Gut microbial features may influence antiviral IgG levels after vaccination against viral respiratory infectious diseases: the evidence from two-sample bidirectional mendelian randomization.

BACKGROUND: Vaccination is effective in preventing viral respiratory infectious diseases through protective antibodies and the gut microbiome has been proven to regulate human immunity. This study explores the causal correlations between gut microbial features and serum-specific antiviral immunoglobulin G (IgG) levels. METHODS: We conduct a two-sample bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to explore the causal relationships between 412 gut microbial features and four antiviral IgG (for influenza A, measles, rubella, and mumps) levels. To make the results more reliable, we used four robust methods and performed comprehensive sensitivity analyses. RESULTS: The MR analyses revealed 26, 13, 20, and 18 causal associations of the gut microbial features influencing four IgG levels separately. ​Interestingly, ten microbial features, like genus Collinsella, species Bifidobacterium longum, and the biosynthesis of L-alanine have shown the capacity to regulate multiple IgG levels with consistent direction (rise or fall). The ​reverse MR analysis suggested several potential causal associations of IgG levels affecting microbial features. CONCLUSIONS: The human immune response against viral respiratory infectious diseases could be modulated by changing the abundance of gut microbes, which provided new approaches for the intervention of viral respiratory infections.

Accurate prediction of HCC risk after SVR in patients with hepatitis C cirrhosis based on longitudinal data.

BACKGROUND: Most existing predictive models of hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) are built on data collected at baseline and therefore have limited accuracy. The current study aimed to construct an accurate predictive model incorporating longitudinal data using a novel modeling strategy. The predictive performance of the longitudinal model was also compared with a baseline model. METHODS: A total of 400 patients with HCV-related cirrhosis who achieved SVR with direct-acting antivirals (DAA) were enrolled in the study. Patients were randomly divided into a training set (70%) and a validation set (30%). Informative features were extracted from the longitudinal variables and then put into the random survival forest (RSF) to develop the longitudinal model. A baseline model including the same variables was built for comparison. RESULTS: During a median follow-up time of approximately 5 years, 25 patients (8.9%) in the training set and 11 patients (9.2%) in the validation set developed HCC. The areas under the receiver-operating characteristics curves (AUROC) for the longitudinal model were 0.9507 (0.8838-0.9997), 0.8767 (0.6972,0.9918), and 0.8307 (0.6941,0.9993) for 1-, 2- and 3-year risk prediction, respectively. The brier scores of the longitudinal model were also relatively low for the 1-, 2- and 3-year risk prediction (0.0283, 0.0561, and 0.0501, respectively). In contrast, the baseline model only achieved mediocre AUROCs of around 0.6 (0.6113, 0.6213, and 0.6480, respectively). CONCLUSIONS: Our longitudinal model yielded accurate predictions of HCC risk in patients with HCV-relate cirrhosis, outperforming the baseline model. Our model can provide patients with valuable prognosis information and guide the intensity of surveillance in clinical practice.

Trajectories of De Ritis ratio with risk of hepatocellular carcinoma and liver-related mortality following direct-acting antivirals for HCV: a retrospective longitudinal study up to 10 years.

