Perihematomal Neurovascular Protection: Blocking HSP90 Reduces Blood Infiltration Associated with Inflammatory Effects Following Intracerebral Hemorrhage in Rates.

The active hemorrhage surrounding the hematoma is caused by the infiltration of blood into the cerebral parenchyma through the ruptured vessel, including the compromised blood-brain barrier (BBB). This process is thought to be mainly driven by inflammation and serves as a significant pathological characteristic that contributes to the neurological deterioration observed in individuals with intracerebral hemorrhage (ICH). Heat shock protein 90 (HSP90) exhibits abnormally high expression levels in various diseases and is closely associated with the onset of inflammation. Here, we found that blocking HSP90 effectively alleviates the inflammatory damage to BBB and subsequent bleeding around the hematoma. We have observed increased HSP90 levels in the serum of patients with ICH and the perihematoma region in ICH rats. Treatment with anti-HSP90 drugs (Geldanamycin and radicicol) effectively reduced HSP90 levels, resulting in enhanced neurological outcomes, decreased hematoma volume, and prevented peripheral immune cells from adhering to the BBB and infiltrating the brain parenchyma surrounding the hematoma in ICH rats. Mechanistically, anti-HSP90 therapy alleviated BBB injury caused by ICH-induced inflammation by suppressing TLR4 signaling. The study highlights the potential of anti-HSP90 therapy in mitigating BBB disruption and hemorrhage surrounding the hematoma, providing new insights into the management of ICH by targeting HSP90.

IL-6 and TIMP-1 Correlated to Airway Pathogen Colonization and Predict Disease Severity in Patients with Non-Cystic Fibrosis Bronchiectasis.

Background: Non-cystic fibrosis bronchiectasis is associated with airway pathogen colonization. We planned to investigate the inflammatory markers in patients with different airway pathogens and their correlation with disease severity. Methods: We enrolled patients aged between 20 and 75 from October 2021 to August 2022. All patients had sputum evaluation for bacterial and fungal cultures before enrollment, and were classified into four groups according to the culture results. Results: Forty-four patients with non-CF bronchiectasis and six controls were enrolled and categorized as follows: Group 1, no pathogens identified in sputum cultures (n = 14); Group 2, positive fungal culture results (n = 18); Group 3, positive P. aeruginosa culture results (n = 7); and Group 4, positive culture results for both fungi and P. aeruginosa (n = 5). Group 4 had significantly higher serum defensin α1, IL-6 and tissue inhibitors of MMP (TIMP)-1 levels than group 1 patients. The serum levels of IL-6 and TIMP-1 were positively correlated with the FACED score and negatively correlated with distance-saturation product. Conclusion: Significantly higher levels of serum IL-6 and TIMP-1 were found in the patients who had concomitant fungal and P. aeruginosa colonization, and were closely related to clinical severity and may have important roles in disease monitoring.

Sustainable Cr(VI) reduction in a membrane-less TPBC-MFC driven by solid watermelon rind.

Sustainable Cr(VI) reduction by microbial fuel cell (MFC) is a major challenge due to the electrode passivation and available electron donors. In this study, the chromate removal across a period of more than three months in a membrane-less TPBC-MFC with solid watermelon rind (SWMR) as electron donors was investigated. The TPBC benefited the Cr(VI) reduction and voltage output owing to the enhanced mass transfer. The average Cr(VI) removal efficiency (RE) of 97%, effluent COD of 80 mg/L and voltage output of 130 mV were achieved during the long-term operation on the TPBC-MFC. The SEM-EDS analysis showed that all biofilms were predominated by rod- and coccus-shaped bacteria and the Cr(VI) reduction was mainly carried out by the S-cathode. The XPS, XRD and FT-IR analysis revealed that the major product of cathodic Cr(VI) reduction was a Cr(III) precipitate in the form of Cr(OH)3. Microbial community structure disclosed that fermentation microorganisms (e.g. Anaeroarcus) and electroactive bacteria (e.g. Porphyromonadaceae) jointly responsible for SWMR degradation and electricity generation were dominant at the anode, while the chromate-associated microorganisms (e.g. Comamonadaceae and Cloacibacterium) dominated at the cathode. The biofilms adsorbing Cr(OH)3 precipitates fell off from the cathode periodically to avoid the passivation. Overall, our study suggests a really sustainable approach with which a goal of simultaneously reusing watermelon rind, reducing Cr(VI) and producing electricity was attained perfectly.

