Machine learning-based models for advanced fibrosis and cirrhosis diagnosis in chronic hepatitis B patients with hepatic steatosis.

BACKGROUND AND AIMS: The global rise of chronic hepatitis B (CHB) superimposed on hepatic steatosis (HS) warrants non-invasive, precise tools for assessing fibrosis progression. This study leveraged machine learning (ML) to develop diagnostic models for advanced fibrosis and cirrhosis in this patient population. METHODS: Treatment-naive CHB patients with concurrent HS who underwent liver biopsy in ten medical centers were enrolled as a training cohort and an independent external validation cohort (NCT05766449). Six ML models were implemented to predict advanced fibrosis and cirrhosis. The final models, derived from Shapley Additive exPlanations, were compared to Fibrosis-4 Index (FIB-4), Nonalcoholic fatty liver disease Fibrosis Score (NFS), and Aspartate transaminase to platelet ratio index (APRI) using the area under receiver operating characteristic curve (AUROC), and decision curve analysis (DCA). RESULTS: Of 1,198 eligible patients, the random forest (RF) model achieved AUROCs of 0.778 [95% confidence interval (CI) 0.749-0.807] for diagnosing advanced fibrosis (RF-AF model) and 0.777 (95%CI 0.748-0.806) for diagnosing cirrhosis (RF-C model) in the training cohort, and maintained high AUROCs in the validation cohort. In the training cohort, the RF-AF model obtained an AUROC of 0.825 (95% CI 0.787-0.862) in patients with HBV DNA ≥105 IU/ml, and RF-C model had an AUROC of 0.828 (95% CI 0.774-0.883) in female patients. The two models outperformed FIB-4, NFS, and APRI in the training cohort, and also performed well in the validation cohort. CONCLUSION: The RF models provide reliable, non-invasive tools for identifying advanced fibrosis and cirrhosis in CHB patients with concurrent HS, offering a significant advancement in the co-management of the two diseases.

Antiviral therapy response in patients with chronic hepatitis B and fatty liver: A systematic review and meta-analysis.

The impact of concurrent fatty liver (FL) on response to antiviral therapy in chronic hepatitis B (CHB) patients has not been well characterized. We aimed to systematically review and analyse antiviral treatment response in CHB patients with and without FL. We searched PubMed, Embase, Web of Science and the Cochrane Library databases from inception to 31 May 2023 for relevant studies. Biochemical response (BR), complete viral suppression (CVS) and hepatitis B e antigen (HBeAg) seroconversion in CHB patients with FL (CHB-FL) and without FL (non-FL CHB) were compared. In an initial pool of 2101 citations, a total of 10 studies involving 2108 patients were included. After 12 weeks of treatment, CHB-FL patients as compared with non-FL CHB patients had lower BR rate (48.37% [108/227] vs. 72.98% [126/174], p = .04) but similar trend for CVS (36.86% [80/227] vs. 68.81% [114/174], p = .05) and similar rates of HBeAg seroconversion (6.59% [7/103] vs. 7.40% [7/110], p = .89). However, at week 48, there were no statistically significant differences between CHB-FL and non-FL CHB patients in any of the outcomes, including BR (60.03% [213/471] vs. 69.37% [314/717], p = .67), CVS (65.63% [459/746] vs. 73.81% [743/1132], p = .27) and HBeAg seroconversion (10.01% [30/275] vs. 14.06% [65/453], p = .58) with similar findings for week 96. BR rate was lower in CHB-FL patients after 12 weeks of antiviral treatment. However, after a longer follow-up of either 48 or 96 weeks, no statistically significant differences were observed in BR, CVS or HBeAg seroconversion rates between CHB patients with and without FL.