The De Ritis ratio has good diagnostic accuracy in patients with chronic viral liver disease. However, its prognostic utility has remained controversial. This study was to identify different trajectories of De Ritis ratio in those hepatitis C patients cured and analyze the relationship between trajectory groups and risk of hepatocellular carcinoma (HCC) with liver-related mortality by the retrospective cohort study. This retrospective longitudinal cohort included 1241 patients with hepatitis C who underwent antiviral therapy since follow-up in 2012. De Ritis ratio trajectories were identified by the latent class growth mixed model. Patients were grouped into subgroups by De Ritis ratio according to longitudinal trajectories. The endpoints were HCC and liver-related mortality. Three distinct trajectory groups were characterized for serum De Ritis ratio: low-stable, middle-stable and high-rising. Fifty-one HCC and 11 liver-related mortality were recorded and tracked. Compared to the low-stable group, the adjusted hazard ratios (HRs) and 95% confidence interval (CI) associated with HCC and liver-related mortality were 2.02 (1.12 to 3.63), 9.36 (3.61 to 24.29), for the middle-stable, and high-rising group, respectively. Notably, the high-rising trajectory group still had prognostic significance after adjusting for preoperative levels. Likewise, for the high-rising trajectory group of sustained virological response, the HRs (95% CI) were 2.85 (1.03 to 10.75) for HCC and liver-related mortality, and in patients with cirrhosis, the HRs (95% CI) were 3.44 (1.64 to 7.19) and 4.35 (1.27 to 14.84) in the middle-stable trajectory group and the high-rising trajectory group, respectively. The dynamic measurements of De Ritis ratio are recommended to monitor the prognosis of Hepatitis C patients.

Activation of NF-κB-Inducing Kinase in Islet ß Cells Causes ß Cell Failure and Diabetes.

Islet ß cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the ß cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that ß cell-specific overexpression of NIK (ß-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, ß cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H2O2-induced ß cell death and also reduces streptozotocin (STZ)-induced ß cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, ß cell death, and diabetes. In all, this study not only uncovers a role of NIK in ß cell failure but also provides a potential therapeutic target for the treatment of diabetes.

Distinct Associations of Cognitive Impairments and Reduced Gray Matter Volumes in Remitted Patients with Schizophrenia and Bipolar Disorder.

Background: Cognitive impairments are documented in schizophrenia (SZ) and bipolar disorder (BD) and may be related to gray matter volumes (GMVs). Thus, this study is aimed at exploring whether the association between cognitive impairments and GMV alterations is similar in patients with SZ and BD and understanding the underlying neurobiological mechanisms. Methods: A total of 137 adult subjects (46 with SZ, 35 with BD, and 56 age-, sex-, and education-matched healthy controls (HC)) completed the MATRICS Consensus Cognitive Battery (MCCB) and structural magnetic resonance imaging scanning. We performed group comparisons of the cognitive impairments, the GMV alterations, and the association between them. Results: Compared with HC, the patients with SZ and BD showed shared deficits in 4 cognitive domains (i.e., processing speed, working memory, problem solving, and social cognition) and the composite. SZ and BD had commonly decreased GMVs, mainly in the insula, superior temporal pole, amygdala, anterior cingulate, and frontal cortices (superior, middle, opercular inferior, and orbital frontal gyrus). No correlation between MCCB scores and GMVs was detected in SZ. However, for BD, working memory was relevant to the right hemisphere (i.e., right insula, amygdala, superior temporal pole, and medial and dorsolateral superior frontal gyrus). Limitations. The major limitations were that not all patients were the first-episode status and no medication. Conclusions: The association was mainly limited to the BD group. Thus, the underlying pathophysiology of the cognitive deficits, in terms of GMV alterations, may be diverse between two disorders.

A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.

Potent and selective chemical probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chemical probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-molecule inhibitor of NIK, B022, was found to be a potent and selective chemical probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo Furthermore, in vivo administration of B022 protected against not only NIK but also CCl4-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.-Ren, X., Li, X., Jia, L., Chen, D., Hou, H., Rui, L., Zhao, Y., Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.

A long non-coding RNA, APOA4-AS, regulates APOA4 expression depending on HuR in mice.

