Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Predicting the Onset of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome with rapid progression. This study aimed to develop and validate a prognostic score to predict the onset of ACLF in hepatitis B virus (HBV) etiology. METHODS: The prospective clinical data of 1373 patients with acute deterioration of HBV-related chronic liver disease were used to identify clinical characteristics and develop a prognostic score for the onset of ACLF. RESULTS: Of the patients assessed using the Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF criteria, 903 patients with non-ACLF at admission (1 received transplantation at 5 days) were stratified: 71 with progression to ACLF and 831 without progression to ACLF at 7 days. Four predictors (total bilirubin, international normalized ratio, alanine aminotransferase, and ferritin) were associated significantly with ACLF onset at 7 days. The COSSH-onset-ACLF score was constituted as follows: (0.101 × ln [alanine aminotransferase] + 0.819 × ln [total bilirubin] + 2.820 × ln [international normalized ratio] + 0.016 × ln [ferritin]). The C-indexes of the new score for 7-/14-/28-day onset (0.928/0.925/0.913) were significantly higher than those of 5 other scores (Chronic Liver Failure Consortium ACLF development score/Model for End-stage Liver Disease score/Model for End-stage Liver Disease sodium score/COSSH-ACLF score/Chronic liver failure Consortium ACLF score; all P < .001). The improvement in predictive errors, time-dependent receiver operating characteristic, probability density function evaluation, and calibration curves of the new score showed the highest predictive value for ACLF onset at 7/14/28 days. Risk stratification of the new score showed 2 strata with high and low risk (≥6.3/<6.3) of ACLF onset. The external validation group further confirmed the earlier results. CONCLUSIONS: A new prognostic score based on 4 predictors can accurately predict the 7-/14-/28-day onset of ACLF in patients with acute deterioration of HBV-related chronic liver disease and might be used to guide clinical management.

Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis.

BACKGROUND: Sepsis is defined as a systemic inflammatory response to microbial infections with multiple organ dysfunction. This study analysed untargeted metabolomics combined with proteomics of serum from patients with sepsis to reveal the underlying pathological mechanisms involved in sepsis. METHODS: A total of 63 patients with sepsis and 43 normal controls were enrolled from a prospective multicentre cohort. The biological functions of the metabolome were assessed by coexpression network analysis. A molecular network based on metabolomics and proteomics data was constructed to investigate the key molecules. RESULTS: Untargeted metabolomics analysis revealed widespread dysregulation of amino acid metabolism, which regulates inflammation and immunity, in patients with sepsis. Seventy-three differentially expressed metabolites (|log2 fold change| > 1.5, adjusted P value < 0.05 and variable importance in the projection (VIP) > 1.5) that could predict sepsis were identified. External validation of the hub metabolites was consistent with the derivation results (area under the receiver operating characteristic curve (AUROC): 0.81-0.96/0.62-1.00). The pentose phosphate pathway was found to be related to sepsis-associated encephalopathy. Phenylalanine metabolism was associated with sepsis-associated acute kidney injury. The key molecular alterations of the multiomics network in sepsis compared to normal controls implicate acute inflammatory response, platelet degranulation, myeloid cell activation involved in immune response and phenylalanine, tyrosine and tryptophan biosynthesis, and arginine biosynthesis. CONCLUSIONS: Integrated analysis of untargeted metabolomics and proteomics revealed characteristic metabolite and protein alterations in sepsis, which were mainly involved in inflammation-related pathways and amino acid metabolism. This study depicted the pathological characteristics and pathways involved in sepsis and potential therapeutic targets.

PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF.

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

Serum proteomics reveals disorder of lipoprotein metabolism in sepsis.

