The efficacy and safety of maternal tenofovir disoproxil fumarate (TDF) in reducing mother‐to‐infant hepatitis B virus (HBV) transmissions is not clearly understood. We conducted a prospective, ...multicenter trial and enrolled 118 hepatitis B surface antigen (HBsAg)– and hepatitis B e antigen–positive pregnant women with HBV DNA ≥7.5 log10 IU/mL. The mothers received no medication (control group, n = 56, HBV DNA 8.22 ± 0.39 log10 IU/mL) or TDF 300 mg daily (TDF group, n = 62, HBV DNA 8.18 ± 0.47 log10 IU/mL) from 30‐32 weeks of gestation until 1 month postpartum. Primary outcome was infant HBsAg at 6 months old. At delivery, the TDF group had lower maternal HBV DNA levels (4.29 ± 0.93 versus 8.10 ± 0.56 log10 IU/mL, P < 0.0001). Of the 121/123 newborns, the TDF group had lower rates of HBV DNA positivity at birth (6.15% versus 31.48%, P = 0.0003) and HBsAg positivity at 6 months old (1.54% versus 10.71%, P = 0.0481). Multivariate analysis revealed that the TDF group had lower risk (odds ratio = 0.10, P = 0.0434) and amniocentesis was associated with higher risk (odds ratio 6.82, P = 0.0220) of infant HBsAg positivity. The TDF group had less incidence of maternal alanine aminotransferase (ALT) levels above two times the upper limit of normal for ≥3 months (3.23% versus 14.29%, P = 0.0455), a lesser extent of postpartum elevations of ALT (P = 0.007), and a lower rate of ALT over five times the upper limit of normal (1.64% versus 14.29%, P = 0.0135) at 2 months postpartum. Maternal creatinine and creatinine kinase levels, rates of congenital anomaly, premature birth, and growth parameters in infants were comparable in both groups. At 12 months, one TDF‐group child newly developed HBsAg positivity, presumably due to postnatal infection and inefficient humoral responses to vaccines. Conclusions: Treatment with TDF for highly viremic mothers decreased infant HBV DNA at birth and infant HBsAg positivity at 6 months and ameliorated maternal ALT elevations. (Hepatology 2015;62:375–386
Hepatitis D virus (HDV) is a defective virus that completes its life cycle only with hepatitis B virus (HBV). The HBV with HDV super-infection has been considered as one of the most severe forms of ...the chronic viral hepatitis. However, there is a scarcity of data on the global burden of HDV infection.
We searched PubMed, Embase, Cochrane Library and China Knowledge Resource Integrated databases from 1 January 1977 to 31 December 2016. We included studies with a minimum sample size of 50 patients. Our study analysed data from a total of 40 million individuals to estimate the prevalence of HDV by using Der-Simonian Laird random-effects model. The data were further categorised according to risk factors.
From a total of 2717 initially identified studies, only 182 articles from 61 countries and regions met the final inclusion criteria. The overall prevalence of HDV was 0.98% (95% CI 0.61 to 1.42). In HBsAg-positive population, HDV pooled prevalence was 14.57% (95% CI 12.93 to 16.27): Seroprevalence was 10.58% (95% CI 9.14 to 12.11) in mixed population without risk factors of intravenous drug use (IVDU) and high-risk sexual behaviour (HRSB). It was 37.57% (95% CI 29.30 to 46.20) in the IVDU population and 17.01% (95% CI 10.69 to 24.34) in HRSB population.
We found that approximately 10.58% HBsAg carriers (without IVDU and HRSB) were coinfected with HDV, which is twofold of what has been estimated before. We also noted a substantially higher HDV prevalence in the IVDU and HRSB population. Our study highlights the need for increased focus on the routine HDV screening and rigorous implementation of HBV vaccine programme.
Integrating thermodynamically favorable ethanol reforming reactions with hybrid water electrolysis will allow room‐temperature production of high‐value organic products and decoupled hydrogen ...evolution. However, electrochemical reforming of ethanol has not received adequate attention due to its low catalytic efficiency and poor selectivity, which are caused by the multiple groups and chemical bonds of ethanol. In addition to the thermodynamic properties affected by the electronic structure of the catalyst, the dynamics of molecule/ion dynamics in electrolytes also play a significant role in the efficiency of a catalyst. The relatively large size and viscosity of the ethanol molecule necessitates large channels for molecule/ion transport through catalysts. Perforated CoNi hydroxide nanosheets are proposed as a model catalyst to synergistically regulate the dynamics of molecules and electronic structures. Molecular dynamics simulations directly reveal that these nanosheets can act as a “dam” to enrich ethanol molecules and facilitate permeation through the nanopores. Additionally, the charge transfer behavior of heteroatoms modifies the local charge density to promote molecular chemisorption. As expected, the perforated nanosheets exhibit a small potential (1.39 V) and high Faradaic efficiency for the conversion of ethanol into acetic acid. Moreover, the concept in this work provides new perspectives for exploring other molecular catalysts.
Nanoporous ultrathin bimetallic compound sheets are used as a model catalyst to realize synergistic optimization of ethanol molecular spatial distribution and chemisorption. They exhibit a small potential (1.39 V) and high Faradaic efficiency for acetic acid.
