Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells.

Background: Cystic Fibrosis causing mutations in the gene CFTR , reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. Methods: A novel small molecule potentiator (SK-POT1), previously identified in CFTR binding studies, was tested for its activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. Results: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. Conclusion: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

Tanshinone IIA induces ER stress and JNK activation to inhibit tumor growth and enhance anti-PD-1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains at the forefront of new cancer cases, and there is an urgent need to find new treatments or improve the efficacy of existing therapies. In addition to the application in the field of cerebrovascular diseases, recent studies have revealed that tanshinone IIA (Tan IIA) has anticancer activity in a variety of cancers. PURPOSE: To investigate the potential anticancer mechanism of Tan IIA and its impact on immunotherapy in NSCLC. METHODS: Cytotoxicity and colony formation assays were used to detect the Tan IIA inhibitory effect on NSCLC cells. This research clarified the mechanisms of Tan IIA in anti-tumor and programmed death-ligand 1 (PD-L1) regulation by using flow cytometry, transient transfection, western blotting and immunohistochemistry (IHC) methods. Besides, IHC was also used to analyze the nuclear factor of activated T cells 1 (NFAT2) expression in NSCLC clinical samples. Two animal models including xenograft mouse model and Lewis lung cancer model were used for evaluating tumor suppressive efficacy of Tan IIA. We also tested the efficacy of Tan IIA combined with programmed cell death protein 1 (PD-1) inhibitors in Lewis lung cancer model. RESULTS: Tan IIA exhibited good NSCLC inhibitory effect which was accompanied by endoplasmic reticulum (ER) stress response and increasing Ca2+ levels. Moreover, Tan IIA could suppress the NFAT2/ Myc proto oncogene protein (c-Myc) signaling, and it also was able to control the Jun Proto-Oncogene(c-Jun)/PD-L1 axis in NSCLC cells through the c-Jun N-terminal kinase (JNK) pathway. High NFAT2 levels were potential factors for poor prognosis in NSCLC patients. Finally, animal experiments data showed a stronger immune activation phenotype, when we performed treatment of Tan IIA combined with PD-1 monoclonal antibody. CONCLUSION: The findings of our research suggested a novel mechanism for Tan IIA to inhibit NSCLC, which could exert anti-cancer effects through the JNK/NFAT2/c-Myc pathway. Furthermore, Tan IIA could regulate tumor PD-L1 levels and has the potential to improve the efficacy of PD-1 inhibitors.

Genome-wide analysis of ATP-binding cassette (ABC) transporter in Penaeus vannamei and identification of two ABC genes involved in immune defense against Vibrio parahaemolyticus by affecting NF-κB signaling pathway.

The ATP-binding cassette (ABC) transporters have crucial roles in various biological processes such as growth, development and immune defense in eukaryotes. However, the roles of ABC transporters in the immune system of crustaceans remain elusive. In this study, 38 ABC genes were systematically identified and characterized in Penaeus vannamei. Bioinformation analysis revealed that PvABC genes were categorized into ABC A-H eight subfamilies with 17 full-transporters, 11 half transporters and 10 soluble proteins, and multiple immunity-related cis-elements were found in gene promoter regions. Expression analysis showed that most PvABC genes were widely and highly expressed in immune-related tissues and responded to the stimulation of Vibrio parahaemolyticus. To investigate whether PvABC genes mediated innate immunity, PvABCC5, PvABCF1 and PvABCB4 were selected for dsRNA interference experiment. Knockdown of PvABCF1 and PvABCC5 not PvABCB4 increased the cumulative mortality of P. vannamei and bacterial loads in hepatopancreas after infection with V. parahaemolyticus. Further analysis showed that the PvABCF1 and PvABCC5 knockdown decreased expression levels of NF-κB pathway genes and antimicrobial peptides (AMPs). Collectively, these findings indicated that PvABCF1 and PvABCC5 might restrict V. parahaemolyticus challenge by positively regulating NF-κB pathway and then promoting the expression of AMPs, which would contribute to overall understand the function of ABC genes in innate immunity of invertebrates.