Different minimal alcohol consumption in male and female individuals with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIMS: The relationship between moderate alcohol intake and health outcomes among individuals with metabolic dysfunction-associated fatty liver disease (MAFLD) is complex. Our aim was to investigate the association of minimal alcohol consumption with all-cause and cause-specific mortality among MAFLD individuals of different genders. METHODS: Our study included 2630 MAFLD individuals from the Third National Health and Nutrition Examination Survey. Cox regression analysis was performed to assess the association between alcohol use measures and all-cause and cause-specific mortality. Restricted cubic spline curves were used to evaluate the relationship between alcohol consumption per week and all-cause mortality. RESULTS: In the entire MAFLD cohort, we observed significant disparities in clinical characteristics between male and female individuals with MAFLD. Higher weekly alcohol consumption was significantly associated with all-cause and cause-specific mortality (male, hazard ratios [HRs]: 1.009, 95% CIs: 1.004-1.014; female, HRs: 1.032, 95% CIs: 1.022-1.042). In males with MAFLD, a linear association with all-cause mortality was observed for weekly alcohol consumption (p for non-linearity = .21). Conversely, in females with MAFLD, the risk of all-cause mortality remained relatively stable until 2 drinks per week, after which it rapidly increased with each additional drink consumed, and the increase in mortality risk was higher than that observed in males (p for non-linearity < .05). CONCLUSIONS: Our findings indicate that any increase in weekly alcohol consumption was associated with increased all-cause mortality in men with MAFLD. Conversely, consuming less than 2 drinks per week had minimal impact on the risk of mortality among female.

Modelling phytoplankton-virus interactions: phytoplankton blooms and lytic virus transmission.

A dynamic reaction-diffusion model of four variables is proposed to describe the spread of lytic viruses among phytoplankton in a poorly mixed aquatic environment. The basic ecological reproductive index for phytoplankton invasion and the basic reproduction number for virus transmission are derived to characterize the phytoplankton growth and virus transmission dynamics. The theoretical and numerical results from the model show that the spread of lytic viruses effectively controls phytoplankton blooms. This validates the observations and experimental results of Emiliana huxleyi-lytic virus interactions. The studies also indicate that the lytic virus transmission cannot occur in a low-light or oligotrophic aquatic environment.

Clinical impact of hepatic steatosis on chronic hepatitis B patients in Asia: A systematic review and meta-analysis.

Chronic hepatitis B (CHB) and hepatic steatosis (HS) are two prevalent chronic liver diseases in Asia. The incidence of CHB combined with HS is increasing due to the rising obesity rates. However, the impact of HS on CHB remains a topic of debate. Hereby, this meta-analysis aims to examine the effect of HS on Asian patients with CHB. Searches were conducted on four databases to identify articles published from 2005 to 2023. The random-effects or fixed-effects model was used to calculate pooled odds ratios (ORs), weighted mean difference (WMD), and confidence intervals (CIs) for the included articles. Of the 15,959 records screened, 88 studies were included in the analysis of HS prevalence in Asian CHB patients with a prevalence of 36.5% (95% CI: 33.7%-39.3%). In addition, age, sex, body mass index (BMI), waist circumference (WC), alanine aminotransferase (ALT) and combined metabolic diseases have varying degrees of impact on HS in CHB patients. Furthermore, the coexistence of HS was negatively associated with the response to antiviral therapy, including hepatitis B surface antigen (HBeAg) seroconversion (OR = 0.69, 95% CI: 0.53-0.89) and ALT normalization (OR = 0.75, 95% CI: 0.61-0.92) in CHB patients after 48 weeks of treatment. Regarding disease prognosis, HS was not significantly associated with fibrosis or cirrhosis in CHB patients, while an inverse association was observed between HS and hepatocellular carcinoma (HCC) (OR = 2.93, 95% CI: 1.23-6.99). This implies that the coexistence of HS in CHB patients may exacerbate the progression of HCC, which needs to be verified by further studies.

Alleviated symptoms of SARS-CoV-2 Omicron variant infection in chronic hepatitis B patients with immune control.