Clinical Predictors of Nontuberculous Mycobacteria Lung Disease and Coisolates of Potential Pathogenic Microorganisms in Noncystic Fibrosis Bronchiectasis.

Background: In bronchiectasis, nontuberculous mycobacteria (NTM) lung disease (NTM-LD) is a well-known coexisting infection. However, microorganism coisolates and clinical NTM-LD predictors are poorly studied. Methods: Patients with bronchiectasis diagnosed by means of computed tomography between January 2017 and June 2020 were screened, using the date of computed tomography as the index date. Those with a major bronchiectasis diagnosis in ≥2 follow-up visits after the index date were enrolled in the study, and NTM-LD occurrence and its association with pneumonia and hospitalization within 1 year were analyzed. Results: Of the 2717 participants, 79 (2.9%) had NTM-LD diagnosed. The factors associated with NTM-LD included hemoptysis, postinfectious bronchiectasis, a tree-in-bud score ≥2, a modified Reiff score ≥4, and chronic obstructive pulmonary disease (adjusted odds ratios, 1.80, 2.36, 1.78, 2.95, and 0.51, respectively). Compared with patients in the non-NTM group, those with NTM-LD had higher rates of hospitalization (15.9% vs 32.9%; P < .001) and pneumonia (9.8% vs 20.3%; P = .003). Pseudomonas aeruginosa was the most common microorganism in those with NTM-LD and those in the non-NTM group (10.1% vs 7.8%; P = .40). However, compared with those in the non-NTM group, Acinetobacter baumannii and Escherichia coli were more prevalent in patients with NTM-LD (0.7% vs 3.8% [P = .03%] and 1.0% vs 3.8% [P = .05], respectively). Conclusions: Postinfectious bronchiectasis with hemoptysis, higher radiological involvement, and a tree-in-bud pattern were associated with NTM-LD risk. The rate of A baumannii and E coli coisolation was higher in bronchiectasis populations with NTM-LD.

Alternation of psychological resilience may moderate mentalization toward mental health conditions from macro- and microstructure aspects.

OBJECTIVE: We aim to investigate the interplay between mentalization, brain microstructure, and psychological resilience as potential protective factors against mental illness. METHOD: Four hundred and twenty-six participants (mean age 40.12±16.95; 202 males, 224 females), without psychiatric or neurological history, completed assessments: Dissociative Process Scale (DPS), Peace of Mind (PoM), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Resilience Scale for Adults (RSA), and Magnetic Resonance Imaging (MRI) structures with selected regions of interest, and Diffusion Tensor Imaging (DTI) maps from various tracts in the right hemisphere and connection to the frontal areas, including anterior thalamic radiation (ATR), Cingulum (hippocampus) (CH), Corticospinal tract (CST), Superior longitudinal fasciculus (SLF), Inferior fronto-occipital fasciculus (IFOF), and Uncinate fasciculus (UF) were analyzed. RESULTS: Two clusters, representing hypomentalization (HypoM) and hypermentalization (HyperM), were identified based on DPS, CPSS, and RFQ responses. One-way ANOVA showed no significant age or gender differences between clusters. The HypoM group exhibited lower PoM scores, higher BDI and BAI scores, and lower RSA scores (ps< 0.05). Structural brain metric comparison showed significant differences in GMV in the right caudal middle frontal gyrus (rcMFG), right superior frontal gyrus (rsFG), and right frontal pole (rFP) between groups. In addition, the HyperM individuals with a higher risk of depression and a higher ratio of intrapersonal to interpersonal factors of resilience were found with reduced GMV on the rcMFG. Additionally, analyses of DTI metrics revealed significant differences between two groups in rATR and rSLF in terms of fractional anisotropy (FA) values; rATR, rCST, rUF, rSLF, rCH and rIFOF in terms of mean diffusivity (MD) values, and radial diffusivity (RD) (corrected p = 0.05). Moreover, the positive correlation between different domains of resilience and white matter (WM) integrity implied further enhancement of intrapersonal or interpersonal resilience factors that are different for people with different mentalization. CONCLUSIONS: The findings underscore the importance of considering both intrapersonal and interpersonal factors in understanding the interactions between psychological resilience and mental health conditions relevant to brain mechanisms.