Long non-coding RNAs (lncRNAs) have been shown to be critical biomarkers or therapeutic targets for human diseases. However, only a small number of lncRNAs were screened and characterized. Here, we identified 15 lncRNAs, which are associated with fatty liver disease. Among them, APOA4-AS is shown to be a concordant regulator of Apolipoprotein A-IV (APOA4) expression. APOA4-AS has a similar expression pattern with APOA4 gene. The expressions of APOA4-AS and APOA4 are both abnormally elevated in the liver of ob/ob mice and patients with fatty liver disease. Knockdown of APOA4-AS reduces APOA4 expression both in vitro and in vivo and leads to decreased levels of plasma triglyceride and total cholesterol in ob/ob mice. Mechanistically, APOA4-AS directly interacts with mRNA stabilizing protein HuR and stabilizes APOA4 mRNA. Deletion of HuR dramatically reduces both APOA4-AS and APOA4 transcripts. This study uncovers an anti-sense lncRNA (APOA4-AS), which is co-expressed with APOA4, and concordantly and specifically regulates APOA4 expression both in vitro and in vivo with the involvement of HuR.

Recent advances of adapter proteins in the regulation of heart diseases.

Heart diseases are major causes of mortality. Cardiac hypertrophy, myocardial infarction (MI), viral cardiomyopathy, ischemic and reperfusion (I/R) heart injury finally lead to heart failure and death. Insulin and IGF1 signal pathways play key roles in normal cardiomyocyte growth and physiological cardiac hypertrophy while inflammatory signal pathway is associated with pathological cardiac hypertrophy, MI, viral cardiomyopathy, I/R heart injury, and heart failure. Adapter proteins are the major family proteins, which transduce signals from insulin, IGF1, or cytokine receptors to the downstream pathways and have been shown to regulate variety of heart diseases. Here, we summarized the recent advances in understanding the physiological and pathological roles of adapter proteins in heart failure.

Relationships between the gut microbiome and brain functional alterations in first-episode, drug-naïve patients with major depressive disorder.

OBJECTIVE: Increasing evidence has shown that the microbiota-gut-brain axis (MGB) is involved in the mechanism of major depressive disorder (MDD). However, the relationship between the gut microbiome and brain function in MDD patients has not been determined. Here, we intend to identify specific changes in the gut microbiome and brain function in first-episode, drug-naïve MDD patients and then explore the associations between the two omics to elucidate how the MGB axis plays a role in MDD development. METHODS: We recruited 38 first-episode, drug-naïve MDD patients and 37 healthy controls (HC). The composition of the fecal microbiome and neural spontaneous activity alterations were examined using 16S rRNA gene amplicon sequencing analysis and regional homogeneity (ReHo). Spearman correlation analyses were conducted to assess the associations between the gut microbiome and brain function. RESULTS: Compared with HC, MDD patients exhibited distinct alterations in the gut microbiota and elevated ReHo in the frontal regions. In the MDD group, a positive relationship was noted between the relative abundance of Blautia and the HAMD-17 and HAMA scores, as well as between the relative abundance of Oxalobacteraceae and the HAMD-17 score. The relative abundances of Porphyromonadaceae and Parabacteroides were negatively correlated with the ReHo values of frontal regions. LIMITATIONS: Our study utilized a cross-sectional design, and the number of subjects was relatively small. CONCLUSION: We found that some specific gut microbiomes were associated with frontal function, and others were associated with clinical symptoms in MDD patients, which may support the role of the MGB axis underlying MDD.

DAA treatment for HCV reduce risk of hepatocellular carcinoma: a 10-years follow-up study based on Chinese patients with hepatitis C.

The long-term benefits of direct-acting antiviral (DAA) therapy after achieving sustained virological response (SVR) remain uncertain in the Chinese population. This study evaluates the incidence of hepatocellular carcinoma (HCC), hepatic decompensation, and all-cause mortality among Chinese hepatitis C patients treated with DAAs. We included patients diagnosed since 2011 and followed them until November 1, 2022. The primary outcomes were HCC, hepatic decompensation, and mortality. Multivariable proportional hazards model was used to assess the impact of SVR and cirrhosis status. The cohort consisted of 1272 patients with SVR (92.1%) and 109 without SVR (7.9%), with a median follow-up of 61 months. The incidence of HCC was significantly lower in the SVR group (5.1 per 1000 person-years) compared to the no-SVR group (15.0 per 1000 person-years). Achieving SVR was associated with a significantly reduced risk of HCC (adjusted hazard ratio: 0.32; 95% CI 0.16-0.67). Cirrhosis was linked to an increased risk of developing HCC and hepatic decompensation. These findings highlight the importance of early DAA treatment, particularly for patients with cirrhosis.