International Classification of Functioning, Disability, and Health-based rehabilitation program promotes activity and participation of post-stroke patients.

Background: The International Classification of Functioning, Disability, and Health (ICF) model has been applied in post-stroke rehabilitation, yet limited studies explored its clinical application on enhancing patients' Activity and Participation (ICF-A&P) level. Purpose: This study gathered evidence of the effects of an ICF-based post-stroke rehabilitation program (ICF-PSRP) in enhancing community reintegration in terms of ICF-A&P of post-stroke patients. Methods: Fifty-two post-stroke patients completed an 8 to 12 weeks multidisciplinary ICF-PSRP after setting personal treatment goals in an outpatient community rehabilitation center. Intake and pre-discharge assessments were administered for primary outcomes of Body function (ICF-BF; e.g., muscle strength) and ICF-A&P (e.g., mobility), and secondary outcomes of perceived improvements in ability (e.g., goal attainment and quality of life). Results: There were significantly higher levels in the ICF-BF and ICF-A&P domains, except cognitive function under the ICF-BF. Improvements in the primary outcomes predicted corresponding secondary outcomes. Firstly, expressive and receptive functions (ICP-BF) were mediated by the everyday language (ICF-A&P) which predicted patients' satisfaction with the language-related quality of life. Secondly, upper extremity function (ICP-BF) was mediated by the lower extremity mobility (ICF-A&P) predicting work and productivity-related quality of life. Content analyses showed that combined ICF-BF and ICF-A&P contents throughout the ICF-PSRP contributed to the positive treatment effects. Conclusion: The ICF-PSRP was effective in promoting body function, and activity and participation levels of post-stroke patients. Positive treatment effects are characterized by goal-setting process, cross-domain content design, and community-setting delivery.Clinical trial registration: https://clinicaltrials.gov/study/NCT05941078?id=NCT05941078&rank=1, identifier NCT05941078.

Goal-setting and personalization under the International Classification of Functioning, Disability, and Health framework: Community reintegration program for post-stroke patients.

Background: Body functions and structures, activities, and participation are the core components in the International Classification of Functioning, Disability, and Health (ICF) to identify post-stroke patients' health conditions. The specification of health conditions enhances the outcomes of post-stroke rehabilitation. Purpose: This study aimed to explore the extent and the processes in an ICF-based post-stroke rehabilitation program (ICF-PSRP) that could enhance patients' community reintegration level. Methods: Post-stroke patients who completed the ICF-PSRP participated in intake and pre-discharge individual face-to-face semi-structured interviews. In addition, case therapists were invited to a face-to-face semi-structured group interview. Clinician experts were invited to complete an interview with the same interview contents as case therapists but in an online format. All interview recordings were analyzed with the Framework analysis. Patients' treatment goals were mapped with the ICF Core Set for Stroke. Results: Out of 37 invited post-stroke patients, thirty-three of them completed the interview. Three case therapists and five clinicians completed the interviews. The goals set by the patients and their caregivers showed a broadening of their scope over the course of the program. The changes in scope ranged from the activities to the participation and environmental components. Increases in patient-therapist interactions played an essential role in the goal-setting process, which were integral to personalizing the treatment content. These characteristics were perceived by all parties who contributed to the program outcomes. Conclusion: The application of ICF's principles and core components offers a useful framework for enhancing post-stroke patients' community reintegration level. Future studies should explore the way in which patient-therapist interaction, exposure to environmental factors, and personalized interventions maximize the benefits of applying this framework to the community integration of post-stroke patients.

Composition and contents of fatty acids and amino acids in the mycelia of Lentinula edodes.