Bacterial Genomics for National Antimicrobial Resistance Surveillance in Cambodia.

BACKGROUND: Antimicrobial resistance (AMR) surveillance in low- and middle-income countries (LMICs) often relies on poorly resourced laboratory processes. Centralized sequencing was combined with cloud-based, open-source bioinformatics solutions for national AMR surveillance in Cambodia. METHODS: Blood cultures growing gram-negative bacteria were collected at six Cambodian hospitals (January 2021 - October 2022). Isolates were obtained from pure plate growth and shotgun DNA sequencing performed in-country. Using public nucleotide and protein databases, reads were aligned for pathogen identification and AMR gene characterization. Multilocus sequence typing was performed on whole genome assemblies and haplotype clusters compared against published genomes. FINDINGS: Genes associated with acquired resistance to fluoroquinolones were identified in 59%, TMP/SMX in 45%, and aminoglycosides in 52% of 715 isolates. Extended-spectrum beta-lactamase encoding genes were identified in 34% isolates, most commonly blaCTX-M-15, blaCTX-M-27, and blaCTX-M-55 in E. coli sequence types 131 and 1193. Carbapenemase genes were identified in 12% isolates, most commonly blaOXA-23, blaNDM-1, blaOXA-58 and blaOXA-66 in Acinetobacter species. Phylogenetic analysis revealed clonal strains of A. baumannii, representing suspected nosocomial outbreaks, and genetic clusters of quinolone-resistant typhoidal Salmonella and ESBL E. coli cases suggesting community transmission. INTERPRETATION: With accessible sequencing platforms and bioinformatics solutions, bacterial genomics can supplement AMR surveillance in LMICs. FUNDING: Research was supported by the National Institute of Allergy and Infectious Diseases and the Bill and Melinda Gates Foundation [OPP1211806].

Intravenous thrombolysis versus dual antiplatelet therapy in minor ischemic stroke within the thrombolytic window (TAMIS): a multicenter cohort study.

Intravenous thrombolysis (IVT) and dual antiplatelet therapy (DAPT) have been widely used in minor ischemic stroke (MIS) treatment. However, the clinical outcomes and safety of these two treatments have not been compared within the early thrombolytic time window. Here, we conducted a multicenter, ambispective cohort study involving patients with MIS presenting within 4.5 h of symptom onset at 3 affiliated hospitals of Jinan University from 2018-2022. The patients were divided into the IVT group and DAPT group. The primary outcome was a 90-day excellent outcome (mRS ≤ 1). A total of 1,026 patients were enrolled, of whom 492 were assigned to the IVT group and 534 were assigned to the DAPT group. The IVT group had better 90-day excellent outcomes (mRS ≤ 1) than the DAPT group (OR 1.69, 95% CI 1.14-2.52, P = 0.010). Among the 623 patients with nondisabling stroke, the proportion of mRS ≤ 1 in the IVT group was higher than the DAPT group (P = 0.009). In the subtypes of MIS with large vessel occlusion/stenosis and with isolated symptoms, the 90-day outcomes of the IVT group and DAPT group were not different (P > 0.05). In conclusion, compared with DAPT, IVT was associated with better 90-day clinical outcomes in patients with MIS (in particular, for those with mRS > 1), including earlier clinical improvement.IVT also benefited the early neurological improvement of patients with severe stenosis/occlusion of intracranial large vessels, nondisabling mild stroke, nondisabling mild stroke with isolated symptoms.