Sepsis is defined as an organ dysfunction syndrome and it has high mortality worldwide. This study analysed the proteome of serum from patients with sepsis to characterize the pathological mechanism and pathways involved in sepsis. A total of 59 patients with sepsis were enrolled for quantitative proteomic analysis. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network specific to sepsis. Key regulatory modules that were detected were highly correlated with sepsis patients and related to multiple functional groups, including plasma lipoprotein particle remodeling, inflammatory response, and wound healing. Complement activation was significantly associated with sepsis-associated encephalopathy. Triglyceride/cholesterol homeostasis was found to be related to sepsis-associated acute kidney injury. Twelve hub proteins were identified, which might be predictive biomarkers of sepsis. External validation of the hub proteins showed their significantly differential expression in sepsis patients. This study identified that plasma lipoprotein processes played a crucial role in sepsis patients, that complement activation contributed to sepsis-associated encephalopathy, and that triglyceride/cholesterol homeostasis was associated with sepsis-associated acute kidney injury.

Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND & AIMS: Early determination of the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to guide clinical management and decrease mortality. The aim of this study was to develop a new simplified prognostic score to accurately predict outcomes in patients with HBV-ACLF. METHODS: Prospective clinical data from 2,409 hospitalized patients with acute deterioration of HBV-related chronic liver disease were used to develop a new prognostic score that was validated in an external group. RESULTS: A total of 954 enrolled patients with HBV-ACLF were diagnosed based on the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria. Six predictive factors were significantly related to 28-day mortality and constituted a new prognostic score (=1.649×ln(international normalized ratio)+0.457×hepatic encephalopathy score+0.425×ln(neutrophil)+0.396×ln(total bilirubin)+0.576×ln(serum urea)+0.033×age). The C-indices of the new score for 28-/90-day mortality (0.826/0.809) were significantly higher than those of 4 other scores (COSSH-ACLF, 0.793/0.784; CLIF-C ACLF, 0.792/0.770; MELD, 0.731/0.727; MELD-Na, 0.730/0.726; all p <0.05). The prediction error rates of the new score for 28-day mortality were significantly lower than those of the 4 other scores: COSSH-ACLF (15.9%), CLIF-C ACLF (16.3%), MELD (35.3%) and MELD-Na (35.6%). The probability density function evaluation and risk stratification of the new score also showed the highest predictive values for mortality. These results were then validated in an external cohort. CONCLUSION: A new prognostic score based on 6 predictors, without an assessment of organ failure, can accurately predict short-term mortality in patients with HBV-ACLF and might be used to guide clinical management. LAY SUMMARY: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome that is associated with a high short-term mortality rate. We developed a simplified prognostic score for patients suffering from this condition based on a prospective multicentre cohort. This new score had better predictive ability than 4 other commonly used scores.

Efficacy and safety of weekly rifapentine and isoniazid for tuberculosis prevention in Chinese silicosis patients: a randomized controlled trial.

OBJECTIVE: The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients. METHODS: Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated. RESULTS: A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity. DISCUSSION: Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02430259.

Comprehensive Transcriptome Profiling of Peripheral Blood Mononuclear Cells from Patients with Sepsis.

Background: Sepsis, as a clinical emergency, usually causes multiorgan dysfunction and can lead to high mortality. Establishment of specific and sensitive biomarkers for early diagnosis is critical to identify patients who would benefit from targeted therapy. In this study, we investigated this syndrome by analyzing the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with sepsis and identified sepsis-specific biomarkers. Methods: In this study, a total of 87 patients with sepsis and 40 healthy controls from a prospective multicenter cohort were enrolled. Samples from 44 subjects (24 patients with sepsis and 20 healthy controls) were sequenced and the remaining patients were included in the validation group. Using high-throughput sequencing, a gene expression profile of PBMCs from patients with sepsis was generated to elucidate the pathophysiology of sepsis and identify sepsis-specific biomarkers. Results: Principal component analysis (PCA) and unsupervised hierarchical cluster analysis showed that patients with sepsis separated from healthy controls. A total of 1639 differentially expressed genes (DEGs) were identified (|log2 fold change|>2, adjusted P value <0.05) between these two groups, with 1278 (78.0%) upregulated and 361 (22.0%) downregulated in patients with sepsis. Gene Ontology (GO) analysis of the upregulated DEGs identified 194 GO terms that were clustered into 27 groups, and analysis of the downregulated DEGs identified 20 GO terms that were clustered into 4 groups. Four unique genes were identified that could be predictive of patients with sepsis. External validation of the four genes using quantitative real-time polymerase chain reaction (qRT-PCR) was consistent with the results of mRNA sequencing, revealing their potential in sepsis diagnosis. Conclusions: The transcriptome characteristics of PBMCs, which were significantly altered in sepsis patients, provide new insights into sepsis pathogenesis. The four identified gene expression changes differentiated patients with sepsis from healthy subjects, which could serve as a convenient tool contributing to sepsis diagnosis.

