Clinical characteristics and antimicrobial susceptibility profiles of Mycobacterium abscessus and Mycobacterium massiliense pulmonary infection.

INTRODUCTION: Mycobacterium abscessus complex (MABC) is the most common rapidly growing Mycobacterium species in structural pulmonary diseases and can be life-threatening. This study aimed to assess the clinical characteristics and drug susceptibility statuses of different Mycobacterium abscessus (MAB) subspecies. METHODS: DNA sequencing was used to differentiate clinical MABC subspecies isolates. The Clinical and Laboratory Standards Institute guidelines were used to determine vitro susceptibility of imipenem-relebactam, omadacycline, and other conventional antibiotics. Patient's clinical characteristics were collected and analysed. RESULTS: There were 139 M. abscessus, 39 M. massiliense, and 1 M. bolletii, accounting for 77.7%, 21.8%, and 0.5% of the MABC isolates, respectively. Patients with M. abscessus pulmonary disease (M.ab-PD) had higher proportions of older adults, tuberculosis history, chronic pulmonary disease, and malignancy than those with M. massiliense pulmonary disease (M.ma-PD). Patients with M.ab-PD had higher rates of bilateral middle- and lower-lobe involvement than patients with M.ma-PD. Both subspecies showed high resistance rates to doxycycline and moxifloxacin, and clarithromycin-induced resistance was more common in M.ab than in M.ma. Relebactam with imipenem resulted in a 2-fold reduction in the minimum inhibitory concentration (MIC) value compared to imipenem alone among MAB; furthermore, the MIC was lower in M.ab than in M.ma. Omadacycline and tigecycline had comparable in vitro susceptibility, and the MIC showed no statistically significant difference between M.ab and M.ma. CONCLUSIONS: M.ab is the most prevalent MABC subspecies in the Zhejiang Province. Patients with M.ab-PD have complex underlying diseases and broader lobar lesions. Imipenem-relebactam and omadacycline are promising antibiotics for MABC infection treatment.

Psoralea corylifolia L. and its active component isobavachalcone demonstrate antibacterial activity against Mycobacterium abscessus.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. (Fabaceae) is a traditional medicinal herb used to treat various diseases, including kidney disease, asthma, psoriasis and vitiligo. AIM OF THE STUDY: To explore the antibacterial activity of Psoralea corylifolia L. and its bioactive components against Mycobacterium abscessus (M. abscessus). MATERIALS AND METHODS: Ultra high performance liquid chromatography was utilized to analyze the bioactive fractions and compounds present in 30%, 60%, and 90% ethanol extracts of Psoralea corylifolia L.. The antibacterial effects of Psoralea corylifolia L. and potential active ingredients were determined by minimum inhibitory concentration (MIC). The bactericidal activity of the active ingredient isobavachalcone was evaluated and then scanning electron microscopy was used to explore the bactericidal mechanism of isobavachalcone. RESULTS: The 90% ethanol extracts of Psoralea corylifolia L. showed significant antibacterial activity against M. abscessus, with an MIC of 156 µg/mL. Isobavachalcone was identified as the bioactive ingredient, and testing of 118 clinical isolates of M. abscessus indicated their MICs ranged from 2 to 16 µg/mL, with an average MIC of 8 µg/mL. Furthermore, the minimum bactericidal concentration/MIC ratio and the time-kill test indicated rapid bactericidal activity of isobavachalcone against M. abscessus. Finally, we found that the bactericidal mechanism of isobavachalcone involved damage to the bacterial cell membrane, causing wrinkled and sunken cell surface and a noticeable reduction in bacterial length. CONCLUSION: Psoralea corylifolia L. ethanol extracts as well as its active component isobavachalcone show promising antimicrobial activity against M. abscessus.

Identification of essential oils with strong activity against stationary phase Mycobacterium abscessus.

