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.

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.

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 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.

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.

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.

The applied value in brain gray matter nuclei of patients with early-stage Parkinson's disease : a study based on multiple magnetic resonance imaging techniques.

PURPOSE: This study compares the observation efficiency of brain gray matter nuclei of patients with early-stage Parkinson's disease among various Magnetic Resonance Imaging techniques, which include susceptibility weighted imaging (SWI), quantitative susceptibility imaging (QSM), diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI). Based on the findings, this study suggests an efficient combination of scanning techniques for brain gray matter nuclei observation, aiming to provide an opportunity to advance the understanding of clinical diagnosis of early-stage Parkinson's disease. METHODS: Forty examinees, including twenty patients who were clinically diagnosed with early Parkinson's disease with a course of 0.5-6 years (PD group) and twenty healthy controls (HC group), underwent head MRI examination. Philips 3.0T (tesla) MR machine was used to measure the imaging indexes of gray matter nuclei in patients with early Parkinson's disease. SWI, QSM, DTI and DKI were used for diagnosis. SPSS (Statistical Product and Service Solutions) 21.0 was used for data analysis. RESULTS: When SWI was used, fifteen PD patients and six healthy volunteers were diagnosed correctly. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic coincidence rate about the diagnosis of nigrosome-1 on imaging were 75.0%, 30.0%, 51.7%, 54.5% and 52.5% respectively. By contrast, when QSM was used, 19 PD patients and 11 healthy volunteers were diagnosed correctly. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic coincidence rate about the diagnosis of Nigrosome-one on imaging were 95.0%, 55.0%, 67.9%, 91.7% and 75.0% respectively. The mean kurtosis (MK) value within both the substantia nigra and thalamus, together with the mean diffusivity (MD) within both the substantia nigra and the head of caudate nucleus in PD group was greater than that of HC group. The susceptibility values within the substantia nigra, red nucleus, head of caudate nucleus and putamen of PD group was greater than that of HC group. The MD value in substantia nigra reveals the optimal diagnostic efficiency to distinguish the HC group and the PD group, followed by the MK value in substantia nigra. Specifically, the maximum area under ROC curve (AUC) of the MD value was 0.823, the sensitivity 70.0%, the specificity 85.0%, and the diagnostic threshold 0.414. The area under ROC curve (AUC) of the MK value was 0.695, the sensitivity 95.0%, the specificity 50.0%, and the diagnostic threshold was 0.667. Both of them were statistically significant. CONCLUSIONS: In the early diagnosis of Parkinson's disease, QSM is more efficient than SWI in observing nigrosome-1 in substantia nigra. In the early diagnosis of Parkinson's disease, MD and MK values of substantia nigra in DKI parameters have higher diagnostic efficiency. The combined scanning of DKI and QSM has the highest diagnostic efficiency and provides imaging basis for clinical diagnosis of early Parkinson's disease.

Pretreatment of 3-MA prevents doxorubicin-induced cardiotoxicity through inhibition of autophagy initiation.

Anthracycline antineoplastics are effective in the treatment of hematological malignancies and solid tumors. However, the anthracycline-induced cardiotoxicity (AIC) limits their use as chemotherapeutic agents. Autophagy-based therapies have been explored to prevent AIC. Yet, whether inhibition of autophagy during its early stage could alleviate AIC remains unclear. In this study, we firstly observed the activation of autophagy during AIC in both cardiomyocyte cell lines AC16 and H9c2. Moreover, knockdown of Atg7, a key regulatory factor in early autophagy, could ameliorate the effects of DOX-induced AIC. Importantly, the use of early autophagy inhibitor 3-MA protected cardiomyocyte cells from DOX-induced cardiotoxicity in vitro and in a chronic AIC mouse model. Our findings demonstrate that inhibiting early stage of autophagy may be an effective preventative therapeutic strategy to protect cardiac function from AIC.

The Mediating Role of Brain Structural Imaging Markers in Connecting Adverse Childhood Experiences and Psychological Resilience.

The impact of adverse childhood experiences (ACEs) on brain structure has been noticed. Resilience has been considered a protective characteristic from being mentally ill; however, the link between ACEs, psychological resilience, and brain imaging remains untested. A total of 108 participants (mean age 22.92 ± 2.43 years) completed the ACEs questionnaire and the Resilience Scale for Adults (RSA), with five subscales: personal strength (RSA_ps), family cohesion (RSA_fc), social resources (RSA_sr), social competence (RSA_sc), and future structured style (RSA_fss), and Magnetic Resonance Imaging (MRI) to acquire imaging data, and the fusion-independent component analysis was employed to determine multimodal imaging components. The results showed a significantly negative association between ACE subscales and RSA_total score (ps < 0.05). The parallel mediation model showed significant indirect mediation of mean gray matter volumes in the regions of the middle frontal gyrus, superior frontal gyrus, posterior cingulate, superior temporal gyrus, middle temporal gyrus, postcentral gyrus, middle temporal gyrus, and precuneus between childhood maltreatment and RSA_sr and RSA_sc. (ps < 0.05). This study highlighted the ACEs effect on gray matter volumes in the regions of the middle frontal gyrus, superior frontal gyrus, posterior cingulate, superior temporal gyrus, middle temporal gyrus, postcentral gyrus, middle temporal gyrus, and precuneus leading to decreased psychological resilience.