Identifying misdiagnosed bipolar disorder using support vector machine: feature selection based on fMRI of follow-up confirmed affective disorders.

Nearly a quarter of bipolar disorder (BD) patients were misdiagnosed as major depressive disorder (MDD) patients, which cannot be corrected until mania/hypomania develops. It is important to recognize these obstacles so that the appropriate treatment can be initiated. Thus, we sought to distinguish patients with BD from MDD, especially to identify misdiagnosed BD before mania/hypomania, and further explore potential trait features that allow accurate differential diagnosis independent of state matters. Functional magnetic resonance imaging scans were performed at baseline on 92 MDD patients and 48 BD patients. The MDD patients were then followed up for more than two years. After follow-up, 23 patients transformed into BD (tBD), and 69 patients whose diagnoses remained unchanged were eligible for unipolar depression (UD). A support vector machine classifier was trained on the amygdala-based functional connectivity (FC) of 48 BD and 50 UD patients using a novel region-based feature selection. Then, the classifier was tested on the dataset, encompassing tBD and the remaining UD. It performed well for known BD and UD and can also distinguish tBD from UD with an accuracy of 81%, sensitivity of 82.6%, specificity of 79%, and AUC of 74.6%, respectively. Feature selection results revealed that ten regions within the cortico-limbic neural circuit contributed most to classification. Furthermore, in the FC comparisons among diseases, BD and tBD shared almost overlapped FC patterns in the cortico-limbic neural circuit, and both of them presented pronounced differences in most regions within the circuit compared with UD. The FC values of the most discriminating brain regions had no prominent correlations with the severity of depression, anxiety, and mania/hypomania (FDR correction). It suggests that BD possesses some trait features in the cortico-limbic neural circuit, rendering it dichotomized by the classifier based on known-diagnosis data.

Enhancing nitrate attenuation in groundwater via selectively applying surface agricultural practices: A novel and sustainable strategy for non-point source pollution mitigation.

Non-point nitrate pollution in groundwater has been accelerated by agricultural development, but sustainable nitrogen removal is a challenge because of its wide distribution and negative side effects. Surface agricultural practices (SAPs), which are demonstrably effective in driving the downward infiltration of dissolved organic carbon (DOC), have not been well explored for their potential to enhance nitrate attenuation in groundwater. Therefore, a combination of soil column and groundwater incubation experiments was performed to investigate the carbon and nitrogen responses to different SAPs (manure fertilization, lucerne planting, and straw return). The soil column experiment showed that SAPs promoted DOC and reduced nitrate leaching into groundwater, and straw treatment witnessed the highest DOC leaching flux (252.71 g m-2 yr-1) and lowest nitrate leaching flux (9.51 g m-2 yr-1). The groundwater incubation experiment showed that leachates from the straw treatment displayed the best denitrification-enhancement performance, with the highest NO3--N reduction efficiency (92.93%) and rate (1.627 mg/day), N2 selectivity (99.78%), and net nitrogen removal (0.09 mg). Furthermore, Fourier transform ion cyclotron resonance mass spectrometry confirmed that CHOS molecules with lower double bond equivalents (0-5) and larger carbon numbers (10-15) were more accessible to denitrifiers. This study provides a new path for the sustainable control of non-point source nitrate pollution.

Using multi-tissue transcriptome-wide association study to identify candidate susceptibility genes for respiratory infectious diseases.