Purpose: To identify essential oils (EOs) active against non-growing stationary phase Mycobacterium abscessus and multidrug-resistant M. abscessus strains. Methods: The activity of EOs against both stationary and log phase M. abscessus was evaluated by colony forming unit (CFU) assay and minimum inhibitory concentration (MIC) testing. Results: We assessed the activity of 80 EOs against stationary phase M. abscessus and found 12 EOs (Cinnamon, Satureja montana, Palmarosa, Lemon eucalyptus, Honey myrtle, Combava, Health shield, Mandarin, Thyme, Rosewood, Valerian Root and Basil) at 0.5% concentration to be active against both growing and non-growing stationary phase M. abscessus. Among them, Satureja montana essential oil and Palmarosa essential oil could eliminate all stationary phase M. abscessus at 0.125% and Cinnamon essential oil could eliminate stationary phase bacteria at 0.063% after 1-day treatment. Interestingly, these EOs also exhibited promising activity against multidrug-resistant M. abscessus clinical strains. Conclusions: Our study indicates that some EOs display outstanding effectiveness against both drug susceptible M. abscessus and multidrug-resistant M. abscessus isolates. These findings may be significant for the treatment of persistent M. abscessus infections.

The type III secretion system facilitates systemic infections of Pseudomonas aeruginosa in the clinic.

IMPORTANCE: The identification of decisive virulence-associated genes in highly pathogenic P. aeruginosa isolates in the clinic is essential for diagnosis and the start of appropriate treatment. Over the past decades, P. aeruginosa ST463 has spread rapidly in East China and is highly resistant to ß-lactams. Given the poor clinical outcome caused by this phenotype, detailed information regarding its decisive virulence genes and factors affecting virulence expression needs to be deciphered. Here, we demonstrate that the T3SS effector ExoU has toxic effects on mammalian cells and is required for virulence in the murine bloodstream infection model. Moreover, a functional downstream SpcU is required for ExoU secretion and cytotoxicity. This work highlights the potential role of ExoU in the pathogenesis of disease and provides a new perspective for further research on the development of new antimicrobials with antivirulence ability.

Concentration of contezolid in cerebrospinal fluid and serum in a patient with tuberculous meningoencephalitis: A case report.

Central nervous system (CNS) tuberculosis (TB) is a devastating and often life-threatening disease caused by Mycobacterium tuberculosis. Contezolid, a new oxazolidinone, has demonstrated potent antimycobacterial activity in both in-vivo and in-vitro studies, with lower toxicity than linezolid. However, pharmacokinetic data are still not available for contezolid in the CNS of patients with CNS TB. This article reports the steady-state concentrations of contezolid in serum and cerebrospinal fluid (CSF) of a patient receiving contezolid as part of multi-drug treatment for tuberculous meningoencephalitis. At weeks 7 and 11 (7 h post-dose) after initiation of contezolid therapy, the serum concentrations of contezolid were 9.64 mg/L and 9.36 mg/L, respectively. In CSF, the observed concentrations of contezolid were 0.54 mg/L and 1.15 mg/L, respectively. The CSF:serum concentration ratios were 0.056 and 0.123 at weeks 7 and 11, respectively. The observed concentrations in CSF were above the minimum inhibitory concentration of contezolid against M. tuberculosis, and were close to the estimated serum unbound fraction of contezolid (10%), suggesting that unbound contezolid has high CSF permeability.

Resynchronized rhythmic oscillations of gut microbiota drive time-restricted feeding induced nonalcoholic steatohepatitis alleviation.

With the drive of the endogenous circadian clock and external cues such as feeding behavior, the microbial community generates rhythmic oscillations in composition and function. Microbial oscillations are crucial in orchestrating host metabolic homeostasis during the predictable 24-hour diurnal cycle. A time-restricted feeding (TRF) regimen is a promising dietary strategy to optimize energy utilization, alleviate metabolic syndrome and reinforce microbial cyclical fluctuations. However, the causative relationship between reinforced microbial rhythmicity and TRF-induced metabolic improvement remains elusive. In this study, we corroborated that the TRF regimen notably alleviated obesity and nonalcoholic steatohepatitis (NASH) with reinstated rhythmicity of genera such as Lactobacillus, Mucispirillum, Acetatifactor, and Lachnoclostridium. The reshaped microbial oscillations correlate with cyclical fluctuations in intestinal amino acids. Furthermore, fecal microbiota transplantation (FMT) indicated that only the TRF feeding phase-derived microbiota, but not the TRF fasting phase-derived microbiota, could protect mice from NASH and reinstate microbial rhythmicity, confirming that the microbiota improved NASH in a time-of-day-specific manner. The unique role of the TRF-feeding phase-derived microbiota was accompanied by regulation of the serotonergic synapse pathway and rejuvenation of the microbial production of indole derivatives. Our results revealed the discrepant characteristics between the feeding and fasting phases and the time-of-day-specific configuration of microbiota functionality in the TRF regimen.

