Plasma metabolome analysis for predicting antiviral treatment efficacy in chronic hepatitis B: diagnostic biomarkers and therapeutic insights.

The early and accurate identification of predictive biomarkers for antiviral treatment efficacy remains a significant clinical challenge, particularly in the management of chronic hepatitis B (CHB). This study aimed to assess whether the plasma metabolome could reliably predict the success of antiviral therapy in CHB patients. We conducted a retrospective analysis on 56 treatment-naive CHB patients at the First Affiliated Hospital of Zhejiang University from December 2013 to March 2016. Patients who underwent a 48-week treatment regimen of entecavir (ETV) and interferon-alpha (IFN-α) were randomly assigned to either a discovery cohort (n=29) or a validation cohort (n=27). Based on the outcome of the treatment, patients were classified as HBeAg seroconversion group (High responders, Hrp) or the non-remission group (Low responder, Lrp). Our methodology involved an untargeted analysis of the amine/phenol and carboxylic acid submetabolomes in the CHB patients under treatment, utilizing chemical isotope labeling (CIL) techniques with liquid chromatography-mass spectrometry (LC-MS). Several metabolites were identified as having significant diagnostic potential for distinguishing Hrp from Lrp, with areas under the receiver operating characteristic curve (AUC) exceeding those typical clinical indicators. Notably, four metabolites, namely 2-methyl-3-ketovaleric acid, 2-ketohexanoic acid, 6-oxo-1,4,5,6-tetrahydronicotinic acid, and α-ketoisovaleric acid, demonstrated exceptionally high sensitivity and specificity in both cohorts, nearing 100%. In contrast, the clinical indicators, including HBcAb, log(HBsAg), and HBeAb, demonstrated lower and inconsistent sensitivity and specificity between the discovery and validation cohorts. Using HBcAb as a marker, the sensitivity was 87.5% with 76.9% specificity in the discovery cohort; however, the sensitivity dropped to 46.7% with 91.7% specificity in the validation cohort. Using log(HBsAg), the sensitivity was 84.6% with 69.2% specificity in the discovery cohort, compared to 85.7% sensitivity and 83.3% specificity in the validation cohort. For HBeAb, the separation of Hrp and Lrp had a sensitivity of 87.5% with 69.2% specificity in the discovery cohort, while the validation cohort showed 86.7% sensitivity and 91.7% specificity.

Impact of COVID-19 Nonpharmaceutical Interventions on Respiratory Syncytial Virus Infections in Hospitalized Children.

BACKGROUND: Nonpharmaceutical interventions (NPIs) targeted at SARS-CoV-2 have remarkably affected the circulation of other respiratory pathogens, including respiratory syncytial virus (RSV). This study aimed to assess the changes in epidemiological and clinical characteristics of RSV infections in hospitalized children before and during the pandemic in Suzhou, China. METHODS: We prospectively enrolled children aged < 18 years who were hospitalized in Soochow University Affiliated Children's Hospital with acute lower respiratory infection (ALRIs) from January 2018 to July 2022. Changes in epidemiological and clinical characteristics of RSV infections were analyzed. RESULTS: Compared with the same period in 2018-2019, the difference in the overall positive rate of RSV was not statistically significant in 2020, while it increased significantly in 2021 (11.8% [662/5621] vs. 20.8% [356/1711], p < 0.001) and 2022 (9.0% [308/3406] vs. 18.9% [129/684], p < 0.001). Specifically, the positive rates declined considerably from October to December 2020 but sharply increased during the summer of 2021. Compared to prepandemic period, RSV infections were more frequently observed in older children during the pandemic. RSV-positive children exhibited milder clinical characteristics during the COVID-19 pandemic, including decreased proportion of patients with hospital stay ≥ 11 days (10.3% vs. 6.7%, p < 0.05), less requirement for oxygen therapy (13.7% vs. 6.9%, p < 0.001), and fewer cases of polypnea (12.2% vs. 9.7%, p < 0.05) and wheeze (50.1% vs. 42.9%, p < 0.001). CONCLUSIONS: The implementation of multilayered NPIs targeted at COVID-19 has affected the activity of RSV. Ongoing monitoring of RSV is warranted as the changing RSV epidemiology can provide valuable insights for future healthcare system planning.