Clinical manifestations and outcomes of fungus-associated asthma: A multi-institution database study in Taiwan.

BACKGROUND: Differences in the clinical phenotypes and outcomes of fungus-associated asthma remain unclear. We aimed to investigate the presentation of asthmatics with fungal sensitization and/or positive fungal isolates. METHODS: Clinical characteristics, pulmonary function, microbiological data, allergy test reports, emergency department (ED) visits and hospitalizations were retrieved from the Chang Gung Research Database between 2010 and 2018; the largest electronic medical record-based database in Taiwan. Follow-up care was provided to each patient for 3 years. RESULTS: A total of 30,754 asthmatics were enrolled, and 7976 were eligible for analysis after applying the exclusion criteria. Of these patients, 694 had sputum examinations for fungi. The patients were divided into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n = 386); group 2, positive fungal sensitization (n = 58); group 3, positive fungal isolates (n = 217); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n = 33). Asthmatic patients with fungal sensitization (groups 2 and 4) demonstrated significantly higher IgE levels compared with those without (groups 1 and 3). Group 4 patients had a higher frequency of hospitalization. Amongst patients under Global Initiative for Asthma (GINA) step 4-5 therapies, group 4 asthmatics possessed significantly higher incidence of respiratory failure. CONCLUSIONS: The prevalence of fungal sensitization and fungal isolates from sputum were even across asthmatic severities, but the clinical impact of fungi may be more significant among patients with more severe disease.

Single-cell RNA sequencing analysis revealed cellular and molecular immune profiles in lung squamous cell carcinoma.

Although breakthroughs have been made in the treatment of non-small cell lung cancer, there are only a few choices for advanced-stage or recurrent lung squamous cell carcinoma (LUSC) patients. In our study, we identified 7 major cell types in thedepicted the immunolandscape of LUSC microenvironment using single-cell RNA sequencing. We found that an immunosuppressive receptor, T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), was highly expressed by regulatory T cells (Tregs) and exhausted CD8+T cells, suggesting that upregulation of TIGIT might promote an immunosuppressive microenvironment and inhibit the cytotoxic ability of CD8+T cells. We also identified tumor-associated neutrophil (TAN), characterized by CXCR2, CSF3R and CXCL8, in the tumor region, and TANs upregulated the expression of interleukin 1 receptor antagonist (IL1RN) which suggested that TAN might exert an immunosuppressive role via expressing IL1RN. Furthermore, the number of SPP1+ macrophages(SPP1+M) significantly increased in tumor microenvirnment, which was correlated with the poor survival of patients. Additionally, regulatory networks based on SPP1+M revealed that the disparities of several ligand-receptor pairs existed between tumor and normal tissues. Among these pairs, SPP1-CD44 showed the most interactions between SPP1+M and other cell types. Our results provided deep insight into the immune landscape of LUSC and an essential resource for drug discovery in the future.

Age differences in the functional organization of the prefrontal cortex: analyses of competing hypotheses.

We employed a mixed design task for block and event-related functional magnetic resonance imaging with manipulations of levels of abstraction and duration in task-relevant cues and probes. Age-related differences between younger and older adults in task-related functional brain activity patterns of the prefrontal cortex (PFC) were reported. The results showed that (1) the low episodic condition evoked more activity in the more anterior PFC than the high episodic control condition for both age groups; (2) the low abstraction condition evoked more activity in the more anterior PFC than the high abstraction condition for both age groups; and (3) the signal change did not vary as a function of activity dynamics (transient and sustained responses) and maintenance duration (single-trial and multiple-trial). The findings showed that baseline conditions evoked more activity in the more anterior PFC for the older group than the younger group across most task contrasts and conditions, where these additional activities in the brain regions overlapped within the default mode network (DMN). We tentatively concluded that deficiency in the anterior DMN deactivation during externally driven tasks might be attributed to less efficiency in modulating local connectivity propagate to surrounding tissue, which may paradoxically increase brain activity.

Metagenomic Pathogen Sequencing in Resource-Scarce Settings: Lessons Learned and the Road Ahead.