Exercise habits and mental health: Exploring the significance of multimodal imaging markers.

Engaging in regular physical activity and establishing exercise habits is known to have multifaceted benefits extending beyond physical health to cognitive and mental well-being. This study explores the intricate relationship between exercise habits, brain imaging markers, and mental health outcomes. While extensive evidence supports the positive impact of exercise on cognitive functions and mental health, recent advancements in multimodal imaging techniques provide a new dimension to this exploration. By using a cross-sectional multimodal brain-behavior statistic in participants with different exercise habits, we aim to unveil the intricate mechanisms underlying exercise's influence on cognition and mental health, including the status of depression, anxiety, and quality of life. This integration of exercise science and imaging promises to substantiate cognitive benefits on mental health and uncover functional and structural changes underpinning these effects. This study embarks on a journey to explore the significance of multimodal imaging metrics (i.e., structural and functional metrics) in deciphering the intricate interplay between exercise habits and mental health, enhancing the comprehension of how exercise profoundly shapes psychological well-being. Our analysis of group comparisons uncovered a strong association between regular exercise habits and improved mental well-being, encompassing factors such as depression, anxiety levels, and overall life satisfaction. Additionally, individuals who engaged in exercise displayed enhanced brain metrics across different modalities. These metrics encompassed greater gray matter volume within the left frontal regions and hippocampus, improved white matter integrity in the frontal-occipital fasciculus, as well as more robust functional network configurations in the anterior segments of the default mode network. The interplay between exercise habits, brain adaptations, and mental health outcomes underscores the pivotal role of an active lifestyle in nurturing a resilient and high-functioning brain, thus paving the way for tailored interventions and improved well-being.

Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder.

Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.

Correlating Reiff scores with clinical, functional, and prognostic factors: characterizing noncystic fibrosis bronchiectasis severity: validation from a nationwide multicenter study in Taiwan.

BACKGROUND: Our study aimed to confirm a simplified radiological scoring system, derived from a modified Reiff score, to evaluate its relationship with clinical symptoms and predictive outcomes in Taiwanese patients with noncystic fibrosis bronchiectasis (NCFB). METHODS: This extensive multicenter retrospective study, performed in Taiwan, concentrated on patients diagnosed with NCFB verified through high-resolution computed tomography (HRCT) scans. We not only compared the clinical features of various types of bronchiectasis (cylindrical, varicose, and cystic). Furthermore, we established relationships between the severity of clinical factors, including symptom scores, pulmonary function, pseudomonas aeruginosa colonization, exacerbation and admission rates, and HRCT parameters using modified Reiff scores. RESULTS: Data from 2,753 patients were classified based on HRCT patterns (cylindrical, varicose, and cystic) and severity, assessed by modified Reiff scores (mild, moderate, and severe). With increasing HRCT severity, a significant correlation was found with decreased forced expiratory volume in the first second (FEV1) (p < 0.001), heightened clinical symptoms (p < 0.001), elevated pathogen colonization (pseudomonas aeruginosa) (p < 0.001), and an increased annual hospitalization rate (p < 0.001). In the following multivariate analysis, elderly age, pseudomonas aeruginosa pneumonia, and hospitalizations per year emerged as the only independent predictors of mortality. CONCLUSION: Based on our large cohort study, the simplified CT scoring system (Reiff score) can serve as a useful adjunct to clinical factors in predicting disease severity and prognosis among Taiwanese patients with NCFB.