Atom-ProteinQA: Atom-level protein model quality assessment through fine-grained joint learning.

MOTIVATION: Protein model quality assessment (ProteinQA) is a fundamental task that is essential for biologically relevant applications, i.e., protein structure refinement, protein design, etc. Previous works aimed to conduct ProteinQA only on the global structure or per-residue level, ignoring potentially usable and precise cues from a fine-grained per-atom perspective. In this study, we propose an atom-level ProteinQA model, named Atom-ProteinQA, in which two innovative modules are designed to extract geometric and topological atom-level relationships respectively. Specifically, on the one hand, a geometric perception module exploits 3D sparse convolution to capture the geometric features of the input protein, generating fine-grained atom-level predictions. On the other hand, natural chemical bonds are utilized to construct an atom-level graph, then message passing from a topological perception module is applied to output residue-level predictions in parallel. Eventually, through a cross-model aggregation module, features from different modules mutually interact, enhancing performance on both the atom and residue levels. RESULTS: Extensive experiments show that our proposed Atom-ProteinQA outperforms previous methods by a large margin, regardless of residue-level or atom-level assessment. Concretely, we achieved state-of-the-art performance on CATH-2084, Decoy-8000, public benchmarks CASP13 & CASP14, and the CAMEO. AVAILABILITY: The repository of this project is released on: https://github.com/luyfcandy/Atom_ProteinQA.

Predicting valuable missense variants with AlphaMissense in a multiple pulmonary infection patient.

AlphaMissense is proficient in predicting the clinical classification of missense variants. we utilized AlphaMissense to find disease-relevant variants within a polymicrobial pulmonary infection case. Exome sequencing was performed in this patient, and AlphaMissense and Phenolyzer were combined to investigate disease-relevant variants screening from exome sequencing results.

Single-cell RNA sequencing reveals the immunoregulatory roles of PegIFN-α in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is caused by HBV infection and affects the lives of millions of people worldwide by causing liver inflammation, cirrhosis, and liver cancer. Interferon-alpha (IFN-α) therapy is a conventional immunotherapy that has been widely used in CHB treatment and achieved promising therapeutic outcomes by activating viral sensors and interferon-stimulated genes (ISGs) suppressed by HBV. However, the longitudinal landscape of immune cells of CHB patients and the effect of IFN-α on the immune system are not fully understood. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing (scRNA-seq) to delineate the transcriptomic landscape of peripheral immune cells in CHB patients before and after PegIFN-α therapy. Notably, we identified three CHB-specific cell subsets, pro-inflammatory (Pro-infla) CD14+ monocytes, Pro-infla CD16+ monocytes and IFNG+ CX3CR1- NK cells, which highly expressed proinflammatory genes and positively correlated with HBsAg. Furthermore, PegIFN-α treatment attenuated percentages of hyperactivated monocytes, increased ratios of long-lived naive/memory T cells and enhanced effector T cell cytotoxicity. Finally, PegIFN-α treatment switched the transcriptional profiles of entire immune cells from TNF-driven to IFN-α-driven pattern and enhanced innate antiviral response, including virus sensing and antigen presentation. CONCLUSIONS: Collectively, our study expands the understanding of the pathological characteristics of CHB and the immunoregulatory roles of PegIFN-α, which provides a new powerful reference for the clinical diagnosis and treatment of CHB.

Modeling the optimal seasonal monoclonal antibody administration strategy for respiratory syncytial virus (RSV) prevention based on age-season specific hospitalization rate of RSV in Suzhou, China, 2016-2022.

