Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this ...increase in HCC, although the etiology of HCC in 15%‐50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH‐derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity. (HEPATOLOGY 2010;51:1820–1832)
The transcription factor AmrZ regulates genes important for P. aeruginosa virulence, including type IV pili, extracellular polysaccharides, and the flagellum; however, the global effect of AmrZ on ...gene expression remains unknown, and therefore, AmrZ may directly regulate many additional genes that are crucial for infection. Compared to the wild type strain, a ΔamrZ mutant exhibits a rugose colony phenotype, which is commonly observed in variants that accumulate the intracellular second messenger cyclic diguanylate (c-di-GMP). Cyclic di-GMP is produced by diguanylate cyclases (DGC) and degraded by phosphodiesterases (PDE). We hypothesized that AmrZ limits the intracellular accumulation of c-di-GMP through transcriptional repression of gene(s) encoding a DGC. In support of this, we observed elevated c-di-GMP in the ΔamrZ mutant compared to the wild type strain. Consistent with other strains that accumulate c-di-GMP, when grown as a biofilm, the ΔamrZ mutant formed larger microcolonies than the wild-type strain. This enhanced biofilm formation was abrogated by expression of a PDE. To identify potential target DGCs, a ChIP-Seq was performed and identified regions of the genome that are bound by AmrZ. RNA-Seq experiments revealed the entire AmrZ regulon, and characterized AmrZ as an activator or repressor at each binding site. We identified an AmrZ-repressed DGC-encoding gene (PA4843) from this cohort, which we named AmrZ dependent cyclase A (adcA). PAO1 overexpressing adcA accumulates 29-fold more c-di-GMP than the wild type strain, confirming the cyclase activity of AdcA. In biofilm reactors, a ΔamrZ ΔadcA double mutant formed smaller microcolonies than the single ΔamrZ mutant, indicating adcA is responsible for the hyper biofilm phenotype of the ΔamrZ mutant. This study combined the techniques of ChIP-Seq and RNA-Seq to define the comprehensive regulon of a bifunctional transcriptional regulator. Moreover, we identified a c-di-GMP mediated mechanism for AmrZ regulation of biofilm formation and chronicity.
Functional status assessment methods are important as outcome measures for pediatric critical care studies.
To investigate the relationships between the 2 functional status assessment methods ...appropriate for large-sample studies, the Functional Status Scale (FSS) and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category (POPC/PCPC) scales.
Prospective cohort study with random patient selection at 7 sites and 8 children's hospitals with general/medical and cardiac/cardiovascular pediatric intensive care units (PICUs) in the Collaborative Pediatric Critical Care Research Network. Participants included all PICU patients younger than 18 years.
Functional Status Scale and POPC/PCPC scores determined at PICU admission (baseline) and PICU discharge. We investigated the association between the baseline and PICU discharge POPC/PCPC scores and the baseline and PICU discharge FSS scores, the dispersion of FSS scores within each of the POPC/PCPC ratings, and the relationship between the FSS neurologic components (FSS-CNS) and the PCPC.
We included 5017 patients. We found a significant (P < .001) difference between FSS scores in each POPC or PCPC interval, with an FSS score increase with each worsening POPC/PCPC rating. The FSS scores for the good and mild disability POPC/PCPC ratings were similar and increased by 2 to 3 points for the POPC/PCPC change from mild to moderate disability, 5 to 6 points for moderate to severe disability, and 8 to 9 points for severe disability to vegetative state or coma. The dispersion of FSS scores within each POPC and PCPC rating was substantial and increased with worsening POPC and PCPC scores. We also found a significant (P < .001) difference between the FSS-CNS scores between each of the PCPC ratings with increases in the FSS-CNS score for each higher PCPC rating.
The FSS and POPC/PCPC system are closely associated. Increases in FSS scores occur with each higher POPC and PCPC rating and with greater magnitudes of change as the dysfunction severity increases. However, the dispersion of the FSS scores indicated a lack of precision in the POPC/PCPC system when compared with the more objective and granular FSS. The relationship between the PCPC and the FSS-CNS paralleled the relationship between the FSS and POPC/PCPC system.
Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of ...poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.
The demand for green hydrogen as an energy carrier is projected to exceed 350 million tons per year by 2050, driven by the need for sustainable distribution and storage of energy generated from ...sources. Despite its potential, hydrogen production currently faces challenges related to cost efficiency, compliance, monitoring, and safety. This work proposes Hydrogen 4.0, a cyber-physical approach that leverages Industry 4.0 technologies-including smart sensing, analytics, and the Internet of Things (IoT)-to address these issues in hydrogen energy plants. Such an approach has the potential to enhance efficiency, safety, and compliance through real-time data analysis, predictive maintenance, and optimised resource allocation, ultimately facilitating the adoption of renewable green hydrogen. The following sections break down conventional hydrogen plants into functional blocks and discusses how Industry 4.0 technologies can be applied to each segment. The components, benefits, and application scenarios of Hydrogen 4.0 are discussed while how digitalisation technologies can contribute to the successful integration of sustainable energy solutions in the global energy sector is also addressed.