Randomized control study of the use of faropenem for treating patients with pulmonary tuberculosis.

OBJECTIVES: Faropenem has antituberculosis activity in vitro but its utility in treating patients with tuberculosis (TB) is unclear. METHODS: We conducted an open-label, randomized trial in China, involving newly diagnosed, drug-susceptible pulmonary TB. The control group was treated with the standard 6-month regimen. The experimental group replaced ethambutol with faropenem for 2 months. The primary outcome was the treatment success rate after 6 months of treatment. Noninferiority was confirmed if the lower limit of a 95% one-sided confidence interval (CI) of the difference was greater than -10%. RESULTS: A total of 227 patients eligible for the study were enrolled in the trial group and the control group in a ratio of 1:1. Baseline characteristics of participants were similar in both groups. In the modified intention-to-treat population, 88.18% of patients in the faropenem group achieved treatment success, and 85.98% of those in the control group were successfully treated, with a difference of 2.2% (95% CI, -6.73-11.13). In the per-protocol population, treatment success was 96.04% in the faropenem group and 95.83% in the control group, with a difference of 2.1% (95% CI, -5.31-5.72). The faropenem group showed noninferiority to the control group in the 6-month treatment success rates. The faropenem group had significantly fewer adverse events (P <0.01). CONCLUSIONS: Our study proved that oral faropenem regimen can be used for the treatment of TB, with fewer adverse events. (Chinese Clinical Trial Registry, ChiCTR1800015959).

A case of severe leptospirosis with Jarisch-Herxheimer reaction presenting as respiratory failure.

Background: Leptospirosis is a widespread zoonotic disease caused by pathogenic Leptospira spp. The treatment of penicillin or tetracycline can cause a Jarisch-Herxheimer reaction (JHR), which can lead to acute respiratory distress syndrome (ARDS) and multi-organ failure in severe cases. The overall course of evolution and imaging features of a JHR exacerbation of leptospirosis have rarely been reported. Case presentation: We present a case of leptospirosis complicated by pulmonary alveolar hemorrhage and a Jarisch-Herxheimer reaction (JHR) that required respiratory and vasopressor support. This case demonstrates a well-defined course of evolution of JHR and the imaging features. Conclusions: Leptospirosis is easily misdiagnosed in some sporadic areas, and JHR complicates its management. Early diagnosis and appropriate treatment can reduce the mortality of severe leptospirosis with JHR.

Impact of cirrhosis-related complications on posttransplant survival in patients with acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome defined as acute decompensation in patients with chronic liver disease. Liver transplantation (LT) is the most effective treatment. We aimed to assess the impact of cirrhosis-related complications pre-LT on the posttransplant prognosis of patients with ACLF. METHODS: This was an observational cohort study conducted between January 2018 and December 2020. Clinical characteristics, cirrhosis-related complications at LT and patient survival post-LT were collected. All liver recipients with ACLF were followed for 1 year post-LT. RESULTS: A total of 212 LT recipients with ACLF were enrolled, including 75 (35.4%) patients with ACLF-1, 64 (30.2%) with ACLF-2, and 73 (34.4%) with ACLF-3. The median waiting time for LT was 11 (4-24) days. The most prevalent cirrhosis-related complication was ascites (78.8%), followed by hepatic encephalopathy (57.1%), bacterial infections (48.1%), hepatorenal syndrome (22.2%) and gastrointestinal bleeding (11.3%). Survival analyses showed that patients with complications at LT had a significantly lower survival probability at both 3 months and 1 year after LT than those without complications (all P < 0.05). A simplified model was developed by assigning one point to each complication: transplantation for ACLF with cirrhosis-related complication (TACC) model. Risk stratification of TACC model identified 3 strata (≥ 4, = 3, and ≤ 2) with high, median and low risk of death after LT (P < 0.001). Moreover, the TACC model showed a comparable ability for predicting the outcome post-LT to the other four prognostic models (chronic liver failure-consortium ACLF score, Chinese Group on the Study of Severe Hepatitis B-ACLF score, model for end-stage liver disease score and Child-Turcotte-Pugh score). CONCLUSIONS: The presence of cirrhosis-related complications pre-LT increases the risk of death post-LT in patients with ACLF. The TACC model based on the number of cirrhosis-related complications pre-LT could stratify posttransplant survival, which might help to determine transplant timing for ACLF.