Artificial liver treatment improves survival in patients with hepatitis B virus-related acute-on-chronic liver failure: A case-control matched analysis.

AIM: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) patients. However, patient survival remains unknown. We aim to assess the effects of ALSS on survival in HBV-ACLF patients. METHODS: The clinical data of HBV-ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment. The main end-points were cumulative survival rates at days 21, 28, and 90. Four different rigorous analyses were carried out to reduce bias and confounding. RESULTS: In the entire cohort, the cumulative survival rates at days 21, 28, and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P < 0.01) than in those who underwent SMT only. In the 276-pair case-control matched cohort, a significantly higher survival rate was also observed in the ALSS group than in the SMT group on days 21, 28, and 90 (72.5% vs. 60.3%, 68.3% vs. 57.4%, 55.9% vs. 48.5%, respectively, P < 0.05), especially in patients with ACLF-1 and -2. By a multivariable-adjusted analysis, ALSS treatment was associated with a significantly lower risk of mortality, especially for ACLF-2 at days 21, 28, and 90. These findings were also confirmed through propensity score matching and inverse probability treatment weighting analysis. CONCLUSIONS: ALSS treatment can improve short-term survival and is associated with a significantly lower risk of short-term mortality in patients with HBV-ACLF, especially ACLF-2.

Bacterial Infections in Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a newly recognized clinical syndrome characterized by preexisting chronic liver disease or cirrhosis with organ failure and high 28-day mortality (50-90%). Bacterial infections (BIs) play pivotal roles in the development and progression of ACLF either as a main precipitating event or a specific complication. The main organisms isolated as triggering ACLF are Gram-positive bacteria, followed by Gram-negative bacteria. Spontaneous bacterial peritonitis, pneumonia, urinary tract infections, and skin infections are prevalent infections that trigger and complicate ACLF. Despite appropriate antibiotic treatment, BIs account for poor ACLF outcomes and lead to a worse clinical course and higher intensive care unit admission and short-term mortality. Early diagnosis and novel nonantibiotic methods are highly important for managing BIs. Thus, this review focuses on the epidemiology, prognosis, and diagnosis of and management strategies for BIs in ACLF patients as well as the relationship between BIs and ACLF.

Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure.

OBJECTIVE: The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. DESIGN: The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. RESULTS: Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. CONCLUSIONS: Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.

Physiological Evaluation of Cooling Devices in Conjunction With Personal Protective Ensembles Recommended for Use in West Africa.

OBJECTIVE: Cooling devices (CDs) worn under personal protective equipment (PPE) can alleviate some of the heat stress faced by health care workers responding to the Ebola outbreak in West Africa. METHODS: Six healthy, young individuals were tested while wearing 4 different CDs or no cooling (control) under PPE in an environmental chamber (32°C/92% relative humidity) while walking (3 METs, 2.5 mph, 0% grade) on a treadmill for 60 minutes. Exercise was preceded by a 15-minute stabilization period and a 15-minute donning period. RESULTS: The control condition resulted in a significantly higher rectal temperature (Tre) at the end of the exercise than did all CD conditions (CD1, P=0.004; CD2, P=0.01; CD3, P=0.000; CD4, P=0.000) with CD1 and CD2 resulting in a higher Tre than CD3 and CD4 (P<0.05). The control condition resulted in a higher heart rate (HR) at the end of exercise than did the CD3 (P=0.01) and CD4 (P=0.009) conditions, whereas the HR of the CD1 and CD2 conditions was higher than that of the CD3 and CD4 conditions (P<0.05). Weight loss in the control condition was higher than in the CD3 (P=0.003) and CD4 (P=0.01) conditions. Significant differences in subjective measurements of thermal stress were found across conditions and time. CONCLUSIONS: Use of CDs can be advantageous in decreasing the negative physiological and subjective responses to the heat stress encountered by health care workers wearing PPE in hot and humid environments. (Disaster Med Public Health Preparedness. 2017;11:573-579).