The impact of hepatitis B virus (HBV) infection on the progression of coronavirus disease 2019 (COVID-19) disease remains controversial. We aimed to investigate whether pre-existing chronic HBV (CHB) infection and therapy with anti-HBV nucleos(t)ide analogs (NAs) influence the clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant infection. In this study, clinical information was collected via a questionnaire from patients with COVID-19, and their clinical symptoms were quantitatively assessed for comparative analyses. Additionally, hepatitis B-related laboratory data were collected for CHB patients. Propensity score matching (PSM) was used to minimize confounding biases. A total of 785 patients with COVID-19 were included in the cohort, of which 387 were identified as being infected with CHB infection and they were categorized as being in the immune control or clearance phase. After PSM, the CHB group (n = 222) had a shorter duration of fever and disease course, milder clinical symptoms, and lower incidence of pneumonia than the non-CHB group (n = 222) after Omicron variant infection (p < 0.05). After the adjustment of confounding factors, CHB patients showed a lower risk of prolonged fever, severe clinical symptoms, and pneumonia (p < 0.05). However, there were no statistically significant differences in the clinical symptoms and incidence of pneumonia between CHB patients who received and did not receive NAs, or CHB patients who received tenofovir disoproxil fumarate and entecavir (p > 0.05). In conclusion, our findings suggest that the crosstalk of anti-HBV immunity may contribute to the alleviated symptoms of SARS-CoV-2 Omicron variants infection in the CHB patients, independent of anti-HBV NA therapy.

Impact of nonalcoholic fatty liver disease status change on antiviral efficacy of nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B.

Data on the dynamic changes in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD) during antiviral therapy are scarce. We aimed to investigate the evolution of NAFLD status change in CHB patients treated with nucleos(t)ide analogues (NAs) and its influence on therapeutic outcomes. This retrospective study included 164 HBeAg-positive CHB patients from a randomized controlled trial who were treated with NAs for 104 weeks and underwent paired liver biopsies. Histological evaluation was performed at baseline and Week 104. The patients were divided into four groups according to NAFLD status changes. From baseline to Week 104, the overall percentage of CHB patients with concurrent NAFLD increased from 17.1% to 26.2% (p = 0.044). Among them, 7 of 28 patients (25.0%) with NAFLD at baseline showed NAFLD remission at week 104, while 22 of 136 patients (16.2%) without NAFLD at baseline developed new-onset NAFLD. In subgroup analyses, the new-onset and sustained NAFLD groups showed significantly lower rates of biochemical response at week 104 as compared to the sustained non-NAFLD group (77.3% and 57.1% vs. 93.9%, respectively; all p < 0.05), as well as fibrosis improvement (31.8% and 42.9% vs. 69.3%, respectively; all p < 0.05). NAFLD status changes did not influence the virological response, HBeAg seroconversion, and necroinflammation improvement (all p > 0.05). In HBeAg-positive CHB patients receiving NAs therapy, new-onset and sustained NAFLD may counteract the benefits of antiviral therapy, reducing the rate of biochemical response and fibrosis improvement.

Genome-wide meta-analysis identifies susceptibility loci for autoimmune hepatitis type 1.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. APPROACH AND RESULTS: We conducted a case-control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta-analysis was performed to ascertain variants associated with AIH type 1. A single-nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10-73 ). The meta-analysis also identified two non-HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10-9 ) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10-9 ). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10-7 ), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10-7 ), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10-6 ), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10-6 ) had suggestive association signals with AIH. CONCLUSIONS: Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome-wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro-immune interaction in the pathogenesis of AIH.

Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome.

BACKGROUND: CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. CONCLUSION: The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

Association of nonalcoholic fatty liver disease and growth hormone deficiency: a systematic review and meta-analysis.

An association exists between nonalcoholic fatty liver disease (NAFLD) and growth hormone (GH). Patients with growth hormone deficiency (GHD) may be more susceptible to NAFLD. The prevalence of NAFLD and nonalcoholic steatohepatitis (NASH) in GHD patients is currently unknown. Multiple databases were searched for experiments related to NAFLD (or NASH) and GHD. Screening, quality evaluation and data extraction were carried out independently by two authors. Analyses used random or fixed effects models, including NAFLD prevalence, NASH prevalence, odds ratio (OR) and 95% confidence interval (CI). We included 10 studies with a total of 782 participants. The results showed that the prevalence of NAFLD in GHD patients was 51% (95% CI: 39-63). The risk of NAFLD in GHD patients was significantly higher than that in controls (age-, sex- or body mass index-matched, without GHD) (pooled OR = 4.27, 95% CI: 1.33-13.68%, p = 0.015). The prevalence of NASH in GHD patients was 18% (95% CI: 5-31). The prevalence of NAFLD in GHD patients is significantly higher than that in the general population, especially NASH. There is a need to develop targeted strategies for the early identification, prevention, or control of NAFLD/NASH in patients with GHD.