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bstract
From the S-matrix of spinning particles, we extract the 2 PM conservative potential for binary spinning black holes up to quartic order in spin operators. An important ingredient is the ...exponentiated gravitational Compton amplitude in the classical spin-limit for all graviton helicity sectors. The validity of the resulting Hamiltonian is verified by matching to known lower spin order results, as well as direct computation of the 2PM impulse and spin kicks from the eikonal phase and that from the test black hole scattering based on Mathisson-Papapetrou-Dixon equations.
Abstract
Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, ...glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.
A 16-channel closed-loop neuromodulation system-on-chip (SoC) for human epileptic seizure control is proposed and designed. In the proposed SoC, a 16-channel neural-signal acquisition unit (NSAU), a ...biosignal processor (BSP), a 16-channel high-voltage-tolerant stimulator (HVTS), and wireless power and bidirectional data telemetry are designed. In the NSAU, the input protection circuit is used to prevent MOSFET from overstressing by the high-voltage stimulations. Hence, NSAUs can share electrodes with stimulators. The auto-reset chopper-stabilized capacitive-coupled instrumentation amplifiers (AR-CSCCIAs) are designed with the chopper-stabilized technique with a new offset reduction loop. The measured input-referred noise is 2.09 <inline-formula> <tex-math notation="LaTeX">\mu \textrm {V}_{\mathrm {rms}} </tex-math></inline-formula> and the noise-efficiency factor (NEF) is 3.78. The entropy-and-spectrum seizure detection algorithm is implemented in the BSP with 0.76-s seizure detection latency and 97.8% detection accuracy. When the seizure onset is detected by the BSP, the HVTS with adaptive supply control delivers 0.5-3-mA biphasic current stimulation to suppress the seizure onset. The proposed SoC is powered wirelessly, and the bidirectional data telemetry is realized through the same pair of coils in 13.56 MHz. The downlink data rate is 211 Kb/s with the binary phase-shift keying (BPSK) modulation and a new BPSK demodulator. The uplink data rate is 106 Kb/s with the load-shift keying (LSK) modulation. The proposed SoC is fabricated in a 0.18-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> CMOS technology and occupies 25 mm 2 . Electrical tests have been performed to characterize the SoC performance. In vivo animal experiments using mini-pigs have been performed to successfully verify the closed-loop neuromodulation functions on epileptic seizure suppression.
MAVS and MITA are essential adaptor proteins mediating innate antiviral immune responses against RNA and DNA viruses, respectively. Here we show that RNF115 plays dual roles in response to RNA or DNA ...virus infections by catalyzing distinct types of ubiquitination of MAVS and MITA at different phases of viral infection. RNF115 constitutively interacts with and induces K48-linked ubiquitination and proteasomal degradation of homeostatic MAVS in uninfected cells, whereas associates with and catalyzes K63-linked ubiquitination of MITA after HSV-1 infection. Consistently, the protein levels of MAVS are substantially increased in Rnf115
organs or cells without viral infection, and HSV-1-induced aggregation of MITA is impaired in Rnf115
cells compared to the wild-type counterparts. Consequently, the Rnf115
mice exhibit hypo- and hyper-sensitivity to EMCV and HSV-1 infection, respectively. These findings highlight dual regulation of cellular antiviral responses by RNF115-mediated ubiquitination of MAVS and MITA and contribute to our understanding of innate immune signaling.
Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists ...at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.
Personalized medical care focuses on prediction of disease risk and response to medications. To build the risk models, access to both large-scale genomic resources and human genetic studies is ...required. The Taiwan Biobank (TWB) has generated high-coverage, whole-genome sequencing data from 1492 individuals and genome-wide SNP data from 103,106 individuals of Han Chinese ancestry using custom SNP arrays. Principal components analysis of the genotyping data showed that the full range of Han Chinese genetic variation was found in the cohort. The arrays also include thousands of known functional variants, allowing for simultaneous ascertainment of Mendelian disease-causing mutations and variants that affect drug metabolism. We found that 21.2% of the population are mutation carriers of autosomal recessive diseases, 3.1% have mutations in cancer-predisposing genes, and 87.3% carry variants that affect drug response. We highlight how TWB data provide insight into both population history and disease burden, while showing how widespread genetic testing can be used to improve clinical care.
Overweight and obesity are important risk factors of gestational diabetes mellitus (GDM). Clustering of metabolic risk factors in early pregnancy may be a potential pathogenesis between the link of ...overweight/obesity and GDM. Since it remains unexplored, we investigated if overweight and obesity are associated with clustering of metabolic risk factors in early pregnancy and the risk of GDM in this cohort study.
Total 527 women who visited National Taiwan University Hospital for prenatal care in between November 2013 to April 2018 were enrolled. Risk factors of GDM in the first prenatal visit (FPV) were recorded. Overweight/obesity was defined if body mass index ≥24 kg/m2. GDM was diagnosed from the result of a 75g oral glucose tolerance test in 24-28 gestational weeks.
Overweight/obesity was associated with clustering of metabolic risk factors of GDM, including high fasting plasma glucose, high HbA1c, insulin resistance, high plasma triglyceride and elevated blood pressure in FPV (p<0.05). There was a positive relationship between the number of metabolic risk factors and the incidence of GDM (p <0.05). The odds ratios of HbA1c and diastolic blood pressure were higher in overweight/obese women, compared with those in normal-weight women.
Overweight/obesity is associated with clustering of metabolic risk factors in early pregnancy, which is correlated with higher risk of GDM. Our findings suggest that metabolic risk factors during early pregnancy should be evaluated in overweight/obese women.
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