .025). Both groups showed no significant intraoperative changes in respiratory parameters; there were no postoperative respiratory complications. Conclusion Active humidification warms the patient's body effectively, lessening the incidence and duration of hypothermia during OLT with no respiratory risks.

We have developed a flexible drill device that makes arthroscopic transosseous repair possible, and report preliminary results. Twelve patients with post-traumatic anterior inferior glenohumeral instability were selected. Surgical technique: the flexible drill device is inserted into the shoulder joint through the posterior portal and the guide pipe unit is placed 5 mm posterior to the margin of the anterior glenoid rim. The flexible drill is driven through the glenoid with the power drill, creating a hole in the glenoid. A non-absorbable suture is passed through the hole and a sliding knot tying is performed over the capsule and labrum after completing stitches with the suture hook loaded. The same procedures are repeated in the 2, 3 and 4 o’clock positions of the glenoid. There was no recurrence of dislocation at the mean follow-up period of 52.3 months. The mean Rowe score was 89.5.

Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = −0.835, 95% confidence interval (CI) = −1.291 to −0.380, p = 3.3 × 10−4). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = −0.455, 95% CI = −0.763 to −0.147, p = 0.004; SMD = −0.887, 95% CI = −1.261 to −0.513, p = 3.4 × 10−4; SMD = −0.535, 95% CI = −0.923 to −0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = −0.361, 95% CI = −0.553 to −0.169, p = 2.3 × 10−4; SMD = −1.546, 95% CI = −2.583 to −0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = −0.699, 95% CI = −1.511 to −0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated.

The aim of this study was to determine whether polymorphisms in solute carrier family 2 and facilitated glucose transporter member 9 (SLC2A9) are associated with susceptibility to gout. A meta-analysis was conducted on associations between the rs12510549, rs16890979, and rs1014290 polymorphisms of SLC2A9 and gout susceptibility using fixed and random effects models. Eleven comparative studies comprising 1,472 patients and 3,269 controls from Caucasian and Asian populations were included in this meta-analysis. The meta-analysis identified a significant negative association between gout and allele 2 (minor) of the rs12510549 polymorphism in the overall population (OR = 0.641, 95 % CI = 0.540–0.761, P = 4.1 × 10−7). Stratification by ethnicity identified a significant negative association between this polymorphism and gout in Caucasians (OR = 0.647, 95 % CI = 0.542–0.771, P = 1.2 × 10−6) but not in Asians (OR = 0.515, 95 % CI = 0.214–1.236, P = 0.137). The meta-analysis showed a significant negative association between gout and allele 2 of the rs16890979 polymorphism in all study subjects (OR = 0.229, 95 % CI = 0.084–0.628, P = 0.004). Stratification by ethnicity identified a significant negative association between this polymorphism and gout in Caucasians (OR = 0.469, 95 % CI = 0.317–0.695, P = 1.6 × 10−6) and in Asians (OR = 0.192, 95 % CI = 0.072–0.513, P = 0.001). A significant negative association was found between allele 2 of the rs1014290 polymorphism and gout susceptibility in Asians (OR = 0.597, 95 % CI = 0.478–0.746, P = 5.4 × 10−6) but not in Caucasians (OR = 0.778, 95 % CI = 0.595–1.043, P = 0.095). This meta-analysis shows that the rs12510549, rs16890979, and rs1014290 polymorphisms of SLC2A9 protect against the development of gout in Caucasians and/or Asians.

Recently, researches about the eco-friendly vehicles such as hybrid electric vehicle, fuel cell vehicle and electric vehicle have been actively carried out. The regenerative braking system is a key technology to improve the vehicle energy utilization efficiency because it transforms the kinetic energy to the electric energy through the electric motor. This new braking system requires cooperative control between electric controlled brake and regenerative brake. Therefore, it is necessary to establish fault-diagnosis and fail-safe evaluation criteria to secure reliability of the regenerative braking system. In this paper, the failure types and causes in regenerative braking system were analyzed. The transient behavior characteristics were examined based on fault-diagnosis and fail-safe upon failure of regenerative braking system.

