Recent reports of acute hepatitis of unknown origin in previously healthy children have been increasing worldwide. The main characteristics of the affected children were jaundice and gastrointestinal symptoms. Their serum aminotransaminase levels were above 500 IU/L, with negative tests for hepatitis viruses A–E. By 31 May 2022, the outbreak had affected over 800 children under the age of 16 years in more than 40 countries, resulting in acute liver failure in approximately 10%, including at least 21 deaths and 38 patients requiring liver transplantation. There was still no confirmed cause or causes, although there were several different working hypotheses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adenovirus serotype 41, or SARS-CoV-2 superantigen-mediated immune cell activation. Here, we review early observations of the 2022 outbreak which may inform diagnosis, treatment, and prevention in the context of an overlapping COVID-19 pandemic.

The COVID-19 pandemic raised awareness of the complexities of the patient, the disease, and the practice of medicine. The impact of these reaches beyond healthcare (e.g., supply chains, politics, socioeconomic factors) to include nations, individuals, and molecules. In personalized medicine, “accurate diagnosis” is critical as it affects patient management, clinical trial recruitment, regulatory approval, and reimbursement policies for payers. Conventional statistics evaluate hypothesis-driven reductionist practices in medicine, e.g., the use of “scores” combining individual measurements, and are often limited by the data:variables ratio. True personalization (N of 1) is not practical but better stratification of diseases and patients can improve diagnoses. This work describes our approach and tests its ability to identify patient complexity and clinical markers in the trial of a candidate HFpEF drug better than prior methods.

This study evaluated discovery or data-driven approaches, by applying community detection (CD), forgoing statistical significance to identify unknown relationships. We reanalyzed data from the I-PRESERVE study of heart failure with preserved-ejection fraction, where subgroup analysis was unsuccessful. We initially performed unipartite CD analysis and evolved to address the complexity in real-world data using a bipartite model. The mathematically grounded modularity metric enabled greater confidence in community assignments.

This reanalysis with CD revealed novel patient subgroups with stronger supporting rationale for group assignments, pointing to further refined and targeted studies.

We believe that generalization of the CD approach to higher-dimensional data can lead to a “next generation of phenotyping” that encompasses the temporal progression of the patient.

The World Health Organization (WHO) has set the goal of eliminating hepatitis as a threat to public health by 2030. Blocking mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is not only the key to eliminating viral hepatitis, but also a hot issue in the field of hepatitis B prevention and treatment. To standardize the clinical management of preventing MTCT of HBV and achieve zero HBV infection among infants, the Chinese Foundation for Hepatitis Prevention and Control organized experts to compile a management algorithm for prevention of MTCT of HBV based on the latest research progress and guidelines, including 10 steps of pregnancy management and postpartum follow-up, among which screening, antiviral treatment, and infant immunization are its core components.

The National Centralized Drug Procurement (NCDP) policy was launched in mainland China in April 2019, with entecavir (ETV) and tenofovir disoproxil fumarate (TDF) being included in the procurement list. We conducted the current study to investigate the impact of the NCDP policy on the utilization and expenditures of antiviral therapy for chronic hepatitis B (CHB) in China.

Procurement records, including monthly purchase volume, expenditure, and price of nucleos(t)ide analogs (NAs), were derived from the National Healthcare Security Administration from April 2018 to March 2021. The changes in volumes and expenditures of the first-line NAs and bid-winning products were calculated. The effects of price, volume, and structure related to drug expenditure were calculated by the Addis and Magrini (AM) Index System Analysis.

The purchase volume of NAs significantly increased from 134.3 to 318.3 million DDDs, whereas the expenditure sharply decreased from 1,623.41 to 490.43 million renminbi (RMB) or 241.94 to 73.09 million US dollars (USD). The proportions of first-line NAs rose from 72.51% (ETV: 69.00%, TDF: 3.51%) to 94.97% (ETV: 77.42%, TDF: 17.55%). AM analysis showed that the NCDP policy decreased the expenditure of all NAs (S=0.91) but increased that of the first-line NAs in the bid-winning list (S=1.13). Assuming the population size of CHB patients remains stable and a compliance rate of ≥75%, the proportion of CHB patients receiving first-line antiviral therapy would increase from 6.36–8.48% to 11.56–15.41%.

