Summary
Background
Patients with nonalcoholic steatohepatitis (NASH) have gut dysbiosis and intestinal bacterial overgrowth.
Aim
To test the hypothesis that endotoxemia is associated with the ...histological severity of nonalcoholic fatty liver disease (NAFLD) and determine factors associated with endotoxemia.
Methods
The endotoxemia markers lipopolysaccharide‐binding protein (LBP) and endotoxin levels were measured in 237 NAFLD patients 1 day before liver biopsy. Biomarkers of liver injury and transient elastography were performed as additional markers of disease severity.
Results
A total of 114/237 (48%) patients had NASH and 80/237 (34%) had F2‐4 fibrosis. LBP was correlated with lobular inflammation (P=.001), while both LBP (P=.0004) and endotoxin levels (P=0.008) were correlated with fibrosis. LBP was also correlated with cytokeratin‐18 fragments (P=.002) and aspartate aminotransferase‐to‐alanine aminotransferase ratio (P=.006), and both LBP (P=.019) and endotoxin (P=.006) were correlated with liver stiffness measurement by transient elastography. LBP was increased in patients with NASH (15.3±4.6 vs 13.8±3.3 μg/mL; P=.005) and F2‐4 fibrosis (15.4±4.4 vs 14.0±3.7 μg/mL; P=.008). Interestingly, patients harbouring the TM6SF2 rs58542926 T allele that predispose to NAFLD/NASH had higher LBP level. By multivariate analysis, gender, higher body mass index and glycated haemoglobin, and TM6SF2 variants were independent factors associated with increased LBP level.
Conclusions
Endotoxemia is positively associated with NASH and significant fibrosis. The association between TM6SF2 and endotoxemia warrants further investigations. The findings may shed light on the pathogenesis of NASH and inform a novel treatment target.
Linked ContentThis article is linked to Valenti and Romeo paper. To view this article visit https://doi.org/10.1111/apt.14154.
Summary
Background
Metabolic syndrome is a known risk factor of cirrhosis in chronic hepatitis B (CHB).
Aim
To investigate the effects of coincidental metabolic syndrome on liver fibrosis progression ...in treatment‐naïve CHB patients.
Methods
A total of 1466 CHB patients underwent liver stiffness measurement (LSM) by transient elastography in 2006–2008; 663 patients remained treatment‐naïve and had second LSM in 2010–2012. Liver fibrosis progression was defined as an increase in LSM ≥30% at the second assessment. The impact of coincidental metabolic syndrome and its factors on liver fibrosis progression were evaluated after adjustment for viral load and hepatitis activity.
Results
At baseline, the mean age was 43 ± 12 years, 55% were males, serum alanine aminotransferase (ALT) was 44 ± 40 IU/L, HBV DNA was 4.0 ± 2.0 log IU/mL and LSM was 6.3 ± 3.6 kPa. Metabolic syndrome was diagnosed in 80 (12%) and 142 (21%) patients at baseline and follow‐up visit, respectively; 84 (13%) and 22 (3%) patients had coincidental and resolved metabolic syndrome respectively. After an interval of 44 ± 7 months, 107 (16%) patients developed liver fibrosis progression. Coincidental metabolic syndrome adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.1–3.5, P = 0.015, central obesity (aOR 2.0, 95% CI 1.0–4.1, P = 0.05) and low level of high‐density lipoprotein cholesterol (aOR 1.9, 95% CI 1.0–3.7, P = 0.04) were associated with liver fibrosis progression independent of change in viral load and ALT level. The effects of coincidental metabolic syndrome were most apparent in the immune‐tolerant phase.
Conclusion
Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B infection, independent of viral load and hepatitis activity.
Background & Aims
How adiposity influences the effect of genetic variants on non‐alcoholic fatty liver disease (NAFLD) in the Asian population remains unclear. We aimed to study the association ...between genetic risk variants and susceptibility/severity of NAFLD in the lean, overweight and obese individuals.
Methods
Nine hundred and four community subjects underwent proton‐magnetic resonance spectroscopy and transient elastography examination. Lean (<23 kg/m2), overweight (23‐24.9 kg/m2) and obesity (≥25 kg/m2) were defined according to the body mass index cut‐offs for Asians. NAFLD was defined as intrahepatic triglycerides ≥5%. PNPLA3, TM6SF2, MBOAT7 and 9 other gene polymorphisms were analysed by rhAMPTM SNP assays.