BACKGROUND: The approval of nirsevimab brings light to reducing the heavy disease burden caused by respiratory syncytial virus (RSV). Considering the seasonality of RSV, the timing of administrating monoclonal antibody (mAb) is critical to maximize health utility. This study aimed to model and seek the optimal seasonal mAb administration strategy for preventing RSV-associated hospitalization. METHODS: Age-season specific hospitalization rates for RSV-associated acute lower respiratory infection (RSV-ALRI) were estimated from a hospital-based birth cohort. Using these rates, we simulated and evaluated the effect of diverse mAb administration strategies on preventing RSV-ALRI hospitalization. Optimal strategies were selected based on their effectiveness and relative cost-effectiveness. RESULTS: Compared with the year-round strategy of administration mAb at birth for all children, 291 out of the 854 candidate strategies, featuring diverse administration timing and age thresholds, demonstrated a greater number of averted RSV-ALRI hospitalizations and a lower number needed to treat (NNT). The NNT represents the number of mAb doses needed to prevent one case of RSV-ALRI hospitalization. Among the 291 strategies, administration mAb to children born in July-January or August-January at birth and administrating to the remaining <12 months old children in September, exhibited the highest increase in averted RSV-ALRI hospitalizations than the year-round strategy, with a magnitude of 23 %, while also achieve an 18 % reduction in NNT. CONCLUSION: Administrating monoclonal antibodies to children born in July to January at birth, and administrating to the remaining <1-year-old children in September or October would be the optimal seasonal mAb administration strategy for children in Suzhou, China.

Immunomodulatory and Antiviral Therapy Improved Functional Cure Rate in CHB Patients with High HBsAg Level Experienced NA.

Background and Aims: A functional cure, or hepatitis B virus (HBV) surface antigen (HBsAg) loss, is difficult to achieve in patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B. The HBV vaccine and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been reported to help reduce HBsAg levels and promote HBsAg loss. In this prospective randomized trial, we evaluated HBsAg loss in patients receiving pegylated interferon-α2b (PEGIFN-α2b) and tenofovir disoproxil fumarate (TDF), with and without GM-CSF and HBV vaccination. Methods: A total of 287 patients with HBeAg positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment were assigned randomly to three treatment groups for 48 weeks, TDF alone (control), PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine. The primary endpoints were the proportions of patients with HBsAg loss and seroconversion at 48 and 72 weeks. Results: The cumulative HBsAg loss rates in the control, PEGIFN-α2b + TDF, and PEGIFN-α2b + TDF + GM-CSF + HBV vaccine groups at week 48 were 0.0%, 28.3%, and 41.1%, respectively. The cumulative HBsAg seroconversion rates in these groups at week 48 were 0.0%, 21.7%, and 33.9%, respectively. Multivariate regression analysis showed that GM-CSF use plus HBV vaccination was significantly associated with HBsAg loss (p=0.017) and seroconversion (p=0.030). Conclusions: In patients with HBeAg-positive chronic hepatitis B and seroconversion after nucleot(s)ide analog treatment, immunomodulatory/antiviral treatment regimens effectively improved HBsAg loss, and the regimen including GM-CSF and HBV vaccination was most effective.

Exploring the gut mycobiome: differential composition and clinical associations in hypertension, chronic kidney disease, and their comorbidity.

Background: Hypertension (HTN) and chronic kidney disease (CKD) pose significant global health challenges and often coexist, amplifying cardiovascular risks. Recent attention has turned to the gut mycobiome as a potential factor in their pathophysiology. Our study sought to examine the gut fungal profile in individuals with HTN, CKD, and the concurrent HTN+CKD condition, investigating its connections with serum cytokines, renal function, and blood pressure. Methods and materials: We investigated three distinct participant groups: a cohort of 50 healthy controls (HC), 50 individuals diagnosed with HTN-only, and 50 participants suffering from both HTN and CKD (HTN+CKD). To facilitate our research, we gathered fecal and blood samples and conducted a comprehensive analysis of serum cytokines. Moreover, fungal DNA extraction was conducted with meticulous care, followed by sequencing of the Internal Transcribed Spacer (ITS) region. Results: HTN+CKD patients displayed distinctive fungal composition with increased richness and diversity compared to controls. In contrast, HTN-only patients exhibited minimal fungal differences. Specific fungal genera were notably altered in HTN+CKD patients, characterized by increased Apiotrichum and Saccharomyces levels and reduced Candida abundance. Our correlation analyses revealed significant associations between fungal genera and serum cytokines. Moreover, certain fungal taxa, such as Apiotrichum and Saccharomyces, exhibited positive correlations with renal function, while others, including Septoria, Nakaseomyces, and Saccharomyces, were linked to blood pressure, particularly diastolic pressure. Conclusion: Gut mycobiome dysbiosis in individuals with comorbid HTN and CKD differs significantly from that observed in HTN-only and healthy controls. The interactions between serum cytokines, renal function, and blood pressure emphasize the potential impact of the fungal microbiome on these conditions. Additional research is required to clarify the underlying mechanisms and identify therapeutic opportunities associated with mycobiome dysbiosis in HTN and CKD.