Objective: We explore the candidate susceptibility genes for influenza A virus (IAV), measles, rubella, and mumps and their underlying biological mechanisms. Methods: We downloaded the genome-wide association study summary data of four virus-specific immunoglobulin G (IgG) level data sets (anti-IAV IgG, anti-measles IgG, anti-rubella IgG, and anti-mumps virus IgG levels) and integrated them with reference models of three potential tissues from the Genotype-Tissue Expression (GTEx) project, namely, whole blood, lung, and transformed fibroblast cells, to identify genes whose expression is predicted to be associated with IAV, measles, mumps, and rubella. Results: We identified 19 significant genes (ULK4, AC010132.11, SURF1, NIPAL2, TRAP1, TAF1C, AC000078.5, RP4-639F20.1, RMDN2, ATP1B3, SRSF12, RP11-477D19.2, TFB1M, XXyac-YX65C7_A.2, TAF1C, PCGF2, and BNIP1) associated with IAV at a Bonferroni-corrected threshold of p < 0.05; 14 significant genes (SOAT1, COLGALT2, AC021860.1, HCG11, METTL21B, MRPL10, GSTM4, PAQR6, RP11-617D20.1, SNX8, METTL21B, ANKRD27, CBWD2, and TSFM) associated with measles at a Bonferroni-corrected threshold of p < 0.05; 15 significant genes (MTOR, LAMC1, TRIM38, U91328.21, POLR2J, SCRN2, Smpd4, UBN1, CNTROB, SCRN2, HOXB-AS1, SLC14A1, AC007566.10, AC093668.2, and CPD) associated with mumps at a Bonferroni-corrected threshold of p < 0.05; and 13 significant genes (JAGN1, RRP12, RP11-452K12.7, CASP7, AP3S2, IL17RC, FAM86HP, AMACR, RRP12, PPP2R1B, C11orf1, DLAT, and TMEM117) associated with rubella at a Bonferroni-corrected threshold of p < 0.05. Conclusions: We have identified several candidate genes for IAV, measles, mumps, and rubella in multiple tissues. Our research may further our understanding of the pathogenesis of infectious respiratory diseases.

Altered gray matter volumes and plasma IL-6 level in major depressive disorder patients with suicidal ideation.

BACKGROUNDS: Suicidal ideation (SI) is one of the most serious consequences of major depressive disorder (MDD). Understanding the unique mechanism of MDD with SI (MDD + S) is crucial for treatment development. While abundant research has studied MDD, past studies have not reached a consensus on the mechanism of MDD + S. The study aimed to investigate the abnormalities of the gray matter volumes (GMVs) and plasma IL-6 level in MDD + S to further reveal the mechanism of MDD + S. METHODS: We tested the plasma IL-6 level using Luminex multifactor assays and collected the Structural Magnetic Resonance Imaging (SMRI) data from 34 healthy controls (HCs), 36 MDD patients without SI (MDD - S) and 34 MDD + S patients. We performed a partial correlation between the GMVs of the brain regions with significant differences and plasma IL-6 level with age, sex, medication, scores of HAMD-17 and HAMA as the covariates. RESULTS: Compared with HCs and MDD - S, MDD + S had significantly decreased GMVs in the left cerebellum Crus I/II and significantly increased plasma IL-6 level; compared with HCs, both the MDD + S and MDD - S had significantly decreased GMVs in right precentral and postcentral gyri. No significant correlation was found between the GMVs and the plasma IL-6 level in the MDD + S and MDD - S, respectively. While the GMVs of the right precentral and postcentral gyri negatively correlated with the level of IL-6 in the whole MDD (r = -0.28, P = 0.03). The GMVs of the left cerebellum Crus I/II (r = -0.47, P = 0.02), and the right precentral and postcentral gyri (r = -0.42, P = 0.04) negatively correlated with the level of IL-6 in HCs. CONCLUSION: The altered GMVs and the plasma IL-6 level may provide a scientific basis to understand the pathophysiological mechanisms of MDD + S.

Shared Transdiagnostic Neuroanatomical Signatures Across First-episode Patients with Major Psychiatric Diseases and Individuals at Familial Risk.