Results
Five hundred and twenty‐nine (58.5%), 162 (17.9%) and 213 (23.6%) subjects were lean, overweight and obese, respectively. The prevalence of NAFLD was 12.4%, 41.4% and 59.1% in the three groups (P < .001). Amongst those with NAFLD, lean subjects (30.3%) were more likely to carry the PNPLA3 rs738409 GG genotype than overweight (17.9%) and obese subjects (17.4%) (P = .003). Compared with the CC genotype, the GG genotype was associated with the greatest increase in the risk of NAFLD in lean subjects (odds ratio OR 6.04), compared with overweight (OR 3.43, 95% CI 1.06, 11.14) and obese subjects (OR 2.51, 95% CI 0.93, 6.78). Additionally, the TM6SF2 rs58542926 TT genotype was associated with reduced serum triglycerides only in lean subjects. A gene‐BMI effect was not observed for the other gene polymorphisms.
Conclusions
The PNPLA3 rs738409 gene polymorphism has a greater effect on liver fat in Asian lean individuals than in overweight or obese ones.
A scarlet fever outbreak occurred in Hong Kong in 2011. The majority of cases resulted in the isolation of Streptococcus pyogenes emm12 with multiple antibiotic resistances. Phylogenetic analysis of ...22 emm12 scarlet fever outbreak isolates, 7 temporally and geographically matched emm12 non-scarlet fever isolates, and 18 emm12 strains isolated during 2005-2010 indicated the outbreak was multiclonal. Genome sequencing of 2 nonclonal scarlet fever isolates (HKU16 and HKU30), coupled with diagnostic polymerase chain reaction assays, identified 2 mobile genetic elements distributed across the major lineages: a 64.9-kb integrative and conjugative element encoding tetracycline and macrolide resistance and a 46.4-kb prophage encoding superantigens SSA and SpeC and the DNase Spd1. Phenotypic comparison of HKU16 and HKU30 with the S. pyogenes M1T1 strain 5448 revealed that HKU16 displays increased adherence to HEp-2 human epithelial cells, whereas HKU16, HKU30, and 5448 exhibit equivalent resistance to neutrophils and virulence in a humanized plasminogen murine model. However, in contrast to M1T1, the virulence of HKU16 and HKU30 was not associated with covRS mutation. The multiclonal nature of the emm12 scarlet fever isolates suggests that factors such as mobile genetic elements, environmental factors, and host immune status may have contributed to the 2011 scarlet fever outbreak.
We report a measurement of electron antineutrino oscillation from the Daya Bay Reactor Neutrino Experiment with nearly 4 million reactor νover ¯_{e} inverse β decay candidates observed over 1958 days ...of data collection. The installation of a flash analog-to-digital converter readout system and a special calibration campaign using different source enclosures reduce uncertainties in the absolute energy calibration to less than 0.5% for visible energies larger than 2 MeV. The uncertainty in the cosmogenic ^{9}Li and ^{8}He background is reduced from 45% to 30% in the near detectors. A detailed investigation of the spent nuclear fuel history improves its uncertainty from 100% to 30%. Analysis of the relative νover ¯_{e} rates and energy spectra among detectors yields sin^{2}2θ_{13}=0.0856±0.0029 and Δm_{32}^{2}=(2.471_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the normal hierarchy, and Δm_{32}^{2}=-(2.575_{-0.070}^{+0.068})×10^{-3} eV^{2} assuming the inverted hierarchy.
Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter ...presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θμe mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm241, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CLs for Δm241 < 13 eV2. Furthermore, the LSND and MiniBooNE 99% C.L. allowed regions are excluded at 99% CLs for Δm241 < 1.6 eV2.
•Functional anticorrelated connectivity between the subgenual anterior cingulate cortex and left dorsolateral prefrontal cortex cannot serve as biomarker of antidepressant response to repetitive ...transcranial magnetic stimulation.•Four alternative connectivity biomarkers of treatment response were identified.•Poorer pre-treatment connectivity with(in) the central executive network is associated with poorer antidepressant response to transcranial magnetic stimulation.•Pre-processing with global signal regression possibly removed some valuable neural signal.•Combining the biomarkers revealed outstanding results for personalized prediction of antidepressant response.
Functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate (sgACC) may serve as a biomarker for transcranial magnetic stimulation (rTMS) treatment response. The first aim was to establish whether this finding is veridical or artifactually induced by the pre-processing method. Furthermore, alternative biomarkers were identified and the clinical utility for personalized medicine was examined.
Resting-state fMRI data were collected in medication-refractory depressed patients (n = 70, 16 males) before undergoing neuronavigated left DLPFC rTMS. Seed-based analyses were performed with and without global signal regression pre-processing to identify biomarkers of short-term and long-term treatment response. Receiver Operating Characteristic curve and supervised machine learning analyses were applied to assess the clinical utility of these biomarkers for the classification of categorical rTMS response.
Regardless of the pre-processing method, DLPFC-sgACC connectivity was not associated with treatment outcome. Instead, poorer connectivity between the sgACC and three clusters (peak locations: frontal pole, superior parietal lobule, occipital cortex) and DLPFC-central opercular cortex were observed in long-term nonresponders. The identified connections could serve as acceptable to excellent markers. Combining the features using supervised machine learning reached accuracy rates of 95.35% (CI=82.94–100.00) and 88.89% (CI=63.96–100.00) in the cross-validation and test dataset, respectively.