Comparative analysis of elderly hospitalized patients with COVID-19 or influenza A H1N1 virus infections.

OBJECTIVES: This study aimed to investigate the differences between elderly patients hospitalized with COVID-19 or influenza A H1N1 virus infections. METHODS: We contrasted two absolute groups of patients (age ≥60 years) infected with either COVID-19 (n = 222) or influenza A H1N1 virus infections (n = 96). Propensity score matching was used to reduce the imbalance between the two matched groups. The clinical features, imaging presentations, therapies, and prognosis data were compared between the two groups. RESULTS: The patients with influenza showed higher proportions of cough, expectoration, fatigue, and shortness of breath. Higher counts of lymphocytes, hemoglobin, and creatine kinase and lower counts of white blood cells, neutrophils, blood urea nitrogen, and C-reactive protein were found in the patients with COVID-19. Regarding the imaging characteristics, bilateral pneumonia was the most abnormal pattern in the two groups of patients. The incidence of acute respiratory distress syndrome or death was lower among the patients with COVID-19. CONCLUSION: The clinical manifestations of patients with COVID-19 are more concealed than those of patients with influenza. Fewer symptoms of sputum production, fatigue, and shortness of breath, combined with lower counts of white blood cells, neutrophils, and C-reactive protein are the possible predictive factors of COVID-19 among elderly patients.

Pegylated interferon-α-2b combined with tenofovir disoproxil fumarate, granulocyte-macrophage colony-stimulating factor, and hepatitis B vaccine treatment for naïve HBeAg-positive chronic hepatitis B patients: A prospective, multicenter, randomized controlled study.

Hepatitis B surface antigen (HBsAg) loss or seroconversion is an ideal treatment endpoint for patients with chronic hepatitis B but is rarely achievable in  hepatitis B e-antigen (HBeAg)-positive patients using existing treatment strategies. In this study, the effect of pegylated interferon (peg-IFN) alfa-2b plus tenofovir disoproxil fumarate (TDF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hepatitis B vaccine was evaluated. This randomized controlled trial was conducted at nine liver centers in Chinese university hospitals from May 2018 to July 2020. Patients (n = 303) enrolled were randomly administered peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine (experimental group); peg-IFN-α-2b plus TDF (control group 2); or interferon-α-2b alone (control group 1). The primary efficacy endpoint was HBsAg seroconversion at 48 weeks and the secondary endpoint included safety. No differences in baseline HBsAg levels were observed among the groups. The primary endpoint was achieved in three (3.0%), one (1.03%), and one (1.19%) patient in the experimental group, control group 2, and control group 1, respectively. The incidence of HBsAg seroconversion at week 48 was not significantly different among the three groups (p = 0.629). However, the decrease in serum levels of HBsAg at week 48 was significantly higher in the experimental and control group 2 compared with that in control group 1 (p = 0.008 and 0.006, respectively). No significant difference between the experimental and control group 2 was observed (p = 0.619). Adverse events were not significantly different among the groups except for the lower incidence of neutropenia in the experimental group. Peg-IFN-α-2b combined with TDF, GM-CSF, and hepatitis B vaccine is not superior to peg-IFN-α-2b combined with TDF in HBeAg-positive naïve patients. Clinical Trials Registration: ChiCTR1800016173.

Flavorubredoxin, a Candidate Trigger Related to Thrombotic Thrombocytopenic Purpura: Screening of the Complete Genome of a Salmonella enterica Serovar Typhimurium Isolate From an AIDS Case.