Physiological Evaluation of Personal Protective Ensembles Recommended for Use in West Africa.

OBJECTIVE: Personal protective equipment (PPE) provides health care workers with a barrier to prevent human contact with viruses like Ebola and potential transmission of the disease. However, PPE can also introduce an additional physiological burden from potentially increased heat stress. This study evaluated the human physiological and subjective responses to continuous light exercise within environmental conditions similar to those in West Africa while wearing 3 different, commonly used PPE ensembles (E1, E2, and E3). METHODS: Six healthy individuals were tested in an environmental chamber (32°C, 92% relative humidity) while walking (3 METs, 2.5 mph, 0% incline) on a treadmill for 60 minutes. All subjects wore medical scrubs and PPE items. E1 also had a face shield and fluid-resistant surgical gown; E2 additionally included goggles, coverall, and separate hood; and E3 also contained a highly impermeable coverall, separate hood, and surgical mask cover over the N95 respirator. RESULTS: Heart rate and core temperature at the end of the exercise were significantly higher for E2 and E3 than for E1. Subjective perceptions of heat and exertion were significantly higher for E2 and E3 than for E1. CONCLUSIONS: Heat stress and PPE training, as well as the implementation of a work-to-rest ratio that avoids dehydration and possible heat stress issues, are recommended. (Disaster Med Public Health Preparedness. 2017;11:580-586).

Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.

OBJECTIVE: Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells' activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application. DESIGN: We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells' activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry. RESULTS: All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs' cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models. CONCLUSIONS: Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

Comparative transcriptome analysis of peripheral blood mononuclear cells in hepatitis B-related acute-on-chronic liver failure.

UNLABELLED: Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is essential to elucidate the pathogenesis of HBV-ACLF and identify HBV-ACLF-specific biomarkers. In this study, high-throughput sequencing was performed to characterize the transcriptome of PMBCs from patients with HBV-ACLF. Specifically, 2381 differentially expressed genes (DEGs) and 776 differentially expressed transcripts were identified through comparisons with patients with chronic hepatitis B (CHB) and healthy controls. Gene Ontology (GO) analysis identified 114 GO terms that were clustered into 12 groups. We merged 10 dysregulated genes selected from these grouped GO terms and non-clustered terms with four significant genes with a specificity of >0.8 in the HBV-ACLF patients to obtain a set of 13 unique genes. The quantitative real-time polymerase chain reaction (qRT-PCR) validation of the top six genes (CYP19A1, SEMA6B, INHBA, DEFT1P, AZU1 and DEFA4) was consistent with the results of messenger ribonucleic acid (mRNA) sequencing. A further receiver operating characteristic (ROC) analysis revealed that the areas under the ROC curves of the six genes were all >0.8, which indicated their significant diagnostic potentials for HBV-ACLF. CONCLUSION: The transcriptome characteristics of PBMCs are altered in patients with HBV-ACLF, and six genes may serve as biomarkers of HBV-ACLF.

Physiologic and fit factor profiles of N95 and P100 filtering facepiece respirators for use in hot, humid environments.