The effect of age and resilience on the dose-response function between the number of adversity factors and subjective well-being.

Background: Encountering challenges and stress heightens the vulnerability to mental disorders and diminishes well-being. This study explores the impact of psychological resilience in the context of adverse events, considering age-related variations in its influence on well-being. Methods: A total of 442 participants (male vs. female =48% vs. 52%) with a mean age of 41.79 ± 16.99 years were collected and completed the following questionnaires Brief Betrayal Trauma Survey (BBTS), Brief Resilience Scale (BRS), Peace of Mind (PoM), The World Health Organization Quality of Life-BREF (WHOQOL-BREF), and Social Support Questionnaire (SSQ). They all underwent structural and resting-state functional magnetic resonance imaging (MRI) scans. Results: Participants were categorized based on adversity levels: 34.39% faced one, 26.24% none, and 19.91, 9.50, and 8.14% encountered two, three, and four adversities, respectively. This categorization helps assess the impact on participants' experiences. As adversity factors increased, PoM decreased. Controlling for age improved PoM model fit (ΔR2 = 0.123, p < 0.001). Adversity factors and age explained 14.6% of PoM variance (df = 2, F = 37.638, p < 0.001). PoM decreased with more adversity and increased with higher age. Conclusion: The study found most participants faced at least one adversity. Adversity negatively affected PoM scores, while resilience acted as a protective factor. Resilience plays a crucial role in buffering the impact of adversities on well-being. Among those with high adversity, higher resilience correlated with stronger DMN-right frontal pole connectivity. Brain volume showed no significant differences, but the quality of life and social support varied between subgroups, with no differences in personal demographic and biophysical features.

Epidemiology and outcomes of multidrug-resistant bacterial infection in non-cystic fibrosis bronchiectasis.

PURPOSE: Multidrug-resistant (MDR) bacteria impose a considerable health-care burden and are associated with bronchiectasis exacerbation. This study investigated the clinical outcomes of adult patients with bronchiectasis following MDR bacterial infection. METHODS: From the Chang Gung Research Database, we identified patients with bronchiectasis and MDR bacterial infection from 2008 to 2017. The control group comprised patients with bronchiectasis who did not have MDR bacterial infection and were propensity-score matched at a 1:2 ratio. The main outcomes were in-hospital and 3-year mortality. RESULTS: In total, 554 patients with both bronchiectasis and MDR bacterial infection were identified. The types of MDR bacteria that most commonly affected the patients were MDR- Acinetobacter baumannii (38.6%) and methicillin-resistant Staphylococcus aureus (18.4%), Extended-spectrum-beta-lactamases (ESBL)- Klebsiella pneumoniae (17.8%), MDR-Pseudomonas (14.8%), and ESBL-E. coli (7.5%). Compared with the control group, the MDR group exhibited lower body mass index scores, higher rate of chronic bacterial colonization, a higher rate of previous exacerbations, and an increased use of antibiotics. Furthermore, the MDR group exhibited a higher rate of respiratory failure during hospitalization (MDR vs. control, 41.3% vs. 12.4%; p < 0.001). The MDR and control groups exhibited in-hospital mortality rates of 26.7% and 7.6%, respectively (p < 0.001); 3-year respiratory failure rates of 33.5% and 13.5%, respectively (p < 0.001); and 3-year mortality rates of 73.3% and 41.5%, respectively (p < 0.001). After adjustments were made for confounding factors, the infection with MDR and MDR bacteria species were determined to be independent risk factors affecting in-hospital and 3-year mortality. CONCLUSIONS: MDR bacteria were discovered in patients with more severe bronchiectasis and were independently associated with an increased risk of in-hospital and 3-year mortality. Given our findings, we recommend that clinicians identify patients at risk of MDR bacterial infection and follow the principle of antimicrobial stewardship to prevent the emergence of resistant bacteria among patients with bronchiectasis.

The role of attitudes towards contradiction in psychological resilience: the cortical mechanism of conflicting resolution networks.