BACKGROUND: Nowadays, increasing evidence has found transdiagnostic neuroimaging biomarkers across major psychiatric disorders (MPDs). However, it remains to be known whether this transdiagnostic pattern of abnormalities could also be seen in individuals at familial high-risk for MPDs (FHR). We aimed to examine shared neuroanatomical endophenotypes and protective biomarkers for MPDs. METHODS: This study examined brain grey matter volume (GMV) of individuals by voxel-based morphometry method. A total of 287 individuals were included, involving 100 first-episode medication-naive MPDs, 87 FHR, and 110 healthy controls (HC). They all underwent high-resolution structural magnetic resonance imaging (MRI). RESULTS: At the group level, we found MPDs were characterized by decreased GMV in the right fusiform gyrus, the right inferior occipital gyrus, and the left anterior and middle cingulate gyri compared to HC and FHR. Of note, the GMV of the left superior temporal gyrus was increased in FHR relative to MPDs and HC. At the subgroup level, the comparisons within the FHR group did not return any significant difference, and we found GMV difference among subgroups within the MPDs group only in the opercular part of the right inferior frontal gyrus. CONCLUSION: Together, our findings uncover common structural disturbances across MPDs and substantial changes in grey matter that may relate to high hereditary risk across FHR, potentially underscoring the importance of a transdiagnostic way to explore the neurobiological mechanisms of major psychiatric disorders.

Altered dynamic amplitude of low-frequency fluctuation between bipolar type I and type II in the depressive state.

BACKGROUND: Bipolar disorder is a chronic and highly recurrent mental disorder that can be classified as bipolar type I (BD I) and bipolar type II (BD II). BD II is sometimes taken as a milder form of BD I or even doubted as an independent subtype. However, the fact that symptoms and severity differ in patients with BD I and BD II suggests different pathophysiologies and underlying neurobiological mechanisms. In this study, we aimed to explore the shared and unique functional abnormalities between subtypes. METHODS: The dynamic amplitude of low-frequency fluctuation (dALFF) was performed to compare 31 patients with BD I, 32 with BD II, and 79 healthy controls (HCs). Global dALFF was calculated using sliding-window analysis. Group differences in dALFF among the 3 groups were compared using analysis of covariance (ANCOVA), with covariates of age, sex, years of education, and mean FD, and Bonferroni correction was applied for post hoc analysis. Pearson and Spearman's correlations were conducted between clusters with significant differences and clinical features in the BD I and BD II groups, after which false error rate (FDR) was used for correction. RESULTS: We found a significant decrease in dALFF values in BD patients compared with HCs in the following brain regions: the bilateral-side inferior frontal gyrus (including the triangular, orbital, and opercular parts), inferior temporal gyrus, the medial part of the superior frontal gyrus, middle frontal gyrus, anterior cingulum, insula gyrus, lingual gyrus, calcarine gyrus, precuneus gyrus, cuneus gyrus, left-side precentral gyrus, postcentral gyrus, inferior parietal gyrus, superior temporal pole gyrus, middle temporal gyrus, middle occipital gyrus, superior occipital gyrus and right-side fusiform gyrus, parahippocampal gyrus, hippocampus, middle cingulum, orbital part of the medial frontal gyrus and superior frontal gyrus. Unique alterations in BD I were observed in the right-side supramarginal gyrus and postcentral gyrus. In addition, dALFF values in BD II were significantly higher than those in BD I in the right superior temporal gyrus and middle temporal gyrus. The variables of dALFF correlated with clinical characteristics differently according to the subtypes, but no correlations survived after FDR correction. LIMITATIONS: Our study was cross-sectional. Most of our patients were on medication, and the sample was limited. CONCLUSIONS: Our findings demonstrated neurobiological characteristics of BD subtypes, providing evidence for BD II as an independent existence, which could be the underlying explanation for the specific symptoms and/or severity and point to potential biomarkers for the differential diagnosis of bipolar subtypes.