The implementation of the NCDP policy significantly increased the utilization of first-line NAs for CHB patients at a lower expenditure. The findings provided evidence for optimizing antiviral therapy strategy and allocating medical resources in China.

Globally, there are emerging cases of acute severe hepatitis of unknown origin in children. These cases have gathered increasing attention, owing to the development of acute liver failure in some cases that resulted in liver transplantation. This review briefly summarizes the outbreak and diagnostic criteria of the disease. We further discuss the possible causes and related mechanisms underlying its occurrence and progression, and analyze the challenges in management. Finally, this review emphasizes patient management in clinical settings and a combination of efforts to unmask the disease.

The impact of drug-induced liver injury (DILI) on patients with chronic liver disease (CLD) is unclear. There are few reports comparing DILI in CLD and non-CLD patients. In this study, we aimed to determine the incidence and outcomes of DILI in patients with and without CLD.

We collected data on eligible individuals with suspected DILI between 2018 and 2020 who were evaluated systematically for other etiologies, causes, and the severity of DILI. We compared the causative agents, clinical features, and outcomes of DILI among subjects with and without CLD who were enrolled in the Thai Association for the Study of the Liver DILI registry. Subjects with definite, or highly likely DILI were included in the analysis.

A total of 200 subjects diagnosed with DILI were found in the registry. Of those, 41 had CLD and 159 had no evidence of CLD in their background. Complementary and alternative medicine (CAM) products were identified as the most common class of DILI agents. Approximately 59% of DILI in the CLD and 40% in non-CLD group were associated with CAM use. Individuals with pre-existing CLD had similar severity including mortality. Twelve patients (6%) developed adverse outcomes related to DILI including seven (3.5%) deaths and five (2.5%) with liver failure. Mortality was 4.88% in CLD and 3.14% in non-CLD subjects over median periods of 58 (8–106) days and 22 (1–65) days, respectively.

In this liver disease registry, the causes, clinical presentation, and outcomes of DILI in subjects with CLD and without CLD patients were not different. Further study is required to confirm our findings.

Intestinal dysbiosis play a role in the adverse outcomes of sepsis and septic shock. However, variations in bacterial diversity and microbiota-related functional metabolic alterations within the gut microbiome in decompensated cirrhosis (DC) patients with infection remain unknown.

We conducted 16-srRNA sequencing on stool samples (n=51: sepsis, 27/no sepsis, 24) collected from consecutive DC patients upon admission. Bacterial diversity, significant taxa, and respective metabolic profiling were performed based on subgroup comparisons. Conet/Cytoscape was utilized to identify significant non-random patterns of bacterial copresence and mutual exclusion for clinical events.

Genera associated with pathogenicity in conditions of immune exhaustion (Corynebacterium, Lautropia) were predominant in patients with sepsis. Metabolic pathways associated with oxidative stress and endotoxemia [lipopolysaccharide (LPS) synthesis and sulfur relay] were significantly upregulated in sepsis. Specific taxa were associated with sites of infection in DC patients. Protective oxidant pathways that increase glutathione were upregulated in those without sepsis. Gammaproteobacteria family of sulfur-metabolizing bacteria, exaggeration of orally predominant pathogens (Prevotella), and pathways of severe LPS-related hyperinflammatory stress were notable in those with interleukin-6 levels >1,000 pg/dL. Pathogenic genera related to an immune deficient state was significant in DC with ≥2 infection episodes. Megamonas was associated with survival during the same admission.

Specific gut microbiota and their metabolites were associated with sepsis and related events in patients with DC. Identifying beneficial strains that reduce immune exhaustion and supplementation of favorable metabolites could improve therapeutics for DC and sepsis, for which larger prospective, well controlled population-based studies remain an unmet need.

Regulatory T cells (Tregs) are a vital cell subset that induces immune tolerance in the tumor microenvironment by secreting suppressive cytokines and inhibiting innate immune cells. Transforming growth factor-beta (TGF-β) plays an important role in this process. However, the effect of TGF-β blockade on intratumoral Tregs and its specific biological role remains unclear.

Quantitative and functional changes in Tregs were evaluated after TGF-β blockade with gradient doses of monoclonal antibody 1D11 in a murine pancreatic ductal adenocarcinoma model.