Managing contradictions and building resilience help us overcome life's challenges. Here, we explored the link between attitudes towards contradictions and psychological resilience, examining the role of cortical conflict resolution networks. We enlisted 173 healthy young adults and used questionnaires to evaluate their cognitive thinking styles and resilience. They underwent structural and functional magnetic resonance imaging scans. Our results revealed that contrasting attitudes toward contradictions, formal logic, and naïve dialecticism thinking styles corresponded with varying degrees of resilience. We noted structural and functional differences in brain networks related to conflict resolution, including the inferior frontal and parietal cortices. The volumetric variations within cortical networks indicated right-hemispheric lateralization in different thinking styles. These findings highlight the potential links between conflict resolution and resilience in the frontoparietal network. We underscore the importance of frontoparietal brain networks for executive control in resolving conflicting information and regulating the impact of contradictions on psychological resilience.

Clinical application of trio-based whole-exome sequencing in idiopathic generalized epilepsy.

PURPOSE: Idiopathic generalized epilepsies (IGEs) are a common group of genetic generalized epilepsies with high genetic heterogeneity and complex inheritance. However, the genetic basis is still largely unknown. This study aimed to explore the genetic etiologies in IGEs. METHODS: Trio-based whole-exome sequencing was performed in 60 cases with IGEs. The pathogenicity of candidate genetic variants was evaluated by the criteria of the American College of Medical Genetics and Genomics (ACMG), and the clinical causality was assessed by concordance between the observed phenotype and the reported phenotype. RESULTS: Seven candidate variants were detected in seven unrelated cases with IGE (11.7%, 7/60). According to ACMG, a de novo SLC2A1 (c.376C>T/p.Arg126Cys) variant identified in childhood absence epilepsy was evaluated as pathogenic with clinical concordance. Six variants were assessed to be uncertain significance by ACMG, but then considered causative after evaluation of clinical concordance. These variants included CLCN4 hemizygous variant (c.2044G>A/p.Glu682Lys) and IQSEC2 heterozygous variant (c.4315C>T/p.Pro1439Ser) in juvenile absence epilepsy, EFHC1 variant (c.1504C>T/p.Arg502Trp) and CACNA1H (c.589G>T/p.Ala197Ser) both with incomplete penetrance in juvenile myoclonic epilepsy, and GRIN2A variant (c.2011C>G/p.Gln671Glu) and GABRB1 variant (c.1075G>A/p.Val359Ile) both co-segregated with juvenile myoclonic epilepsy. Among them, GABRB1 was for the first time identified as potential novel causative gene for IGE. SIGNIFICANCE: Considering the genetic heterogeneity and complex inheritance of IGEs, a comprehensive evaluation combined the ACMG scoring and assessment of clinical concordance is suggested for the pathogenicity analysis of variants identified in clinical screening. GABRB1 is probably a novel causative gene for IGE, which warrants further studies.

Association of FAT1 with focal epilepsy and correlation between seizure relapse and gene expression stage.

PURPOSE: The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy. METHODS: Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform. RESULTS: Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalised tonic-clonic seizures. They responded well toantiseizure medication, but seizures relapsed in three cases when antiseizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be "Strong" by the Clinical Validity Framework of ClinGen. CONCLUSIONS: FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration ofantiseizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.