Altered Levels of Plasma Inflammatory Cytokines and White Matter Integrity in Bipolar Disorder Patients With Suicide Attempts.

Objective: Bipolar disorder (BD) has a higher lifetime rate of suicide attempts (SA) than other psychiatric disorders. Furthermore, BD patients with SA (BD + S) are prone to a worse quality of life. However, the pathophysiology of BD + S is poorly understood. To further reveal the potential mechanisms of BD + S, abnormalities in peripheral plasma inflammatory cytokines and brain white matter (WM) in BD + S, as well as the correlation between them are investigated. Methods: We tested the levels of TNF-α, IL-1ß, and IL-6 in peripheral plasma and collected the diffusion tensor imaging (DTI) data from 14 BD + S, 24 BD patients without SA (BD-S), and 26 healthy controls (HCs). The three groups were matched by age and gender. The levels of TNF-α, IL-1ß, and IL-6 were detected by Luminex multifactor detection technology, and the fractional anisotropy (FA) values were employed to depict the alterations of WM. Partial correlation analyses were conducted to detect correlations between levels of TNF-α, IL-1ß, and IL-6 and changes of WM, and the relationships between severity of clinical symptoms, including scores of HAMD-17 and YMRS, and cytokine levels or FA values in all groups. Results: For plasma inflammatory cytokines, there was no significant difference in their levels except for IL-6 among the three groups. Post-hoc analyses revealed that increased IL-6 level was only detected in BD + S (p < 0.05, Bonferroni correction). For DTI, BD + S showed specifically decreased FA in the bilateral middle cerebellar peduncle and the left superior corona radiata compared to BD-S and HCs (p < 0.05, Bonferroni correction). Additionally, both BD + S and BD-S groups revealed decreased FA in the bilateral body and genu of corpus callosum (CC) compared to HCs (p < 0.05, Bonferroni correction). No significant correlation between plasma inflammatory cytokines and WM integrity was found. In the BD + S group, we found negative correlation between the scores of YMRS and FA values of the left middle cerebellar peduncle (r = -0.74, p = 0.035). Conclusion: The inflammation and impaired WM integrity may provide a scientific basis to understand the potential mechanisms of BD + S.

Repeated Measurement of FIB-4 to Predict Long-Term Risk of HCC Development Up to 10 Years After SVR.

Purpose: It is unclear whether and how the long-term risk of hepatocellular carcinoma (HCC) will change in hepatitis C virus (HCV) infected patients who have reached sustained virologic response (SVR) with direct-acting antivirals (DAA). In this study, we assessed the long-term risk of HCC up to 10 years after SVR using fibrosis 4 score (FIB-4) and its dynamic changes. Patients and Methods: A total of 701 DAA-treated patients who achieved SVR between January 2012 to October 2020 were enrolled in the study. The FIB-4 score of each patient was measured at the date of SVR and each follow-up visit annually. Patients were followed until December 31, 2021, with the longest follow-up time being 9.82 years. Results: Following SVR, 27 cases of HCC were observed. The annual incidence rate of HCC remained stable with no obvious downward trend. Patients with a FIB-4 >3.25 at baseline or anytime during follow-up were at a higher risk of developing HCC than those whose FIB-4 remained below 3.25. Patients with cirrhosis and patients with no cirrhosis but a FIB-4 >3.25 were at higher risk of developing HCC than patients with no cirrhosis and a FIB-4 ≦3.25. Conclusion: FIB-4 >3.25 measured at SVR or any time post-SVR was associated with HCC risks. The repeated measurement of FIB-4 revealed a better predictive ability of HCC risks than the simple measurement of FIB-4 at baseline. The additional stratification of patients by combining FIB-4 and cirrhosis leads to more accurately identifying high-risk patients. Surveillance of HCC is recommended for virologically cured patients with a FIB-4 >3.25 at SVR or anytime afterward and patients diagnosed with cirrhosis.

Distinguishing major depressive disorder from bipolar disorder in remission: A brain structural network analysis.