A Current Noise Cancellation Method Based on Fractional Linear Prediction for Bearing Fault Detection.

The stator current in an induction motor contains a large amount of information, which is unrelated to bearing faults. This information is considered as the noise component for the detection of bearing faults. When there is noise information in the current signal, it can affect the detection of motor bearing faults and lead to the possibility of false alarms. Therefore, to accomplish an effective bearing fault detection, all or some of these noise components must be properly eliminated. This paper proposes the use of fractional linear prediction (FLP) as a noise elimination method in bearing fault diagnosis, which makes these noise components the predictable components and this bearing fault information the unpredictable components. The basis of the FLP is to eliminate noise components in the current signal by predicting predictable components through linear prediction theory and optimal prediction order. Meanwhile, this paper adopts the FLP model with limited memory samples. After determining the optimal number of memories, only the fractional derivative order parameter needs to be optimized, which greatly reduces the computational complexity and difficulty in parameter optimization. In addition, this paper uses spectral analysis of the current signals through experimental simulation to compare the FLP method with the linear prediction (LP) method and the time-shifting (TS) method that have been successfully applied to bearing fault diagnosis. Based on the analysis results, the FLP method can better extract fault features and achieve better bearing fault diagnosis results, verifying the effectiveness and superiority of the FLP method in the field of bearing fault diagnosis. Additionally, the predictive performance of thevFLP and LP was compared based on experimental data, verifying the advantages of the FLP method in predictive performance, indicating that this method has a better noise cancellation effect.

Oral Bacteria Dysbiosis in Patients with Linezolid-Induced Black Hairy Tongue: A Case Series.

Linezolid-induced black hairy tongue is a self-limiting benign disease that is rare. Here, we report three patients who developed black hairy tongue after linezolid treatment. The severe dysbiosis of oral bacterial communities was observed in all these patients. Proteobacteria was the most prevalent phylum (over 90%) at the black tongue stage. Furthermore, the dramatic oral bacterial alteration took a long time to reverse after the BHT resolved.

T-SPOT with CT image analysis based on deep learning for early differential diagnosis of nontuberculous mycobacteria pulmonary disease and pulmonary tuberculosis.

OBJECTIVES: This study aimed to establish a diagnostic algorithm combining T-SPOT with computed tomography image analysis based on deep learning (DL) for early differential diagnosis of nontuberculous mycobacteria pulmonary disease (NTM-PD) and pulmonary tuberculosis (PTB). METHODS: A total of 1049 cases were enrolled, including 467 NTM-PD and 582 PTB cases. A total of 320 cases (160 NTM-PD and 160 PTB) were randomized as the testing set and were analyzed using T-SPOT combined with the DL model. The testing cases were first divided into T-SPOT-positive and -negative groups, and the DL model was then used to separate the cases into four subgroups further. RESULTS: The precision was found to be 91.7% for the subgroup of T-SPOT-negative and DL classified as NTM-PD, and 89.8% for T-SPOT-positive and DL classified as PTB, which covered 66.9% of the total cases, compared with the accuracy rate of 80.3% of T-SPOT alone. In the other two remaining groups, where the T-SPOT prediction was inconsistent with the DL model, the accuracy was 73.0% and 52.2%, separately. CONCLUSION: Our study shows that the new diagnostic system combining T-SPOT with DL based computed tomography image analysis can greatly improve the classification precision of NTM-PD and PTB when the two methods of prediction are consistent.

Aortic Involvement in Disseminated Tuberculosis - Challenges Beyond the Diagnosis.