Drug resistance and genetic diversity of clinical strains of Helicobacter pylori in the Qiannan Prefecture and Guiyang City,and their relationships with diseases / 中国人兽共患病学报

To understand Helicobacter pylori's drug resistance,genetic diversity,and relationship with clinical diseases in the Guiyang and Qiannan minority areas of Guizhou Province,we collected samples through endoscopy,and isolated and cul-tured H.pylori.The drug resistance and genotype characteristics were determined.The differences in different regions and dis-ease types were compared,and the structural characteristics of H.pylori and mixed infections with different strains of H.py-lori in Qiannan Prefecture were analyzed.A difference in the composition ratio of EPYIA typing in the cagA variable region was observed between the two areas(P=0.012),and the composition ratio of the vacA genotype differed(P=0.000).A total of 94.6％(53/56)new sequences of H.pylori strains from two regions were obtained by MLST.The rate of infection by H.pylori mixed with different strains was 44.4％in Qiannan Pre-fecture,and no significant difference was observed in the com-position of H.pylori mixed infections among patients with dif-ferent clinical diseases(P=0.349).Differences in EPI YA typ-ing and the vacA genotype composition ratio in the cagA varia-ble region of H.pylori were observed between the Qiannan Prefecture and Guiyang City.

Predictors of failure of early neurological improvement in early time window following endovascular thrombectomy: a multi-center study.

Background and objective: Endovascular thrombectomy (EVT) has become the gold standard in the treatment of acute stroke patients. However, not all patients respond well to this treatment despite successful attempts. In this study, we aimed to identify variables associated with the failure of improvements following EVT. Methods: We retrospectively analyzed prospectively collected data of 292 ischemic stroke patients with large vessel occlusion who underwent EVT at three academic stroke centers in China from January 2019 to February 2022. All patients were above 18 years old and had symptoms onset ≤6 h. A decrease of more than 4 points on the National Institute of Health Stroke Scale (NIHSS) after 24 h compared with admission or an NIHSS of 0 or 1 after 24 h was defined as early neurological improvement (ENI), whereas a lack of such improvement in the NIHSS was defined as a failure of early neurological improvement (FENI). A favorable outcome was defined as a modified Rankin scale (mRS) score of 0-2 after 90 days. Results: A total of 183 patients were included in the final analyses, 126 of whom had FENI, while 57 had ENI. Favorable outcomes occurred in 80.7% of patients in the ENI group, in contrast to only 22.2% in the FENI group (p < 0.001). Mortality was 7.0% in the ENI group in comparison to 42.1% in the FENI group (p < 0.001). The multiple logistic regression model showed that diabetes mellitus [OR (95% CI), 2.985 (1.070-8.324), p = 0.037], pre-stroke mRS [OR (95% CI), 6.221 (1.421-27.248), p = 0.015], last known well to puncture time [OR (95% CI), 1.010 (1.003-1.016), p = 0.002], modified thrombolysis in cerebral infarction = 3 [OR (95% CI), 0.291 (0.122-0.692), p = 0.005], and number of mechanical thrombectomy passes [OR (95% CI), 1.582 (1.087-2.302), p = 0.017] were the predictors of FENI. Conclusion: Diabetes mellitus history, pre-stroke mRS, longer last known well-to-puncture time, lack of modified thrombolysis in cerebral infarction = 3, and the number of mechanical thrombectomy passes are the predictors of FENI. Future large-scale studies are required to validate these findings.

Targeting autophagy with SAR405 alleviates doxorubicin-induced cardiotoxicity.

Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.

Multimodal magnetic resonance imaging in the diagnosis of cervical cancer and its correlation with the differentiation process of cervical cancer.

