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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

Structural and functional alterations in untreated patients with major depressive disorder and bipolar disorder experiencing first depressive episode: A magnetic resonance imaging study combined with follow-up.

BACKGROUND: Magnetic resonance imaging (MRI) could assist in identifying objective biomarkers and follow-up study could effectively improve subjective diagnostic accuracy. By combining MRI with follow-up, this study aims to determine the shared and distinct alterations between major depressive disorder (MDD) and bipolar disorder (BD). METHODS: Untreated patients with MDD experiencing the first episode were subjected to MRI and subsequent follow-up. Fifteen patients with mania or hypomania were regrouped into BD group. Twenty patients were still grouped as MDD after an average of 37.95 months follow-up. Thirty healthy controls (HCs) were recruited to match the patients. Gray matter volume (GMV) and amygdala-seed functional connectivity (FC) in the whole brain were detected and compared among the three groups. RESULTS: GMV analysis revealed that the MDD and BD groups presented reduced GMV predominantly in the parietal, occipital, and frontal regions in the bilateral cerebrum compared with the HCs. The BD group had reduced GMV predominantly in the parietal, temporal, insular regions and the Rolandic operculum in the right-side cerebrum compared with MDD and HC groups. FC analysis revealed that the MDD and BD patients displayed increased FC values mainly in the bilateral parietal, and left occipital regions. Only the BD group displayed increased FC values in the temporal, occipital, parietal and limbic regions in the right-side cerebrum relative to HCs. LIMITATIONS: The main limitation is the relatively small sample size. CONCLUSIONS: Alterations in the cortical regions and cortico-limbic neural system may provide the scientific basis for differential diagnosis in affective disorders.

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.

Is the Long-Term Use of Benzodiazepines Associated With Worse Cognition Performance in Highly Educated Older Adults?

Background: Benzodiazepines (BZD) are common medications for sedative, hypnotic, and anxiolytic that are especially prevalent in older adults. Previous studies have shown that BZD use could impair users' cognition, significantly affecting their quality of life. Past research has shown that higher education might play a protective role in the process of cognitive decline. Very few studies had examined the cognitive effects of BZD on highly educated older adults. The study aimed to explore how cognitive functions would be affected by benzodiazepines among highly educated older adults. Method: 140 older adults with an average education period of 14.8 years were included in this study. The subjects were divided into three separate groups, the long-term BZD users (≥180 days), short-term BZD users (<180 days), and non-users. Demographics and cognitive assessments for the three groups were analyzed using the analysis of variance (ANOVA), the chi-squared test, and the analysis of covariance (ANCOVA). To examine the association between BZD use and cognition a multiple linear aggression approach was used. Result: All three groups were significantly different from each other when looking at executive functioning in the Trail Making Test B (TMT-B). Compared to the control group, short-term BZD users showed significant defects in TMT-B time (p = 0.002) and TMT-B errors (p < 0.001); long-term BZD users showed significant defect on TMT-B time (p = 0.041). Compared to short-term BZD users, long-term BZD users showed significant merit on TMT-B errors (p = 0.001). No significant differences were found in other cognitive tasks that reflected general cognition, verbal memory, language fluency, and visual memory. After adjusting for demographic, increased BZD use over time was positively associated with scores for the revised Brief Visuospatial Memory Test (r = 0.377, p = 0.012). Conclusion: BZD use may be significantly associated with worse executive functioning in highly educated older adults. However, there is no association between the duration of BZD use and increased cognitive deficits in highly educated older adults. This study identified future experimental directions including potential longitudinal studies, within-subject studies comparing mood disorder patients' cognitive performance before and after onset of BZD use, and between-subject studies that directly compare BZD's effect on subjects with the same baseline of cognitive functioning.

The Effects of Benzodiazepine Use and Abuse on Cognition in the Elders: A Systematic Review and Meta-Analysis of Comparative Studies.