Tuberculous aortitis (TA) is a rare disease with a high mortality rate. Aortic pseudoaneurysm is the most common vascular pattern of TA, and isolated arterial wall thickening and arterial stenosis can also be seen in TA. We report two cases of disseminated tuberculosis involving the aorta with clinical improvement after treatment. One patient who had an aortic ulcer and intermural hematoma received anti-tuberculosis along with steroids therapy. The other patient, who developed a tubercular abdominal aortic pseudoaneurysm during anti-tuberculosis therapy, successfully received endovascular stent implantation. Clinicians should be aware that TA should be considered in patients with aortitis and active tuberculosis.

Prevalence trends of latent tuberculosis infection at the global, regional, and country levels from 1990-2019.

OBJECTIVES: To track the prevalence trends of latent tuberculosis infection (LTBI) at the global, regional, and national levels. METHODS: Data on the prevalence of LTBI were extracted from the Global Burden of Disease database. The average annual percent change (AAPC) was estimated by joinpoint regression and was used to evaluate the epidemic of the disease. RESULTS: Globally, the prevalence rate of LTBI decreased from 30.66% in 1990 to 23.67% in 2019, with an AAPC of -0.9%. The prevalence rate of LTBI varied from 5.02% (Jordan) to 48.35% (Uganda) in 1990 and from 2.51% (Jordan) to 43.75% (Vietnam) in 2019 at the country level. The prevalence decreased in all the six World Health Organization (WHO) regions and in most countries, with the AAPC ranging from -0.5% in the Western Pacific Region to -2.1% in the European Region and from -4.3% (Bhutan) to -0.1% (Malaysia, Myanmar, South Africa, Tokelau, and Vietnam), respectively. Disparities were also observed among different sex and age groups. CONCLUSION: The prevalence of LTBI decreased slightly worldwide in the last three decades, but the decrease is slow and not sufficient to meet the targets of WHO tuberculosis elimination. Much more effort and progress should be made in order to decrease the prevalence of LTBI.

Delayed Clearance of Viral RNA in Sputum for Severity COVID-19 Patients with Initial High Viral Load.

Aim: To analyze the possible risk factors of delayed virus clearance in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: Retrospective analysis of patients with COVID-19 admitted to the isolation wards from our hospital from 19th Jan 2020 to 18th March 2020. We were collected patient's data including demographic, epidemiologic, and clinical information, as well as laboratory and radiologic findings. The possible confounding risk factors for prolonged viral RNA shedding of COVID-19 during hospitalization were explored by univariate analysis and any variables with a p value less than 0.05 after univariate analysis were included in a subsequent multivariate logistic regression model analysis. Results: The 104 patients included 30 mild patients and 74 severe or critically ill patients. The median duration of viral RNA positivity in sputum was 11 days, and the longest duration of viral RNA positivity was 49 days after admission. Multivariate analysis shown that the used with darunavir/cobicistat treatment (odds ratio [OR]: 4.25, 95% confidence interval [CI]: 1.25-14.42, p = 0.020), duration of fever (OR: 1.15, 95% CI: 1.03-1.30, p = 0.015) and time to radiological improvement (OR: 1.14, 95% CI: 1.01-1.30, p = 0.033) were associated with delayed clearance of SARS-CoV-2 in sputum from COVID-19 patients. Then adjusted in the multivariate binary logistic regression analysis model in severe COVID-19 and found that critical COVID-19 patients (OR: 13.25, 95% CI: 1.45-12.07, p = 0.022), lower virus cycle threshold (CT) values of RT-PCR (OR: 0.96, 95% CI: 0.93-0.99, p = 0.004) and used with darunavir/cobicistat treatment (OR: 8.44, 95% CI: 2.21-32.28, p = 0.022) were associated with delayed clearance of SARS-CoV-2 in sputum from COVID-19 patients. Conclude: Clearance of viral RNA in sputum was delayed in severe COVID-19 patients, especially with lower virus CT value. And antivirals with darunavir/cobicistat has little advantage in eliminating SARS-CoV-2.

Epidemic Trends in High Tuberculosis Burden Countries During the Last Three Decades and Feasibility of Achieving the Global Targets at the Country Level.