PURPOSE: This study seeks to evaluate the value of MRI (Magnetic resonance imaging) diffusion weighted images (DWI), diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) in the diagnosis of cervical carcinoma. METHODS: Seventy-nine cases of cervical cancer (CC group) (39 cases of squamous carcinoma (SCC group) and 40 cases of adenocarcinoma (ACC group)) and 30 cases of healthy controls (HC group) were included in this study. All the subjects were informed of the purpose of this study. The study was approved by the Ethics Committee of Beihua University Hospital, Jinlin, China. In this study, images were acquired based on a 3T MR scanner (Ingenia; Philips, Best, the Netherlands) and measured the imaging parameters by DWI, IVIM and DKI techniques. The parameters were obtained by Philips post-processing workstation, DKE and IVIM. These ROIs (region of interest) were manually drawn on each parameter mapping image by MRI physicians. Finally, SPSS 23.0 statistical software was used for data analysis. RESULTS: The ADC (apparent diffusion coefficient) value of M group was lower than that of N group, and the difference was statistically significant (P < 0.05). The D (true diffusion coefficient) value, D*(pseudo diffusion coefficient) value, f (perfusion fraction) value, MD (mean diffusivity) value, and ADC value in the SCC group were lower than those in the ACC group with statistically significant differences (P < 0.05). The MK (mean kurtosis) value was higher than that of the ACC group, and the difference was statistically significant (P < 0.05). Compared with the HC group, the ADC values, D values, MD values of group CC group were lower, and the D* values, f values, MK values were higher; all the parameters were statistically significant (P < 0.05). The higher the differentiation degree of cervical cancer, the higher ADC values, D values, MD values, and the smaller D* values, f values, MK values. The difference of ADC values, D values and MK values was statistically significant (P < 0.05). MK value had the best diagnostic efficiency in the differential diagnosis of cervical cancer with low and medium differentiation, high and low differentiation (P < 0.05). There was no significant difference in the f value between high and low differentiation cervical cancer (P > 0.05). There was no significant difference in the MD value between low and high differentiation cervical cancer (P > 0.05). The strongest correlation between MK values (r = 0.796) and the degree of pathological differentiation of cervical cancer is positively correlated. The D values, MD values, and ADC values are negatively correlated with the degree of pathological differentiation of cervical cancer. CONCLUSION: The ADC value of DWI parameters has important diagnostic value for different menstrual states of cervical cancer. The parameter values of DWI, IVIM, and DKI can be used to differentiate cervical cancer from normal cervical tissue, and thus have important diagnostic value for differentiating pathological types of cervical cancer. This means that these parameter values may have great significance in the differential diagnosis of cervical cancer with different degrees of pathological differentiation. The pathological differentiation degree of cervical cancer is significantly positively correlated with the MK value in the parameter values of DWI, IVIM, and DKI, while negatively correlated with the D value, MD value, and ADC value.

Effect of atrial fibrillation on outcomes in patients with anterior circulation occlusion stroke receiving endovascular therapy.

Objective: Atrial fibrillation is one of the major risk factors of ischemic stroke. Endovascular thrombectomy (EVT) has become the standard treatment for acute ischemic stroke with large vessel occlusion. However, data regarding the impact of AF on the outcome of patients with acute ischemic stroke treated with mechanical thrombectomy are controversial. The aim of our study was to determine whether atrial fibrillation modifies the functional outcome of patients with anterior circulation acute ischemic stroke receiving EVT. Methods: We reviewed 273 eligible patients receiving EVT from January 2019 to January 2022 from 3 comprehensive Chinese stroke centers, of whom 221 patients were recruited. Demographics, clinical, radiological and treatment characteristics, safety outcomes, and functional outcomes were collected. Modified Rankin scale (mRS) score ≤ 2 at 90 days was defined as a good functional outcome. Results: In our cohort, 79 patients (35.74%) were eventually found to have AF. Patients with AF were elder (70.08 ± 11.72 vs. 61.82 ± 13.48 years, p = 0.000) and less likely to be males (54.43 vs. 73.94%, p = 0.03). The significant reperfusion rate (modified thrombolysis in cerebral infarction 2b-3) was 73.42 and 83.80% in patients with and without AF, respectively (p = 0.064). The good functional outcome (90-day modified Rankin scale: 0 to 2) rate was 39.24 and 44.37% in patients with and without AF, respectively (p = 0.460) after adjusting multiple confounding factors. There was no difference in the presence of symptomatic intracerebral hemorrhage between the two groups (10.13 vs. 12.68%, p = 0.573). Conclusion: Despite their older age, AF patients achieved similar outcomes as non-AF patients with anterior circulation occlusion treated with endovascular therapy.