Blood pressure stratification for predicting liver fibrosis risk in metabolic dysfunction associated fatty liver disease.

INTRODUCTION AND OBJECTIVES: The optimal blood pressure (BP) range for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) is currently unknown. This study aimed to explore the relationship between stratified BP levels and MAFLD progression. PATIENTS AND METHODS: The data of adults who underwent yearly health check-ups were screened to establish both a cross-sectional and a 6-year longitudinal cohort of individuals with MAFLD. BP was classified into the following categories optimal, normal, high-normal, and hypertension. Liver fibrosis was diagnosed with fibrosis-4 (FIB-4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and aspartate aminotransferase-to-platelet ratio index (APRI). RESULTS: A total of 10,232 individuals were included in the cross-sectional cohort. In the MAFLD population, individuals with liver fibrosis had significantly higher BP levels and hypertension prevalence (P < 0.001) than those without. Furthermore, liver fibrosis score was significantly associated with BP levels (P < 0.001). In the 6-year longitudinal cohort of 3661 individuals with MAFLD without liver fibrosis, the incidence rates of liver fibrosis increased with increasing BP levels as follows optimal=11.20%, normal=13.90%, high-normal=19.50%, hypertension=26.20% (log-rank 22.205; P < 0.001). Cox regression analysis showed that both baseline high-normal BP (hazard ratio [HR], 1.820; P=0.019) and hypertension (HR, 2.656; P < 0.001) were predictive of liver fibrosis. CONCLUSIONS: BP stratification may be useful in predicting the progression of MAFLD. Individuals having MAFLD with concurrent hypertension or high-normal BP are at a higher risk of liver fibrosis. These findings may provide a criteria for early intervention of MAFLD to prevent liver fibrosis.

Barriers and enabling factors in weight management of patients with nonalcoholic fatty liver disease: A qualitative study using the COM-B model of behaviour.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. Lifestyle modifications aimed at promoting weight loss and weight maintenance remain the current first-line treatments for NAFLD. OBJECTIVE: We aim to identify barriers and enabling factors in weight management among patients with NAFLD using the capability, opportunity, motivation, behaviour (COM-B) model of behaviour. DESIGN: This study adopted a qualitative design using semistructured interviews analysed with content analysis and the COM-B framework. SETTING AND PARTICIPANTS: Interviews were conducted with 27 patients with NAFLD who experienced successful or unsuccessful weight reduction. RESULTS: Our study included 27 participants: 15 participants with successful weight loss (successful weight loss refers to a decrease in body weight ≥7% of the initial body weight for patients with NAFLD) and 12 participants with unsuccessful weight loss. Thirty-five themes (19 barriers and 16 facilitators) were mapped onto the COM-B model as barriers and facilitators to weight management among patients with NAFLD. The key barriers were lack of time and energy, lack of awareness of weight, lack of attention to NAFLD, treating food as a reward or compensation and social entertainment. The key facilitators were having basic weight loss knowledge and skills, strong motivation, attention to NAFLD, unsuccessful weight loss experiences and positive feedback from phased success. CONCLUSION: In addition to identifying factors consistent with existing studies, this study identified factors that influence weight management in NAFLD patients, such as basic weight loss skills and rational thinking before weight loss, which were not previously reported. This has clinical implications for clinical healthcare providers and health management services for the improvement of education and support regarding lifestyle improvement and weight management in patients with NAFLD. PATIENT OR PUBLIC CONTRIBUTION: We recruited potential participants from the Bariatric Clinic, Hepatology Clinic and Physical Examination Center of hospitals between March 2021 and October 2021. Twenty-seven patients with NAFLD who had successful or unsuccessful weight loss experiences participated in the study and responded to questions on weight management.