BACKGROUND: It is challenging to differentiate major depressive disorder (MDD) from bipolar disorder (BD) in depression and remission. To exclude the potential influence of depressive episodes, we compared the white matter (WM) network between MDD and BD patients in remission to find disease-specific alterations in MDD and BD, and then distinguish these two affective disorders. METHODS: We recruited 33 patients with remitted MDD (rMDD), 54 patients with remitted BD (rBD), and 60 healthy controls (HCs). Diffusion tensor imaging and high-resolution 3D T1-weighted image were acquired. Global and nodal topological parameters were used to depict the alterations of the whole-brain WM network. RESULTS: We found that rMDD displayed increased global network efficiency (Eglob) and local network efficiency (Eloc) compared with HCs, whereas we found no significance between rBD and HCs. Compared with rBD and HCs, patients in the rMDD group showed increased nodal degree and nodal efficiency, and decreased nodal shortest path length in the four cerebral regions, including the right calcarine fissure (CAL.R), right cuneus (CUN.R), left lingual gyrus (LING.L), and left middle occipital gyrus (MOG.L). We did not find any rBD specific changes of nodal topological metrics. LIMITATIONS: The main limitation is the possible effects of medication and BD subtypes on the results. CONCLUSIONS: Our findings indicate that rMDD exhibited elevated global properties compared with HCs group, and increased nodal properties in the CAL.R, CUN.R, LING.L, and MOG.L specifically compared with rBD and HCs, which may underlie the distinction of the two affective disorders in remission.

The aberrant dynamic amplitude of low-frequency fluctuations in melancholic major depressive disorder with insomnia.

Background: Insomnia is considered one of the manifestations of sleep disorders, and its intensity is linked to the treatment effect or suicidal thoughts. Major depressive disorder (MDD) is classified into various subtypes due to heterogeneous symptoms. Melancholic MDD has been considered one of the most common subtypes with special sleep features. However, the brain functional mechanisms in melancholic MDD with insomnia remain unclear. Materials and methods: Melancholic MDD and healthy controls (HCs, n = 46) were recruited for the study. Patients were divided into patients with melancholic MDD with low insomnia (mMDD-LI, n = 23) and patients with melancholic MDD with high insomnia (mMDD-HI, n = 30), according to the sleep disturbance subscale of the 17-item Hamilton Depression Rating Scale. The dynamic amplitude of low-frequency fluctuation was employed to investigate the alterations of brain activity among the three groups. Then, the correlations between abnormal dALFF values of brain regions and the severity of symptoms were investigated. Results: Lower dALFF values were found in the mMDD-HI group in the right middle temporal gyrus (MTG)/superior temporal gyrus (STG) than in the mMDD-LI (p = 0.014) and HC groups (p < 0.001). Melancholic MDD groups showed decreased dALFF values than HC in the right middle occipital gyri (MOG)/superior occipital gyri (SOG), the right cuneus, the bilateral lingual gyrus, and the bilateral calcarine (p < 0.05). Lower dALFF values than HC in the left MOG/SOG and the left cuneus in melancholic MDD groups were found, but no significant difference was found between the mMDD-LI group and HC group (p = 0.079). Positive correlations between the dALFF values in the right MTG/STG and HAMD-SD scores (the sleep disturbance subscale of the HAMD-17) in the mMDD-HI group (r = 0.41, p = 0.042) were found. In the pooled melancholic MDD, the dALFF values in the right MOG/SOG and the right cuneus (r = 0.338, p = 0.019), the left MOG/SOG and the left cuneus (r = 0.299, p = 0.039), and the bilateral lingual gyrus and the bilateral calcarine (r = 0.288, p = 0.047) were positively correlated with adjusted HAMD scores. Conclusion: The occipital cortex may be related to depressive symptoms in melancholic MDD. Importantly, the right MTG/STG may play a critical role in patients with melancholic MDD with more severe insomnia.