OBJECTIVE: Benzodiazepines (BZD) are one of the most frequently prescribed drugs worldwide. However, the cognitive effects of benzodiazepines in the elderly are highly debated. This systematic review and meta-analysis aims to explore the following two questions in the elderly population: (i) Do BZD lead to any impairments in cognitive functions in elderly users? and (ii) Which specific cognitive domains are most affected by BZD use and abuse? METHODS: First, we performed a literature search following the PRISMA guidelines. Electronic databases, including PubMed, PsycINFO, EMBASE, Cochrane Library, and Web of Science were searched until May 14th, 2020. After selecting the relevant articles, we integrated the results of the selected studies with a standardized cognitive classification method. Next, we performed meta-analyses with the random-effects model on the cognitive results. Finally, we specifically examined the cognitive impairments of BZD in the abuse subgroup. RESULTS: Of the included studies, eight of the thirteen had meta-analyzable data. Compared to the controls, elderly BZD users had significantly lower digital symbol test scores (n=253; SMD: -0.61, 95% CI: -0.91 to 0.31, I² = 0%, p < 0.0001). There was no significant difference in Mini-Mental State Examination, Auditory Verbal Learning Test, and Stroop Color and Word Test scores between BZD users and controls. According to the subgroup analyses, BZD abusers performed significantly worse than controls in Mini-Mental State Examination (n=7726; SMD: -0.23, 95% CI: -0.44 to -0.03, I² = 86%, p = 0.02), while there was no significant difference between the regular BZD users and the controls (n=1536; SMD: -0.05, 95% CI: -0.59 to 0.48, I² = 92%, p =0.85). CONCLUSION: In the elderly population, the processing speed (digital symbol test scores) was significantly impaired in BZD users; global cognition (Mini-Mental State Examination scores) was significantly impaired in BZD abusers but not in BZD regular users. This study provides insight into the factors that interact with BZD cognitive effects, such as aging, testing tools, and abuse. Clinicians should be cautious when prescribing BZD for the elderly. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42019124711.

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.

METTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice.

Brown adipose tissue (BAT) undergoes rapid postnatal development and then protects against cold and obesity into adulthood. However, the molecular mechanism that determines postnatal development and maturation of BAT is largely unknown. Here we show that METTL3 (a key RNA methyltransferase) expression increases significantly in interscapular brown adipose tissue (iBAT) after birth and plays an essential role in the postnatal development and maturation of iBAT. BAT-specific deletion of Mettl3 severely impairs maturation of BAT in vivo by decreasing m6A modification and expression of Prdm16, Pparg, and Ucp1 transcripts, which leads to a marked reduction in BAT-mediated adaptive thermogenesis and promotes high-fat diet (HFD)-induced obesity and systemic insulin resistance. These data demonstrate that METTL3 is an essential regulator that controls iBAT postnatal development and energy homeostasis.

Purß promotes hepatic glucose production by increasing Adcy6 transcription.

OBJECTIVE: Enhanced glucagon signaling and hepatic glucose production (HGP) can account for hyperglycemia in patients with obesity and type 2 diabetes. However, the detailed molecular mechanisms underlying the enhanced HGP in these patients are not fully understood. Here, we identify Purß as a positive regulator of HGP and study its molecular mechanisms in the regulation of HGP both in vivo and in vitro. METHODS: Adenovirus-mediated knockdown or overexpression of Purß was performed in either primary hepatocytes or the livers of db/db mice. Glucose metabolism, insulin sensitivity, and HGP were determined by glucose, insulin, and lactate tolerance tests, respectively. Purß/ADCY6 protein levels, glucagon signaling (p-CREB/CREB), and insulin signaling (p-Akt/Akt) were measured by immunoblotting. Gene expression was measured by RNA-seq and real-time quantitative polymerase chain reaction. Luciferase reporter and chromatin immunoprecipitation assays were used to study the interaction between Purß and the Adcy6 promoter. RESULTS: Purß was abnormally elevated in obese mice and was also increased under fasting conditions or via the glucagon signaling pathway, which promoted HGP by increasing Adcy6 expression. Liver-specific knockdown of Purß in db/db mice significantly ameliorated hyperglycemia and glucose intolerance by suppressing the glucagon/ADCY6/cAMP/PKA/CREB signaling pathway. Consistent with this observation, the knockdown of Purß also inhibited glucose production in isolated primary hepatocytes by inhibiting the glucagon/ADCY6/cAMP/PKA/CREB signaling pathway, whereas the overexpression of Purß promoted glucose production by activating this signaling pathway. Mechanistically, Purß directly binds to the promoter of the Adcy6 gene and thereby promotes its transcription. CONCLUSIONS: Taken together, these results illustrate a new model in which Purß functions to regulate the glucagon/ADCY6/cAMP/PKA/CREB signaling pathway to help maintain glucose homeostasis.