Metagenomic next-generation sequencing (mNGS) is the process of sequencing all genetic material in a biological sample. The technique is growing in popularity with myriad applications including outbreak investigation, biosurveillance, and pathogen detection in clinical samples. However, mNGS programs are costly to build and maintain, and additional obstacles faced by low- and middle-income countries (LMICs) may further widen global inequities in mNGS capacity. Over the past two decades, several important infectious disease outbreaks have highlighted the importance of establishing widespread sequencing capacity to support rapid disease detection and containment at the source. Using lessons learned from the COVID-19 pandemic, LMICs can leverage current momentum to design and build sustainable mNGS programs, which would form part of a global surveillance network crucial to the elimination of infectious diseases.

Identification of cuproptosis-related subtypes in lung adenocarcinoma and its potential significance.

Cuproptosis is a novel and unique cell death mode that has attracted significant interest in recent years. Little is currently known about whether cuproptosis-related genes (CRGs) are associated with the pathophysiology and survival of patients with lung adenocarcinoma (LUAD). The present study sought to characterize the transcriptional and genetic alteration of CRGs in LUAD and its potential significance in the tumor microenvironment and predicting the prognosis of LUAD. The secondary eventual aim was to study the role of CRGs in predicting immunotherapy response and its clinical value combined with the TNM stage. We found that several CRGs, including FDX1, DLD, SLC31A1, and MTF1, were enriched in macrophages in our single-cell RNA-seq data. Three distinct molecular subtypes were identified and correlated with clinicopathological characteristics, prognosis, biological pathways, and tumor microenvironment (TME) in LUAD. We developed a cuproptosis-related gene score (CRG_score) and validated it in three independent cohorts and clinical subtypes. The low CRG_score group, characterized by a greater immune score, immunophenoscore (IPS), lower tumor immune dysfunction and exclusion (TIDE) score, and T-cell dysfunction score, had a better prognosis, suggesting that the low CRG_score group responded more favorably to immunotherapy, which was validated in the anti-PD-1/L1 immunotherapy cohort (IMvigor210). In contrast, the high CRG_score group was more sensitive to targeted therapy and chemotherapy, with a higher cancer stem cell (CSC) index and lower half-maximal inhibitory concentration (IC50) for many drugs. Given the established crosstalk between CRG_score and tumor TNM stage, we developed an accurate nomogram for clinical application of the CRG_score. Taken together, our rigorous and comprehensive examination of CRGs in LUAD identified their potential functions in TME, clinicopathological characteristics, drug sensitivity, and prognosis. These findings improve the current understanding of cuproptosis in LUAD, paving the way for more accurate prognosis assessment and tailored treatment for this patient population.

Comparative physiological, transcriptomic, and WGCNA analyses reveal the key genes and regulatory pathways associated with drought tolerance in Tartary buckwheat.

Drought stress is one of the major abiotic stress factors that affect plant growth and crop productivity. Tartary buckwheat is a nutritionally balanced and flavonoid-rich pseudocereal crop and also has strong adaptability to different adverse environments including drought. However, little is known about its drought tolerance mechanism. In this study, we performed comparative physiological and transcriptomic analyses of two contrasting drought-resistant Tartary buckwheat genotypes under nature drought treatment in the reproductive stage. Under drought stress, the drought-tolerant genotype XZSN had significantly higher contents of relative water, proline, and soluble sugar, as well as lower relative electrolyte leakage in the leaves than the drought-susceptible LK3. A total of 5,058 (2,165 upregulated and 2,893 downregulated) and 5,182 (2,358 upregulated and 2,824 downregulated) potential drought-responsive genes were identified in XZSN and LK3 by transcriptome sequencing analysis, respectively. Among the potential drought-responsive genes of XZSN, 1,206 and 1,274 genes were identified to be potential positive and negative contributors for XZSN having higher drought resistance ability than LK3. Furthermore, 851 out of 1,206 positive drought-resistant genes were further identified to be the core drought-resistant genes of XZSN based on WGCNA analysis, and most of them were induced earlier and quicker by drought stress than those in LK3. Functional annotation of the 851 core drought-resistant genes found that a large number of stress-responsive genes were involved in TFs, abscisic acid (ABA) biosynthesis, signal transduction and response, non-ABA signal molecule biosynthesis, water holding, oxygen species scavenging, osmotic adjustment, cell damage prevention, and so on. Transcriptional regulatory network analyses identified the potential regulators of these drought-resistant functional genes and found that the HD-ZIP and MYB TFs might be the key downstream TFs of drought resistance in Tartary buckwheat. Taken together, these results indicated that the XZSN genotype was more drought-tolerant than the LK3 genotype as evidenced by triggering the rapid and dramatic transcriptional reprogramming of drought-resistant genes to reduce water loss, prevent cell damage, and so on. This research expands our current understanding of the drought tolerance mechanisms of Tartary buckwheat and provides important information for its further drought resistance research and variety breeding.