Objective: To estimate the epidemic trends of tuberculosis (TB) in 30 high burden countries (HBCs) over the past 30 years, which is crucial for tracking the status of disease control, especially at the country level. Methods: Annual data on incidence and mortality of TB in these 30 HBCs were extracted from the Global Burden of Disease database. The average annual percent change (AAPC) was used to evaluate the trends of incidence and mortality. The trajectory analysis was used to identify different trends among the subgroup countries. The predicted incidence and mortality rates in 2025, 2030, and 2035 were also calculated. Results: The incidence and mortality decreased in most of the HBCs. The AAPCs of incidence ranged between -4.0 (Indonesia) and -0.2% (DR Congo) (all p < 0.05). The incidence trends in Lesotho (AAPC: 0%, 95% CI: -0.4, 0.3, p = 0.8) and South Africa (AAPC: -0.2%, 95% CI: -0.5, 0, p = 0.1) were stable, and increased in Kenya with AAPC of 0.1% (95% CI: 0.1, 0.2, p < 0.05). The AAPCs for mortality ranged between -5.8 (Ethiopia) and -0.6% (Central African Republic) (all p < 0.05). The mortality trends in DPR Korea (AAPC: 0.1%, 95% CI: -0.3, 0.4, p = 0.6) and Russian Federation (AAPC: -0.5%, 95% CI: -1.9, 0.9, p = 0.5) were stable, and increased in Lesotho and Zimbabwe with AAPC of 1.3% (95% CI: 1.1, 1.4, p < 0.05) and 1.6% (95% CI: 1.0, 2.2, p < 0.05), respectively. Trajectory analysis showed that the Central African Republic, Lesotho, Cambodia, Namibia, and South Africa had higher incidences, and the Central African Republic had higher mortality. Brazil and China had relatively lower rates of incidence and mortality. Predictions showed that reduction rates of incidence and mortality could hardly be reached compared with those set for the global targets for the majority HBCs. Conclusions: The disease burden of TB has been reduced among the majority HBCs over the last three decades. According to the current control levels, achieving the ambitious global targets at the country level for these 30 HBCs is challenging.

Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism.

The gut microbiota drives individual sensitivity to excess acetaminophen (APAP)-mediated hepatotoxicity. It has been reported that the bacterium Akkermansia muciniphila protects hosts against liver disease via the liver-gut axis, but its therapeutic potential for drug-induced liver injury remains unclear. In this study, we aimed to investigate the effect of A. muciniphila on APAP-induced liver injury and the underlying mechanism. Administration of A. muciniphila efficiently alleviated APAP-induced hepatotoxicity and reduced the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). A. muciniphila significantly attenuated APAP-induced oxidative stress and the inflammatory response, as evidenced by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, enhanced superoxide dismutase (SOD) activity, reduced proinflammatory cytokine production, and alleviation of macrophage and neutrophil infiltration. Moreover, A. muciniphila maintained gut barrier function, reshaped the perturbed microbial community and promoted short-chain fatty acid (SCFA) secretion. The beneficial effects of A. muciniphila were accompanied by alterations in hepatic gene expression at the transcriptional level and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results suggested that A. muciniphila could be a potential pretreatment for APAP-induced liver injury. IMPORTANCE Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

A novel prognostic model based on single-cell RNA sequencing data for hepatocellular carcinoma.

BACKGROUND: The tumour heterogeneous make-up of immune cell infiltrates is a key factor for the therapy response and prognosis of hepatocellular carcinoma (HCC). However, it is still a major challenge to comprehensively understand the tumour immune microenvironment (TIME) at the genetic and cellular levels. METHODS: HCC single-cell RNA sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) database, and gene expression data were retrieved from The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was performed to evaluate the abundance of immune infiltrating cells. We employed weighted gene coexpression network analysis (WGCNA) to construct a gene coexpression network. Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses were further used to construct a risk model. Moreover, the expression levels of model genes were assessed by qPCR. RESULTS: We defined 25 cell clusters based on the scRNA-seq dataset (GSE149614), and the clusters were labelled as various cell types by marker genes. Then, we constructed a weighted coexpression network and identified a total of 6 modules, among which the brown module was most highly correlated with tumours. Moreover, we found that the brown module was most closely related to monocytes (cluster 21). Through univariate Cox and LASSO analyses, we constructed a 3-gene risk model (RiskScore = 0.257*Expression CSTB + 0.263* Expression TALDO1 + 0.313* Expression CLTA). This risk model showed excellent predictive efficacy for prognosis in the TCGA-LIHC and ICGC cohorts. Additionally, patients with high risk scores were found to be less likely to benefit from immunotherapy. CONCLUSIONS: We developed a 3-gene signature (including CLTA, TALDO1 and CSTB) based on the heterogeneity of the TIME to predict the survival outcome and immunotherapy response.