Thrombotic thrombocytopenic purpura (TTP) is one of the two classic thrombotic microangiopathy (TMA) diseases which could be induced by infections. To the best of our knowledge, this is the first report of an acquired immunodeficiency syndrome (AIDS) patient with acquired TTP induced by infection with Salmonella enterica serovar Typhimurium (hereafter, S. Typhimurium) isolate, S. Typhimurium_zhang, which was confirmed by serology and genetic taxonomy. The literature review identified 17 TMA-related genes encoding the candidate triggers, which were searched in the annotated genome sequence of S. Typhimurium_zhang. Anaerobic nitric oxide reductase flavorubredoxin (FlRd), encoded by norV which is related to another TMA, haemolytic uraemic syndrome (HUS), was found in S. Typhimurium_zhang. Basic local alignment search tool (BLAST) analysis revealed that norV and FlRd in S. Typhimurium_zhang, as well as eight S. Typhimurium type strains, have high identity with HUS-related Escherichia coli O157:H7 strain TW14359. Similar results were obtained from the BLAST analysis of 73 S. enterica isolates for congenital TTP which was also previously reported to be triggered by S. enterica. Phylogenetic analysis and amino acid sequence alignment revealed that FlRd was functional and highly conservative on 69 Enterobacteriaceae, including S. Typimurium_zhang and TW14359. In brief, we found norV in the genome of a S. Typhimurium clinical isolate that induced TTP in an AIDS patient. FlRd, the protein encoded by norV, probably triggered the TTP and was highly conservative, functional, and widespread in S. enterica and Enterobacteriaceae. More in vitro and in vivo studies are required to confirm our findings and determine the underlying mechanism.

Predicting the Risk of Postoperative Complications of Schwannoma Surgery: Development and Assessment of a New Predictive Nomogram.

BACKGROUND: The aim of this study was to develop and internally validate a risk nomogram for postoperative complications of schwannoma surgery. METHODS: From 2016 to 2020, we reviewed 83 patients who underwent schwannoma resection with a total number of 85 schwannomas. A predictive model was developed based on the dataset of this group. During model construction, univariate and multivariate logistic regression analysis were used to determine the independent predictors of postoperative complications. Assessment of the discriminative function, calibrating proficiency, and clinical usefulness of the predicting model was performed using C-index, calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis. Internal validation was assessed using bootstrapping validation. RESULTS: Predictors contained in the prediction nomogram included age, tumor location, symptoms, and surgical approach. The model displayed satisfying abilities of discrimination and calibration, with a C-index of 0.901 (95% confidence [CI]: 0.837-0.965). A high C-index value of 0.853 was achieved in the interval verification. Decision curve analysis showed that the nomogram was clinically useful when intervention was decided at the complication possibility threshold of 2%. CONCLUSION: This new risk nomogram for postoperative complications of schwannoma surgery has taken age, tumor location, symptoms, and surgical approach into account. It has reasonable predictive accuracy and can be conveniently used. It shall help patients understand the risk of postoperative complications before surgery, and offer guidance to surgeons in deciding on the surgical approach.

PointSite: A Point Cloud Segmentation Tool for Identification of Protein Ligand Binding Atoms.

Accurate identification of ligand binding sites (LBS) on a protein structure is critical for understanding protein function and designing structure-based drugs. As the previous pocket-centric methods are usually based on the investigation of pseudo-surface-points outside the protein structure, they cannot fully take advantage of the local connectivity of atoms within the protein, as well as the global 3D geometrical information from all the protein atoms. In this paper, we propose a novel point clouds segmentation method, PointSite, for accurate identification of protein ligand binding atoms, which performs protein LBS identification at the atom-level in a protein-centric manner. Specifically, we first transfer the original 3D protein structure to point clouds and then conduct segmentation through Submanifold Sparse Convolution based U-Net. With the fine-grained atom-level binding atoms representation and enhanced feature learning, PointSite can outperform previous methods in atom Intersection over Union (atom-IoU) by a large margin. Furthermore, our segmented binding atoms, that is, atoms with high probability predicted by our model can work as a filter on predictions achieved by previous pocket-centric approaches, which significantly decreases the false-positive of LBS candidates. Besides, we further directly extend PointSite trained on bound proteins for LBS identification on unbound proteins, which demonstrates the superior generalization capacity of PointSite. Through cascaded filter and reranking aided by the segmented atoms, state-of-the-art performance can be achieved over various canonical benchmarks, CAMEO hard targets, and unbound proteins in terms of the commonly used DCA criteria.