The sample size was moderate, and features for machine learning were based on group differences.
Long-term nonresponders showed greater disrupted connectivity in regions involving the central executive network. Our findings may aid the development of personalized medicine for medication-refractory depression.
Typical repair of common femoral artery (CFA) occlusive disease involves surgical endarterectomy followed by patch closure; however, prosthetic materials may become infected. In addition, in our ...institution, we have experienced an increased incidence of severe patch-related restenosis. We describe a technique for CFA endarterectomy and patchless proximal profundoplasty, and evaluate its feasibility.
We performed a single-centre retrospective cohort study of patients who, between July 1, 2020, and June 30, 2021, underwent a procedure that consisted of transection of the superficial femoral artery (SFA) off the femoral bifurcation in a bevelled manner, eversion endarterectomy of the SFA, remote-type endarterectomy of the CFA, direct visualization of the end point in the profunda femoris artery (PFA) with a longitudinal arteriotomy extension if needed and reimplantation of the SFA "hood" as a patch. We collected clinical information and outcomes from the patients' charts.
Ten patients who underwent a patchless profundoplasty procedure during the study period were identified. Indications for repair included tissue loss (3 patients), rest pain (2 patients), claudication (3 patients) and establishing access for other procedures (2 patients). Profunda femoris artery arteriotomy extensions were used in 5 cases. Six cases included simultaneous iliac or infrainguinal revascularization. All cases were technically successful. There was 1 intraoperative complication of remote tibial balloon angioplasty tear. The mean follow-up time was 199 (range 29-381) days. There were no surgical site infections. All patients were asymptomatic, with patent CFAs, at last follow-up. There was 1 case of surgical site restenosis and 1 reintervention for remote stenosis. The average increase in ankle and toe brachial indices was 44% and 75%, respectively. One patient was readmitted for gastrointestinal bleeding. One patient died from an acute myocardial infarction, on postoperative day 34.
The patchless profundoplasty technique is feasible and results in autologous anatomic repair of CFA disease without the need for vein, and allows direct visualization and tacking sutures of the proximal PFA. This technique may replace the ubiquitous vascular procedure of patch arterioplasty of the CFA, depending on the anatomic configuration.
Background and Purpose
Hypoxia‐mediated neovascularization plays an important role in age‐related macular degeneration (AMD). There are few animal models or effective treatments for AMD. Here, we ...investigated the effects of the flavonoid silibinin on hypoxia‐induced angiogenesis in a rat AMD model.
Experimental Approach
Retinal pigmented epithelial (RPE) cells were subjected to hypoxia in vitro and the effects of silibinin on activation of key hypoxia‐induced pathways were examined by elucidating the hypoxia‐inducible factor‐1 alpha (HIF‐1α) protein level by Western blot. A rat model of AMD was developed by intravitreal injection of VEGF in Brown Norway rats, with or without concomitant exposure of animals to hypoxia. Animals were treated with oral silibinin starting at day 7 post‐VEGF injection and AMD changes were followed by fluorescein angiography on days 14 and 28 post‐injection.
Key Results
Silibinin pretreatment of RPE cells increased proline hydroxylase‐2 expression, inhibited HIF‐1α subunit accumulation, and inhibited VEGF secretion. Silibinin‐induced HIF‐1α and VEGF down‐regulation required suppression of hypoxia‐induced phosphatidylinositol 3‐kinase/Akt/mammalian target of rapamycin (mTOR) pathway. In the rat model of AMD, silibinin administration prevented VEGF‐ and VEGF plus hypoxia‐induced retinal oedema and neovascularization.
Conclusion and Implications
The effects of silibinin, both in vitro and in vivo, support its potential as a therapeutic for the prevention of neovascular AMD.
This Letter reports the first extraction of individual antineutrino spectra from ^{235}U and ^{239}Pu fission and an improved measurement of the prompt energy spectrum of reactor antineutrinos at ...Daya Bay. The analysis uses 3.5×10^{6} inverse beta-decay candidates in four near antineutrino detectors in 1958 days. The individual antineutrino spectra of the two dominant isotopes, ^{235}U and ^{239}Pu, are extracted using the evolution of the prompt spectrum as a function of the isotope fission fractions. In the energy window of 4-6 MeV, a 7% (9%) excess of events is observed for the ^{235}U (^{239}Pu) spectrum compared with the normalized Huber-Mueller model prediction. The significance of discrepancy is 4.0σ for ^{235}U spectral shape compared with the Huber-Mueller model prediction. The shape of the measured inverse beta-decay prompt energy spectrum disagrees with the prediction of the Huber-Mueller model at 5.3σ. In the energy range of 4-6 MeV, a maximal local discrepancy of 6.3σ is observed.
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