The number of tumor infiltrating Tregs decreased significantly (high dose, low dose and control, 38.6 ± 8.1, 38.6 ± 1.8, 74.6 ± 4.9 /40× field, p = 0.024) after 1D11 administration, while CD8+ T cells in the tumor microenvironment significantly increased in the low dose group but reversed in the high dose group (3.1 ± 1.4, 12.3 ± 2.1, 5.4 ± 0.5 /40× field, p = 0.016). The frequency of CD4+, CD8+ or Treg cells in the peripheral blood and spleen showed no significant change. The typical cytokines TGF-β and inerleukin-10 secreted by Tregs as well as interferon-γ produced by cytotoxic T cells in tumor tissues did not change compared with the controls.

TGF-β blockade with a monoclonal antibody can reduce Tregs in the tumor niche, however, its therapeutic efficacy in PDAC patients remains limited. Further investigation of combination therapies is required.

125I radioactive particles implantation have demonstrated efficacy in eradicating hepatocellular carcinoma (HCC). However, progressive resistance of HCC to 125I radioactive particles has limited its wide clinical application.

We investigated the cellular responses to 125I radioactive particles treatment and autophagy-related 9B (ATG9B) silencing in HCC cell lines and Hep3B xenografted tumor model using Cell Counting Kit-8 reagent, western blotting, immunofluorescence, flow cytometry, transmission electron microscopy and immunohistochemistry.

In this study, we demonstrated that 125I radioactive particles induced cell apoptosis and protective autophagy of HCC in vitro and in vivo. Inhibition of autophagy enhanced the radiosensitivity of HCC to 125I radioactive particles. Moreover, 125I radioactive particles induced autophagy by upregulating ATG9B, with increased expression level of LC3B and decreased expression level of p62. Furthermore, ATG9B silencing downregulated LC3B expression and upregulated p62 expression and enhanced radiosensitivity of HCC to 125I radioactive particles in vitro and in vivo.

Inhibition of ATG9B enhanced the antitumor effects of 125I particle radiation against HCC in vitro and in vivo. Our findings suggest that 125I particle radiation plus chloroquine or/and the ATG9B inhibitor may be a novel therapeutic strategy for HCC.

Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV).

Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment.

A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031).

ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Triple-negative breast carcinomas (TNBCs) are defined as estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative breast carcinomas and are composed of a heterogeneous group of breast carcinomas with most of them having aggressive behavior and poor prognosis. However, some TNBC cases are low grade with indolent clinical outcome and low risk of metastasis to other organs or regional lymph nodes. Low-grade TNBCs include low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade invasive (ductal or lobular) carcinoma with apocrine differentiation, classic adenoid cystic carcinoma, secretory carcinoma, tall cell carcinoma with reversed polarity, acinic cell carcinoma, and low-grade mucoepidermoid carcinoma. This review aims to summarize the clinicopathological correlation and the molecular features of low-grade special TNBC subtypes.

Changes in eating habits and a sedentary lifestyle have shifted the primary role of food as an energy source to nutritious food for maintaining good health. A new functional jackfruit beverage was produced using a selected symbiotic culture of bacteria and yeast (SCOBY) with the aim of developing a cost-effective anti-obesity therapy as a preventive measure.

A total of five groups of the Institute of Cancer Research mice consisting of a normal control, positive control, negative control, SCOBY jackfruit pulp, and jackfruit leaves treated mice were used to examine the anti-obesity efficacy of SCOBY jackfruit beverages. An analysis on the gut microbiota, quantitative polymerase chain reaction gene expression, short chain fatty acids, and blood composition profile was also investigated.

High-fat diet-fed obese mice treated with SCOBY jackfruit beverages showed great improvement in the weight management control and significant body weight loss (18.5–20.2%) compared to a commercial anti-obesity drug, Orlistat (11.3%). There were no adverse effects on the blood composition profile and inflammation symptoms observed in the treated obese mice. The expression of the genes relating to glucose transport, lipid biosynthesis, inflammatory cytokines, and chemokines in the adipose tissues was significantly downregulated following the SCOBY jackfruit beverages diet interventions (P < 0.05). The analysis of the 16S rRNA sequencing on the mice fecal samples revealed that SCOBY jackfruit beverages had altered the gut microbiota composition with the enhanced growth of beneficial gut microbes in those treated mice relative to all control groups.