Background Vitiligo is an acquired pigmentary disorder caused by the destruction of melanocytes. Two of the major theories regarding the pathogenesis of vitiligo are the autoimmune theory and autocytotoxicity theory, but, the precise pathogenetic mechanism is still not clarified. Objectives We investigated the effects of ET-1, tacrolimus and tumour necrosis factor-α (TNF-α) on proliferation and migration of cultured normal human melanocytes (NHMs). We also sought to clarify the theoretical rationale underlying the topical tacrolimus monotherapy or tacrolimus-UV combination therapy as tools for vitiligo treatment. Methods The effects of ET-1, tacrolimus and TNF-α on proliferation/migration of cultured NHMs were investigated by MTT assay/Boyden chamber transwell migration assay. We also examined roles of CXC-chemokine receptor II (CXCR II) and matrix metalloproteinases (MMPs) in such conditions. Results ET-1 exerted a stimulatory effect on melanocyte proliferation and migration, but, tacrolimus exerted a stimulatory effect only on melanocyte migration higher than ET-1. TNF-α inhibited melanocyte proliferation in a dose-dependent manner. Paradoxically, TNF-α-pretreated NHMs exhibited an enhanced proliferative efficiency after being switched to ET-1. We found CXCRII was highly expressed in TNF-α-incubated melanocytes than the agents-free control, and ET-1 treatment after TNF-α preincubation showed the higher levels of CXCRII expression than the condition incubated with TNF-α alone. Moreover, the greater activities of MMP-2 and MMP-9 induced by tacrolimus than ET-1, reflected tacrolimus would enhance migration stimulatory effect in cultured NHMs. Conclusions Topical tacrolimus can be used an effective agent for vitiligo treatment as monotherapy, maybe due to its migration stimulatory action or TNF-α inhibitory property, and also as a component in combination therapy with UV treatment, considering the more upregulated MMPs activities are induced and the more effective migrations are feasible by itself than ET-1.

Objective: The objective of this paper is to explore whether the valine/leucine247 (Val/Leu247) polymorphism of β2-glycoprotein I (β2GPI) confers susceptibility to anti-phospholipid syndrome (APS) and thrombosis and predicts positivity for anti-β2GPI antibodies. Methods: A meta-analysis was conducted on the associations between the β2GPI Val/Leu247 polymorphism and susceptibility to APS and thrombosis and positivity for anti-β2GPI. Results: A total of 1507 patients with APS and 1450 controls in 12 comparative studies were included in this meta-analysis. Meta-analysis of the β2GPI Val/Leu247 polymorphism showed significant associations between the β2GPI Val allele and APS, thrombosis, and anti-β2GPI positivity (odds ratio (OR) 1.316, 95% confidence interval (CI) 1.068–1.621, p = 0.010; OR 1.908, 95% CI 1.195–3.046, p = 0.007; OR 1.630, 95% CI 1.018–2.609, p = 0.042, respectively). A direct comparison between anti-β2GPI-positive and -negative patients revealed that the frequency of the Val allele was significantly higher in anti-β2GPI-positive patents (OR 1.514, 95% CI 1.017–1.253, p = 0.041). Furthermore, a direct comparison between thrombosis-positive and -negative patients also indicated that the Val/Val + Val/Leu and the Val/Val vs. Leu/Leu genotypes of the β2GPI polymorphism were significantly elevated in patients with thrombosis (OR 2.817, 95% CI 1.200–6.610, p = 0.017; OR 3.312, 95% CI 1.338–8.200, p = 0.010, respectively). Conclusion: This meta-analysis shows that the β2GPI Val/Leu247 polymorphism is associated with susceptibility to APS and thrombosis and with anti-β2GPI positivity.

Objective Salvage liver transplantation (LT) has been proposed for patients with a small hepatocellular carcinoma (HCC) and preserved liver function. Few reports have been issued on salvage LT in a living-donor (LD) LT setting. Therefore, we performed this study to evaluate differences in tumor invasiveness and other risk factors on survival after salvage versus primary LDLT. Methods Between September 1996 and December 2008, 324 patients with HCC underwent LT. We excluded 138 patient from the analysis, leaving 186 HCC patients for analysis, including 17 (9.1%) who had undergone earlier resection, the salvage LDLT cohort. The other 169 patients underwent primary LDLT. Results Intrahepatic metastasis, Edmonson-Steiner histologic grade, microscopic vascular invasion, and preoperative serum alpha-fetoprotein levels significantly influenced tumor recurrence. Microscopic vascular invasion, intrahepatic metastasis, Edmonson-Steiner histologic grade, and treatment by salvage LDLT were significantly associated with poor patient survival univariate analysis. However, only microscopic vascular invasion was significant on multivariate analysis. The treatment modality (primary or salvage LDLT) was not observed to affect overall or disease-free survival significantly on multivariate analysis. Disease-free survival was significantly better in the primary than in the salvage LDLT group. Furthermore, patients in the primary LDLT group tended to show better survival. However, when stratified by the presence or absence of microscopic vascular invasion, no significant group difference was found for overall or disease-free survival among those without versus with microscopic vascular invasion. Conclusions Five-year overall survival after primary versus salvage LDLT were similar when differences in tumor pathologic features, such as microscopic vascular invasion, were taken into account. Multivariate analysis showed that the treatment itself was not a significant prognostic factor for survival.