BACKGROUND: To determine if hot, humid ambient conditions impact filtering facepiece respirators' (FFRs') fit, and to evaluate differences in physiologic and subjective responses between N95 FFRs and P100 FFRs. METHODS: Twelve subjects had physiologic monitoring and subjective perceptions monitored over 1 hour of treadmill exercise (5.6 km/h) in an environmental chamber (35°C, relative humidity 50%) wearing an N95 FFR, P100 FFR, or no respirator. Respirator quantitative fit testing was done before and after exercise. RESULTS: There was no significant difference in pass rates for both FFRs on initial fit testing, but subjects who passed were more likely to fail the postexercise test with N95 FFRs (P = .01). Wearing FFRs increased the temperature of facial skin covered by the FFR (P = .009) and breathing discomfort (P = .002). No significant differences were noted in other measured variables (heart rate, respiratory rate, oxygen saturation, transcutaneous carbon dioxide level, rectal temperature, global skin temperature, core temperature, and subjective perceptions) between controls and FFRs and between FFR models. CONCLUSION: After 1 hour of exercise in hot, humid ambient conditions, P100 FFRs retained better fit than N95 FFRs, without additional physiologic or subjective impact. Wearing FFRs under these conditions does not add to the body's thermophysiologic or perceptual burdens.

Characterisation of peripheral blood mononuclear cell microRNA in hepatitis B-related acute-on-chronic liver failure.

UNLABELLED: Hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and the mechanisms of its development and progression remain unclear. The aim of this study was to define the characteristics of peripheral blood mononuclear cell microRNAs in patients with HBV-ACLF. In this study, novel microRNA (miRNA) biomarkers of peripheral blood mononuclear cells (PBMCs) in patients with HBV-ACLF were characterised by high-throughput sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). The results showed 78 miRNAs were significantly differentially expressed in patients with HBV-ACLF compared to patients with chronic hepatitis B (CHB) and healthy controls. Among patients with HBV-ACLF, 17 dysregulated miRNAs increased or decreased more than 4-fold, of which eight miRNAs had higher expression levels than median level. qRT-PCR validation demonstrated that six miRNAs (hsa-miR-21-5p, hsa-miR-34c-5p, hsa-miR-143-3p, hsa-miR-143-5p, hsa-miR-374a-3p and hsa-miR-542-3p) may be useful as novel biomarkers for the diagnosis of HBV-ACLF. Five novel miRNAs (L-miR-1~5) were detected and two (L-miR-1 and L-miR-3) were significantly differentially expressed in patients with HBV-ACLF. CONCLUSIONS: The miRNA expression profile of PBMCs is altered in patients with HBV-ACLF, and a signature of six miRNAs may be a promising biomarker for HBV-ACLF progression.

Human bone marrow mesenchymal stem cell-derived hepatocytes express tissue inhibitor of metalloproteinases 4 and follistatin.

BACKGROUND & AIMS: Human bone marrow mesenchymal stem cell (hBMSC) transplantation is expected to become an alternative regenerative technique for liver diseases. However, the mechanism by which hBMSCs differentiate into hepatocytes is still unclear. The aim of this study was to establish the specific characteristics of hBMSC-derived hepatocytes (hBMSC-Heps) for future clinical applications. METHODS: Potential hBMSC-Hep biomarkers were screened using cytokine arrays. Significant biomarkers were then validated by enzyme-linked immunosorbent assay (ELISA) in vitro and in an in vivo xenotransplantation model in fulminant hepatic failure (FHF) pigs. RESULTS: After 20 days of differentiation, the expression levels of tissue inhibitor of metalloproteinases 4 (TIMP-4) and follistatin (FST) in functional hBMSC-Heps were significantly increased, whereas those of activin A, osteoprotegerin and platelet-derived growth factor α polypeptide (PDGF-A) were significantly decreased. The high levels of TIMP-4 and FST were validated by ELISA in hBMSC-Heps grown in differentiation medium. The in vivo xenotransplantation model in FHF pigs showed that the serum levels of TIMP-4 and FST were significantly increased 6 h after hBMSC transplantation and reached their highest levels at 24 and 48 h, respectively, after hBMSC transplantation. Immunohistochemistry confirmed that TIMP-4 and FST were expressed in cultured hBMSC-Heps and in implanted hBMSC-Heps in pig livers. CONCLUSIONS: The transdifferentiation of hBMSCs into hepatocytes is associated with the expression of TIMP-4 and FST. TIMP-4 and FST represent potential novel biomarkers for the characterisation of hBMSC-Heps and may be useful for future clinical applications.