Picornaviruses, including
species A to D (EV) and
species A (PeV-A), are the leading reported causes of pediatric central nervous system infections in the United States. We investigated the molecular ...epidemiology of EV and PeV-A over 10 years in cerebrospinal fluid (CSF) collected from children seen at Children's Mercy-Kansas City (CMKC) from 2007 through 2016. The overall prevalence for EV was 16% (862/5,362) and 7% (271/4,016) for PeV. Among all picornavirus CSF detections, EV was 76%, and PeV-A was 24%. Multiple EV types cocirculated each year, with a total of 31 EV types detected in the 10-year period; the majority belonged to EV-B species (96%). Two PeV-A types were detected; PeV-A3 was the dominant PeV-A type (95%). The top five picornaviruses (PeV-A3, 26%; E30, 11%; E6, 10%; E18, 9%; E9, 7%) in the CSF of infants accounted for two-thirds of all detections, and PeV-A3 was the leading picornavirus detected. Routine testing and reporting of PeV-A in addition to EV, especially in children under 6 months old with acute febrile illnesses, could reduce hospital stays and antibiotic usage.
Coffee caffeine consumption (CC) is associated with reduced hepatic fibrosis in patients with chronic liver diseases, such as hepatitis C. The association of CC with nonalcoholic fatty liver disease ...(NAFLD) has not been established. The aim of this study was to correlate CC with the prevalence and severity of NAFLD. Patients involved in a previously published NAFLD prevalence study, as well as additional NASH patients identified in the Brooke Army Medical Center Hepatology clinic, were queried about their caffeine intake. A validated questionnaire for CC was utilized to assess for a relationship between caffeine and four groups: ultrasound negative (controls), bland steatosis/not‐NASH, NASH stage 0‐1, and NASH stage 2‐4. A total of 306 patients responded to the CC questionnaire. Average milligrams of total caffeine/coffee CC per day in controls, bland steatosis/not‐NASH, NASH stage 0‐1, and NASH stage 2‐4 were 307/228, 229/160, 351/255, and 252/152, respectively. When comparing patients with bland steatosis/not‐NASH to those with NASH stage 0‐1, there was a significant difference in CC between the two groups (P = 0.005). Additionally, when comparing patients with NASH stage 0‐1 to those with NASH stage 2‐4, there was a significant difference in coffee CC (P = 0.016). Spearman's rank correlation analysis further supported a negative relationship between coffee CC and hepatic fibrosis (r = −0.215; P = 0.035). Conclusion: Coffee CC is associated with a significant reduction in risk of fibrosis among NASH patients. (Hepatology 2012)
Large prospective studies to establish the prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are lacking. We prospectively assessed the prevalence and severity of ...NAFLD/NASH in a cohort of asymptomatic middle-aged Americans attending a colonoscopy class at a gastroenterology clinic.
Screening for NAFLD was performed using magnetic resonance (MR)-based LiverMultiScan® proton density fat fraction (LMS-PDFF). MR exams also included corrected T1 and elastography for liver stiffness measurement (LSM). FibroScan® was also used to measure LSM. Participants with predetermined abnormal imaging parameters were offered a liver biopsy. Biopsies were read in a blinded fashion with results based on the consensus by 2 expert pathologists. The prevalence of NAFLD was determined by PDFF ≥5% or by histological diagnosis of NAFLD (if biopsy data were available). The prevalence of NASH was defined by biopsy.
Of 835 participants, 664 met the inclusion and exclusion criteria. The mean age was 56 ± 6.4 years, 50% were male, the mean BMI was 30.48 ± 5.46 kg/m2, and 52% were obese. The prevalence of NAFLD was 38% (95% CI 34–41%) and the prevalence of NASH was 14% (95% CI 12–17%). While no patient had cirrhosis on biopsy, significant fibrosis (F ≥2) was present in 5.9% (95% CI 4–8%) and bridging fibrosis in 1.6% (95% CI 1-3%). In a multivariable analysis, factors associated with the presence of NASH were race, obesity, and diabetes.
Using state-of-the-art liver imaging modalities and reference biopsy, this study establishes an overall prevalence of NAFLD of 38% and NASH by biopsy of 14% in this cohort of asymptomatic middle-aged US adults.
There are no prospective studies to determine how common is nonalcoholic steatohepatitis (NASH), the severe form of non-alcoholic fatty liver disease (NAFLD). In a large number of asymptomatic middle-aged Americans, we used a combination of state-of-the-art liver imaging methods and liver biopsy to prospectively determine the prevalence of NAFLD and NASH. NAFLD was diagnosed in 38%, NASH in 14%, and significant liver fibrosis in 6% of asymptomatic middle-aged Americans.
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•In a prospective large cohort of middle-aged Americans living in Texas, the prevalence of NAFLD was estimated to be 38%.•Based on liver histology data, NASH was diagnosed in 14% of the entire cohort and 37% of those with NAFLD.•NASH was more common in Hispanics and those with obesity or type 2 diabetes.
Enterovirus D68 (EV-D68) causes severe respiratory illness outbreaks among children, particularly those with asthma. We previously detected neutralizing antibodies against the predominant EV-D68 B1 ...clade in the 2014 outbreak in serum collected before the outbreak (2012–2013) from persons 24 months to 85 years of age. We recently detected neutralizing antibodies to the 2014 B1, B2, and D clade viruses in serum collected after the 2014 outbreak (April–May 2017) from 300 children 6 months to 18 years of age. B1 virus neutralizing antibodies were found in 100% of patients, even children born after 2014; B2 in 84.6%, and D in 99.6%. In 2017, titers increased with patient age and were higher than titers in 2012–2013 from comparably aged children. Rate of seronegativity was highest (15.3%) for B2 virus. Multivariate analysis revealed an association between asthma and higher titers against B2 and D viruses. EV-D68 seems to have circulated during 2014–2017.
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