The findings in this study implied that SCOBY jackfruit beverages were potentially useful as a new therapeutic strategy for weight management control.

Though Amaranthus spinosus L. or ‘spiny amaranth’ belonging to the family Amaranthaceae is widely used in folklore and for ethnomedicinal purposes, little is known about the ecotype-based bioavailability of bioactive polyphenolic compounds that could cause health benefits. Hence, this was the objective of the present study.

Reversed-phase high-performance liquid chromatography coupled with a photodiode assay was used to investigate pharmacologically significant bioactive flavonoids and phenolic acids from hydroethanolic leaf extract of two different ecotypes (the Rarh region and coastal plain of West Bengal, India) of Amaranthus spinosus L. Furthermore, the antioxidant capacity of the leaf tissue extract of both the ecotypes of this promising crop was evaluated in terms of the metal chelating property, total antioxidant capacity (2,2-diphenyl-1-picryl-hydrazyl-hydrate assay), anti-lipid peroxidation property, and the total pool of flavonoids and phenolics for validating their health-promoting anti-degenerative chemical properties.

The results exhibited a rich source of pharmacologically important bioactive flavonoids and phenolic acids derived from the chalcone synthase and cinnamate-derived pathways for both the ecotypes, but when comparing the ecotype of the Rarh region, it proved to be superior to the ecotype of the coastal region.

Overall, the study suggests a region-specific ecotype effect on the accumulation of dietary flavonoids, phenolic acids, and antioxidant traits of Amaranthus spinosus L., thus substantiating their utility in the prevention of degenerative diseases. The study also highlighted the significance of plant-environment interaction in a secondary metabolic pathway, which may be explored in the future for improving the medicinal and functional food properties of underutilized crops for the prevention of degenerative diseases.

Sepsis is a common and severe clinical condition with high morbidity and mortality, affecting over 19 million people annually worldwide. This study aimed to find key genes related to the prognosis of sepsis through transcriptomic sequencing of peripheral blood mononuclear cells from survival and death septic patients.

Seventy-eight septic patients were recruited in the emergency intensive care unit of Xijing Hospital from Apr. 1, 2018, to Jun. 30, 2020, and divided into the survival (n = 67) and death (n = 11) groups. Their PBMCs were collected for transcriptomic sequencing. The differentially expressed genes were identified by bioinformatic analyses and validated by reverse transcription polymerase chain reaction.

Bioinformatic analyses revealed 457 differentially expressed genes. The gene ontology function and kyoto encyclopedia of genes and genomes Pathway analyses suggested that the alpha-enolase 1 (ENO1) and adenylate kinase 4 were potential target genes; reverse transcription polymerase chain reaction results exhibited that ENO1, but not adenylate kinase 4, gene expression significantly decreased in the death group compared to the survival.

The ENO1 gene expression is significantly down-regulated in the death group of septic patients, suggesting that low ENO1 may be a potential prognostic biomarker for sepsis.

Excessive false alarms in intensive care units (ICU) cause noise disturbance to patients and develop alarm fatigue among nurses, leading to safety concerns and decreased patient care quality. Evidence-based false alarm reduction strategies are urgently needed in the day-to-day clinical practice. This review aims to synthesize two main human-technology approaches to reduce false alarms generated by the physiologic monitor: customization of alarm settings by nurses and alarm algorithms.

A broad search was performed using four electronic databases, PubMed, Scopus, EMBASE, and Cumulative Index to Nursing and Allied Health Literature. This review included twenty-eight full-text journal articles focused on both customizations of alarm settings and alarm algorithm improvement for false alarm reduction in the ICU.

Clinical customizations of alarm settings on bedside physiological monitors helps to reduce excessive false alarms. Colleagues also developed alarm algorithms to reduce false alarms in the ICU and achieved excellent performance.

This review suggests collaboration between nurses and engineers to optimize personalized machine learning algorithms has the great potential for false alarm reduction in the ICU.

RAS protein activator like 2 (RASAL2) is a newly discovered metabolic regulator involved in energy homeostasis and adipogenesis. However, whether RASAL2 is involved in hepatic lipid metabolism remains undetermined. This study explored the function of RASAL2 and elucidated its potential mechanisms in nonalcoholic fatty liver disease (NAFLD).