Inactivated vaccines prevent severe COVID-19 in patients infected with the Delta variant: A comparative study of the Delta and Alpha variants from China.

The Delta variant has gradually replaced the Alpha variant as the major strain of SARS-COV-2 infection worldwide. We extracted the clinical characteristics and outcomes information about 381 hospitalized patients infected with Delta variant and compared them with 856 patients diagnosed with Alpha variant infection in Zhejiang Province. The majority (85.3%) of patients infected with the Delta variant had received inactivated vaccine. The patients' condition was generally mild. Most of them were mild (35.7%) and common (62.7%) types. Only six patients (1.5%) were severe/critical types. During the follow-up period, patients infected with the Delta variant had longer hospital stays than the Alpha variant (24 [21-26] vs. 18 [14-24], p < 0.001). In addition, the unvaccinated patients infected with the Delta variant had a higher proportion of severe/critical cases than vaccinated patients (11.11% vs. 0.92%, p = 0.024) and a higher usage rate of glucocorticoids (38.89 vs. 14.77%, p = 0.017) and antibiotics (55.56% vs. 32.31%, p = 0.042) during hospitalization. The vaccine's efficacy against severe COVID-19 did not diminish over time for patients who received two doses of the inactivated vaccine. The disease types and clinical manifestations were generally mild in patients infected with the Delta variant, possibly associated with widespread vaccination with inactivated vaccines in China.

Probiotic Lactobacillus casei Shirota prevents acute liver injury by reshaping the gut microbiota to alleviate excessive inflammation and metabolic disorders.

Millions of people die from liver diseases annually, and liver failure is one of the three major outcomes of liver disease. The gut microbiota plays a crucial role in liver diseases. This study aimed to explore the effects of Lactobacillus casei strain Shirota (LcS), a probiotics used widely around the world, on acute liver injury (ALI), as well as the underlying mechanism. Sprague Dawley rats were intragastrically administered LcS suspensions or placebo once daily for 7 days before induction of ALI by intraperitoneal injection of D-galactosamine (D-GalN). Histopathological examination and assessments of liver biochemical markers, inflammatory cytokines, and the gut microbiota, metabolome and transcriptome were conducted. Our results showed that pretreatment with LcS reduced hepatic and intestinal damage and reduced the elevation of serum gamma-glutamyltranspeptidase (GGT), total bile acids, IL-5, IL-10, G-CSF and RANTES. The analysis of the gut microbiota, metabolome and transcriptome showed that LcS lowered the ratio of Firmicutes to Bacteroidetes; reduced the enrichment of metabolites such as chenodeoxycholic acid, deoxycholic acid, lithocholic acid, d-talose and N-acetyl-glucosamine, reduce the depletion of d-glucose and l-methionine; and alleviated the downregulation of retinol metabolism and PPAR signalling and the upregulation of the pyruvate metabolism pathway in the liver. These results indicate the promising prospect of using LcS for the treatment of liver diseases, particularly ALI.

Dynamic metabolic profiles for HBeAg seroconversion in chronic hepatitis B (CHB) patients by gas chromatography-mass spectrometry (GC-MS).