A Predictive Nomogram for Predicting Improved Clinical Outcome Probability in Patients with COVID-19 in Zhejiang Province, China.

The aim of this research was to develop a quantitative method for clinicians to predict the probability of improved prognosis in patients with coronavirus disease 2019 (COVID-19). Data on 104 patients admitted to hospital with laboratory-confirmed COVID-19 infection from 10 January 2020 to 26 February 2020 were collected. Clinical information and laboratory findings were collected and compared between the outcomes of improved patients and non-improved patients. The least absolute shrinkage and selection operator (LASSO) logistics regression model and two-way stepwise strategy in the multivariate logistics regression model were used to select prognostic factors for predicting clinical outcomes in COVID-19 patients. The concordance index (C-index) was used to assess the discrimination of the model, and internal validation was performed through bootstrap resampling. A novel predictive nomogram was constructed by incorporating these features. Of the 104 patients included in the study (median age 55 years), 75 (72.1%) had improved short-term outcomes, while 29 (27.9%) showed no signs of improvement. There were numerous differences in clinical characteristics and laboratory findings between patients with improved outcomes and patients without improved outcomes. After a multi-step screening process, prognostic factors were selected and incorporated into the nomogram construction, including immunoglobulin A (IgA), C-reactive protein (CRP), creatine kinase (CK), acute physiology and chronic health evaluation II (APACHE II), and interaction between CK and APACHE II. The C-index of our model was 0.962 (95% confidence interval (CI), 0.931-0.993) and still reached a high value of 0.948 through bootstrapping validation. A predictive nomogram we further established showed close performance compared with the ideal model on the calibration plot and was clinically practical according to the decision curve and clinical impact curve. The nomogram we constructed is useful for clinicians to predict improved clinical outcome probability for each COVID-19 patient, which may facilitate personalized counselling and treatment.

Cost-Effectiveness of Hepatitis B Mass Screening and Management in High-Prevalent Rural China: A Model Study From 2020 to 2049.

BACKGROUND: Chronic hepatitis B (CHB) is highly prevalent among adults in rural China and better management of those populations is of vital importance for viral hepatitis elimination. Adult immunization has been the subject of much controversy in previous studies. This study estimates the cost-effectiveness of population-based hepatitis B screening, treatment, and immunization strategy (comprehensive strategy) in rural areas with high prevalence under the national policy of sharp-drop drug prices. METHODS: We constructed a Markov model comparing 4 strategies in a 30-year horizon from the healthcare payer perspective: (1) the conventional pattern; (2) screening and treating infected (treatment); (3) screening and immunizing susceptible individuals (immunization); and (4) the comprehensive strategy. Screening intensity ranged from 50% to 100%. Outcomes were measured by costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), and clinical outcomes. RESULTS: The costs for the conventional pattern, treatment strategy, immunization strategy, and comprehensive strategy were US$ 341, 351, 318, and 323, respectively. In addition, effects were 17.45, 17.57, 17.46, and 17.58 QALYs, respectively. The ICER of the comprehensive strategy was US$ 35/QALY gained at 50% screening intensity and 420 US$/QALY gained at 100%. The net monetary benefit increased with increasing screening intensity and declined after 90%, with the highest value of US$40 693. All new infections and 52.5% mortality could be avoided from 2020 to 2049 if all patients were properly treated and all susceptible individuals were immunized. The results were stable within a wide range of parameters. CONCLUSION: It was cost-effective to implement the mass hepatitis B screening, treatment, and immunization strategy in areas of rural China with high prevalence, and the strategy gained the most net monetary benefit at a screening intensity of 90%. Although it was impractical to fulfill 100% coverage, efforts should be made to obtain more people screened.