NAFLD models were established either by feeding mice a high-fat diet or by incubation of hepatocytes with 1 mM free fatty acids (oleic acid:palmitic acid=2:1). Pathological changes were observed by hematoxylin and eosin staining. Lipid accumulation was assessed by Oil Red O staining, BODIPY493/503 staining, and triglyceride quantification. The in vivo secretion rate of very low-density lipoprotein was determined by intravenous injection of tyloxapol. Gene regulation was analyzed by chromatin immunoprecipitation assays and hydroxymethylated DNA immunoprecipitation combined with real-time polymerase chain reaction.

RASAL2 deficiency ameliorated hepatic steatosis both in vivo and in vitro. Mechanistically, RASAL2 deficiency upregulated hepatic TET1 expression by activating the AKT signaling pathway and thereby promoted MTTP expression by DNA hydroxymethylation, leading to increased production and secretion of very low-density lipoprotein, which is the major carrier of triglycerides exported from the liver to distal tissues.

Our study reports the first evidence that RASAL2 deficiency ameliorates hepatic steatosis by regulating lipid metabolism through the AKT/TET1/MTTP axis. These findings will help understand the pathogenesis of NAFLD and highlight the potency of RASAL2 as a new molecular target for NAFLD.

Only a small percentage of chronic hepatitis B (CHB) patients effectively respond to treatment with pegylated-interferon alpha (PegIFNα) or nucleos(t)ide analogues (NUCs). We aimed to detect the correlations of complement regulators-associated single-nucleotide polymorphisms (SNPs) with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients.

A total of 1,763 HBeAg-positive CHB patients were enrolled, 894 received PegIFNα for at least 48 weeks and were followed up for 24 weeks, and 869 received NUCs for 104 weeks. For each patient, nine SNPs in genes encoding for complement regulators were determined and genotyped. To assess the cumulative effect of numerous SNPs, a polygenic score (PGS) was utilized. The correlations of SNPs and PGS with the levels of combined response (CR) and hepatitis B s antigen (HBsAg) loss were also investigated.

In PegIFNα-treated patients, an intronic SNP of CD55, rs28371597, was strongly related to CR, and the CR rate in rs28371597_GG genotype carriers was only approximately half that of rs28371597_GT/TT genotype carriers (20.29% vs. 37.10%, p=2.00 × 10−3). A PGS incorporating CD55_rs28371597 and two additional SNPs, CFB_rs12614 and STAT4_rs7574865, which had been considered as predictors for PegIFNα treatment response before, was strongly correlated with the levels of CR (p-trend=7.94×10−6) and HBsAg loss (p-trend=9.40×10−3) in PegIFNα-treated patients. In NUCs-treated individuals, however, none of the nine SNPs were shown to be significantly linked to CHB treatment response.

CD55_rs28371597 is a promising biomarker for predicting CHB patients’ responsiveness to PegIFNα therapy. The updated PGS may be used for optimizing CHB treatment.

The pandemic emergency has created an urgent need to find suitable drugs to treat coronavirus disease 2019 (COVID-19). Numerous drug trials have been conducted; however, effective and affordable treatments have not been found. The study aimed to find ways out of the current situation based on a better understanding of events, an analysis of the causes of the difficulties encountered on this issue. The study analyzed articles based on the results of COVID-19 treatment identified in PubMed, Clinical Key, ScienceDirect, World Health Organization (WHO), Food and Drug Administration (FDA), and Google Scholar’s online libraries. This review summarizes and critically analyzes the information accumulated over the pandemic on the efficacy of drugs for the treatment of COVID-19 and the reasons for the inconsistency in the results of clinical trials on repurposed drugs, and the role of mutations in new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, in reducing the effectiveness of vaccination and treatment, and determining the possibility of overcoming them in the future. Recent achievements in finding effective ways to combat viral pandemics are shown. According to the results of clinical trials, only remdesivir and sotrovimab have been recommended for the treatment of COVID-19. The prospects in the fight against COVID-19 are the creation of new antiviral drugs, such as cyanorone-20 and antisense oligonucleotides (ASOs), and a proactive strategy for the development of drugs against viral pathogens, which are based on cocktails of panvirus drugs for oral and inhalation administration.

Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT.

581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis.

In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups.

The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.