Chronic hepatitis B (CHB) remains a major public health problem globally. HBeAg seroconversion is a vital hallmark for the improvement of CHB. The plasma metabolic profile has not been clear in CHB patients and searching metabolic candidates to represent HBeAg seroconversion is also difficult currently. In this study, CHB patients were recruited, followed and divided into the HBeAg-positive (HBeAg-pos.) group (n = 29) and the HBeAg-negative (HBeAg-neg.) group (n = 29) based on HBeAg seroconversion or not. The plasma metabolic profiles were measured by gas chromatography-mass spectrometry (GC-MS) at 0 week (0w), 24 weeks (24w) and 48 weeks (48w) after administration. The acquired data was analyzed using orthogonal partial least squares discriminate analysis (OPLS-DA) and the differential metabolites were further assessed by self and group comparison. No differences of age, gender and serological characteristics were observed between two groups at 0w and 48w separately. The OPLS-DA score plots depending on administration time displayed robust metabolic differences no matter HBeAg turned to be negative or not. According to VIP> 1.0, a total of 15 differential metabolites were same in the two groups, 7 differential metabolites (glycolic acid, D-talose, L-proline, L-(-)-arabitol, ethyl-alpha-D-glucopyranoside, L-leucine and dihydroxybutanoic acid) were derived from one group alone and considered as metabolic candidates. At 0w versus (vs.) 24w, only 3 of 7 candidates (L-proline, L-(-)-arabitol, dihydroxybutanoic acid) showed nonuniform in the two groups, while at 0w vs. 48w, all of them varied inconsistently. Conclusively the dynamic metabolic profiles assayed by GC-MS were different between CHB patients with and without HBeAg seroconversion. The 7 metabolic candidates probably had the ability to reflect the CHB progression for HBeAg seroconversion and 3 of them showed strong relationship with HbeAg seroconversion early.

The Salivary Microbiota of Patients With Primary Biliary Cholangitis Is Distinctive and Pathogenic.

The role of host-microbiota interactions in primary biliary cholangitis (PBC) has received increased attention. However, the impact of PBC on the oral microbiota and contribution of the oral microbiota to PBC are unclear. In this study, thirty-nine PBC patients without other diseases and 37 healthy controls (HCs) were enrolled and tested for liver functions and haematological variables. Saliva specimens were collected before and after brushing, microbiota was determined using 16S rDNA sequencing, metabolomics was profiled using Gas Chromatography-Mass Spectrometer (GC-MS), 80 cytokines were assayed using biochips, and inflammation inducibility was evaluated using OKF6 keratinocytes and THP-1 macrophages. Finally, the effect of ultrasonic scaling on PBC was estimated. Compared with HCs, PBC saliva had enriched taxa such as Bacteroidetes, Campylobacter, Prevotella and Veillonella and depleted taxa such as Enterococcaceae, Granulicatella, Rothia and Streptococcus. PBC saliva also had enriched sCD163, enriched metabolites such as 2-aminomalonic acid and 1-dodecanol, and depleted metabolites such as dodecanoic acid and propylene glycol. sCD163, 4-hydroxybenzeneacetic acid and 2-aminomalonic acid were significantly correlated with salivary cytokines, bacteria and metabolites. Salivary Veillonellaceae members, 2-aminomalonic acid, and sCD163 were positively correlated with liver function indicators such as serum alkaline phosphatase (ALP), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PBC salivary microbes induced more soluble interleukin (IL)-6 receptor α (sIL-6Rα), sIL-6Rß and tumour necrosis factor ligand superfamily (TNFSF)13B from OKF6 keratinocytes, and PBC salivary supernatant induced more IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine (C-C motif) ligand (CCL)13, C-X-C motif chemokine (CXC)L1 and CXCL16 from THP-1 macrophages. Toothbrushing significantly reduced the expression of inflammatory cytokines such as IL-1ß, IL-8 and TNF-α and harmful metabolites such as cadaverine and putrescine in PBC but not HC saliva after P-value correction. The levels of ALP and bilirubin in PBC serum were decreased after ultrasonic scaling. Together, PBC patients show significant alterations in their salivary microbiota, likely representing one cause and treatment target of oral inflammation and worsening liver functions.

Preliminary Assessment of Chinese Strategy in Controlling Reemergent Local Outbreak of COVID-19.