Aberrant Spontaneous Brain Activity and its Association with Cognitive Function in Non-Obese Nonalcoholic Fatty Liver Disease: A Resting-State fMRI Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been proven to be associated with an increased risk of cognitive impairment and dementia, and this association is more significant in non-obese NAFLD populations, but its pathogenesis remains unclear. Our study aimed to explore the abnormalities of spontaneous brain activity in non-obese NAFLD patients by resting-state fMRI (RS-fMRI) and their relationship with cognitive function. METHODS: 19 non-obese NAFLD, 25 obese NAFLD patients, and 20 healthy controls (HC) were enrolled. All subjects underwent RS-fMRI scan, psychological scale assessment, and biochemical examination. After RS-fMRI data were preprocessed, differences in low-frequency fluctuation amplitude (ALFF), regional homogeneity (ReHo) and functional connectivity (FC) were compared among the three groups. Furthermore, the relationship between RS-fMRI indicators and cognitive and clinical indicators were performed using correlation analysis. RESULTS: The cognitive function was declined in both NAFLD groups. Compared with obese NAFLD patients, non-obese NAFLD patients showed increased ALFF and ReHo in the left middle temporal gyrus (MTG), increased ReHo in the sensorimotor cortex and reduced FC between left MTG and right inferior frontal gyrus (IFG). Compared with HC, non-obese NAFLD patients showed increased ALFF and ReHo in the left calcarine cortex and fusiform gyrus (FG), decreased ALFF in the bilateral cerebellum, and reduced FC between left FG and right IFG and left angular gyrus. In addition to the same results, obese patients showed increased activity in different regions of the bilateral cerebellum, while decreased ALFF in the right superior frontal gyrus and ReHo in the right orbitofrontal cortex (OFC). Correlation analysis showed that in non-obese patients, the ALFF values in the FG and the FC values between the left MTG and the right IFG were associated with cognitive decline, insulin resistance, and fasting glucose disorder. CONCLUSIONS: Non-obese NAFLD patients showed abnormal local spontaneous activity and FC in regions involved in the sensorimotor, temporo-occipital cortex, cerebellum, and reward system (such as OFC), some of which may be the potential neural mechanism difference from obese NAFLD patients. In addition, the temporo-occipital cortex may be a vulnerable target for cognitive decline in non-obese NAFLD patients.

Pattern formation in marsh ecosystems modeled through the interaction of marsh vegetation, mussels and sediment.

Spatial self-organization, a common feature of multi-species communities, can provide important insights into ecosystem structure and resilience. As environmental conditions gradually worsen (e.g., resource depletion, erosion intensified by storms, drought), some ecological systems collapse to an irreversible state once a tipping point is reached. Spatial patterning may be one way for them to cope with such changes. We use a mathematical model to describe self-organization of an eroding marsh shoreline based on three-way interactions between sediment volume and two ecosystem engineers - smooth cordgrass Spartina alterniflora and ribbed mussels Geukensia demissa. Our model indicates that scale-dependent interactions between multiple ecosystem engineers drive the self-organization of eroding marsh edges and regulate the spatial scale of shoreline morphology. Spatial self-organization of the marsh edge increases the system's productivity, allows it to withstand erosion, and delays degradation that otherwise would occur in the absence of strong species interactions. Further, changes in wavelength and variance of the spatial patterns give insight into marsh recession. Finally, we find that the presence of mussels in the system modulates the spatial scale of the patterns, generates patterns with shorter wavelengths, and allows the system to tolerate a greater level of erosion. Although previous studies suggest that self-organization can emerge from local interactions and can result in increased ecosystem persistence and stability in various ecosystems, our findings extend these concepts to coastal salt marshes, emphasizing the importance of the ecosystem engineers, smooth cordgrass and ribbed mussels, and demonstrating the potential value of self-organization for ecosystem management and restoration.

Bifurcation and Pattern Formation in an Activator-Inhibitor Model with Non-local Dispersal.