Reemergent local outbreaks of coronavirus disease 2019 (COVID-19) have occurred in China, yet few Chinese response strategies and its evaluation have been reported. This study presents a preliminary assessment of Chinese strategy in controlling reemergent local outbreaks of COVID-19. Time course of accumulative and daily new cases and time-varying reproductive numbers (Rt) of outbreak areas were presented. The asymptomatic rate, days required to control the outbreaks, seeding time (ST), and doubling time (DT) of areas with over 96 reemergent cases were calculated. National and local year-on-year growth rates of gross domestic product (GDP) were presented. Accumulative numbers of 30, 8, 11, 430, 15, 139, 1,067, 382, 42, and 94 confirmed reemergent COVID-19 cases were diagnosed in Hulun Buir, Shanghai, Tianjin, Kashgar, Qingdao, Dalian, Urumchi, Beijing, Jilin, and Harbin, respectively. Among them, maximum rate of asymptomatic infections was 81.9%. Time required to control the local outbreaks in the areas given above varied from 29 to 51 days. After activation of outbreak responses, the late-stage DTs of Kashgar, Urumchi, Beijing, and Dalian were apparently lengthened compared to the early-stage DTs. Although the year-on-year GDP growth rate of Urumchi was slightly affected, the GDP growth rate of Dalian, Beijing, Jilin, and Harbin kept rising during the reemergence. Moreover, the year-on-year GDP growth rate of Mainland China turned positive regardless of the reemergent local outbreaks. In general, the Chinese strategy to maintain the status of no or minimal transmission was effective in balancing the control of COVID-19 reemergent local outbreak and the recovery of economy.

Case Report: Proven Diagnosis of Culture-Negative Chronic Disseminated Candidiasis in a Patient Suffering From Hematological Malignancy: Combined Application of mNGS and CFW Staining.

Chronic disseminated candidiasis (CDC) is a severe complication with high morbidity and mortality in patients with hematological malignancies who have undergone chemotherapy. Blood or sterile liver biopsy cultures are negative due to recurrent empirical antifungal therapy. With the escalating resistance to azole-based antifungal drugs in infection by Candida species, pathogen identification is becoming increasingly important for determining definitive diagnosis and treatment strategy. In this case report, we present, for the first time, diagnostic confirmation of a culture-negative CDC case with Candida tropicalis infection using a combination of metagenomics next-generation sequencing and calcofluor white staining.

The serum metabolome of COVID-19 patients is distinctive and predictive.

BACKGROUND: Metabolism is critical for sustaining life, immunity and infection, but its role in COVID-19 is not fully understood. METHODS: Seventy-nine COVID-19 patients, 78 healthy controls (HCs) and 30 COVID-19-like patients were recruited in a prospective cohort study. Samples were collected from COVID-19 patients with mild or severe symptoms on admission, patients who progressed from mild to severe symptoms, and patients who were followed from hospital admission to discharge. The metabolome was assayed using gas chromatography-mass spectrometry. RESULTS: Serum butyric acid, 2-hydroxybutyric acid, l-glutamic acid, l-phenylalanine, l-serine, l-lactic acid, and cholesterol were enriched in COVID-19 and COVID-19-like patients versus HCs. Notably, d-fructose and succinic acid were enriched, and citric acid and 2-palmitoyl-glycerol were depleted in COVID-19 patients compared to COVID-19-like patients and HCs, and these four metabolites were not differentially distributed in non-COVID-19 groups. COVID-19 patients had enriched 4-deoxythreonic acid and depleted 1,5-anhydroglucitol compared to HCs and enriched oxalic acid and depleted phosphoric acid compared to COVID-19-like patients. A combination of d-fructose, citric acid and 2-palmitoyl-glycerol distinguished COVID-19 patients from HCs and COVID-19-like patients, with an area under the curve (AUC) > 0.92 after validation. The combination of 2-hydroxy-3-methylbutyric acid, 3-hydroxybutyric acid, cholesterol, succinic acid, L-ornithine, oleic acid and palmitelaidic acid predicted patients who progressed from mild to severe COVID-19, with an AUC of 0.969. After discharge, nearly one-third of metabolites were recovered in COVID-19 patients. CONCLUSIONS: The serum metabolome of COVID-19 patients is distinctive and has important value in investigating pathogenesis, determining a diagnosis, predicting severe cases, and improving treatment.