In this paper, by approximating the non-local spatial dispersal equation by an associated reaction-diffusion system, an activator-inhibitor model with non-local dispersal is transformed into a reaction-diffusion system coupled with one ordinary differential equation. We prove that, to some extent, the non-locality-induced instability of the non-local system can be regarded as diffusion-driven instability of the reaction-diffusion system for sufficiently small perturbation. We study the structure of the spectrum of the corresponding linearized operator, and we use linear stability analysis and steady-state bifurcations to show the existence of non-constant steady states which generates non-homogeneous spatial patterns. As an example of our results, we study the bifurcation and pattern formation of a modified Klausmeier-Gray-Scott model of water-plant interaction.

[Chinesization of the quality of life scale and its reliability and validity tests for non-alcoholic fatty liver disease].

Objective: To translate the English version of the non-alcoholic fatty liver disease quality of life scale (CLDQ-NAFLD) into the Chinese version in order to test its reliability and validity. Methods: The English version of the CLDQ-NAFLD was translated according to the cross-cultural research tool debugging and validation guidelines to form the Chinese version of the CLDQ-NAFLD. A questionnaire survey was conducted on 515 NAFLD cases in a tertiary hospital in Hangzhou from September 2021 to April 2022 to evaluate the reliability and validity of the scale. Results: The Chinese version of the CLDQ-NAFLD contained six domains with a total of thirty-six items (X2/DF=3.105, RMSEA=0.064, TLI=0.905, CFI=0.912, and IFI=0.913). I-CVI, S-CVI/UA, and S-CVI/Ave was 0.83 to 1.00, 0.86 and 0.98, respectively. The 12-item Short-Form Health Survey (SF-12) was used as the calibration standard, and the correlation validity of the calibration standard was 0.704 (P<0.001). The Cronbach's alpha coefficient of the total scale and each dimension of the scale was 0.964 and 0.807-0.956, respectively. The test-retest reliability was 0.839. Conclusion: The Chinese version of the CLDQ-NAFLD has good reliability and validity. Thus, it can be used to evaluate the quality of life for NAFLD patients with a Chinese cultural background.

Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report.

Patients with non-small cell lung cancer (NSCLC) containing ROS1 fusions can have a marked response to the ROS1-targeted tyrosine kinase inhibitors (TKIs), such as crizotinib. Common resistance mechanisms of ROS1-fusion targeted therapy are acquired mutations in ROS1. Along with the use of next-generation sequencing in the clinical management of patients with NSCLC during sequential targeted therapy, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Besides acquired resistance mutations, bypass mechanisms of resistance to epidermal growth factor receptor (EGFR)-TKI treatment are common in patients with EGFR mutations. Here we describe a patient with metastatic lung adenocarcinoma with CD74-ROS1 fusion who initially responded to crizotinib and then developed resistance by the acquired mutation of D1228N in the MET kinase domain, which showed short-term disease control for cabozantinib. KEY POINTS: The D1228N point mutation of MET is an acquired mutation for crizotinib resistance. The patient obtained short-term clinical benefit from cabozantinib therapy after resistance to crizotinib. The clinical use of next-generation sequencing could maximize the benefits of precision medicine in patients with cancer.

Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers.

BACKGROUND: Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients. METHODS: Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed. RESULTS: IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response. CONCLUSIONS: NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

Corrigendum to "Bistability in a differential equation model of oyster reef height and sediment accumulation" [J. Theor. Biol. 289 (2011) 1-11].

There was a mistake in the Matlab code we used to generate time series solutions of our model, Eqs. (16)-(18). The corrected text below replaces one paragraph on p. 7, and the figures below replace Figs. 4-5 on p. 8. There is no qualitative change to our results. However, there is a quantitative change in the initial dead oyster shell volume B(0) needed for reef survival. The corrected threshold B(0), about 0.40 m3 per m2 of sea floor, is more consistent with a recently experimentally estimated threshold of 0.30 m (Colden, Latour, and Lipcius, Mar Ecol Prog Ser 582: 1-13, 2017) than was our old incorrect threshold of about 0.12 m3.