With the global shortages of animal protein foods, mycoprotein as a low-cost alternative source of protein by its high-protein and low-fat content has become a development trend. Lentinula edodes (L. edodes) is a healthy food with high protein and low fiber. This work evaluated the nutritional value of L. edodes mycelia, and determined the composition and contents of fatty acids and amino acids. Eleven saturated fatty acids (SFAs) and 12 unsaturated fatty acids (UFAs) were detected in the mycelia of L. edodes. The UFA content accounted for 75.7% and 73.1% of the total fatty acid content in the mycelia of strains 18 and 18N44, respectively. Linoleic acid was the major polyunsaturated fatty acid (PUFA) in the mycelia, accounting for 91.0% and 86.3% of the UFAs, respectively. The mycelia of the two strains contained 17 types of amino acids, and the essential amino acids were sufficient (357.92 ± 0.42 and 398.38 ± 4.52 mg/g pro, respectively), both close to the WHO/FAO reference protein pattern value. The most abundant essential amino acid was Lys, and the limiting amino acids were Met + Cys and Ile, respectively. The SRC values in the mycelia of the two strains were 68.07 and 54.86, and the EAAI values were 67.70 and 74.42, respectively, both being close to those of ovalbumin. It is concluded that L. edodes mycelia are rich in easily absorbed high-quality proteins and PUFAs, and can be used as a source for meat analog required by vegetarians. This study provides a scientific basis for the further utilization of mycelial resources.

3D-bioprinting of patient-derived cardiac tissue models for studying congenital heart disease.

Introduction: Congenital heart disease is the leading cause of death related to birth defects and affects 1 out of every 100 live births. Induced pluripotent stem cell technology has allowed for patient-derived cardiomyocytes to be studied in vitro. An approach to bioengineer these cells into a physiologically accurate cardiac tissue model is needed in order to study the disease and evaluate potential treatment strategies. Methods: To accomplish this, we have developed a protocol to 3D-bioprint cardiac tissue constructs comprised of patient-derived cardiomyocytes within a hydrogel bioink based on laminin-521. Results: Cardiomyocytes remained viable and demonstrated appropriate phenotype and function including spontaneous contraction. Contraction remained consistent during 30 days of culture based on displacement measurements. Furthermore, tissue constructs demonstrated progressive maturation based on sarcomere structure and gene expression analysis. Gene expression analysis also revealed enhanced maturation in 3D constructs compared to 2D cell culture. Discussion: This combination of patient-derived cardiomyocytes and 3D-bioprinting represents a promising platform for studying congenital heart disease and evaluating individualized treatment strategies.

Altered contractility, Ca2+ transients, and cell morphology seen in a patient-specific iPSC-CM model of Ebstein's anomaly with left ventricular noncompaction.

Patients with two congenital heart diseases (CHDs), Ebstein's anomaly (EA) and left ventricular noncompaction (LVNC), suffer higher morbidity than either CHD alone. The genetic etiology and pathogenesis of combined EA/LVNC remain largely unknown. We investigated a familial EA/LVNC case associated with a variant (p.R237C) in the gene encoding Kelch-like protein 26 (KLHL26) by differentiating induced pluripotent stem cells (iPSCs) generated from affected and unaffected family members into cardiomyocytes (iPSC-CMs) and assessing iPSC-CM morphology, function, gene expression, and protein abundance. Compared with unaffected iPSC-CMs, CMs containing the KLHL26 (p.R237C) variant exhibited aberrant morphology including distended endo(sarco)plasmic reticulum (ER/SR) and dysmorphic mitochondria and aberrant function that included decreased contractions per minute, altered calcium transients, and increased proliferation. Pathway enrichment analyses based on RNASeq data indicated that the "structural constituent of muscle" pathway was suppressed, whereas the "ER lumen" pathway was activated. Taken together, these findings suggest that iPSC-CMs containing this KLHL26 (p.R237C) variant develop dysregulated ER/SR, calcium signaling, contractility, and proliferation.NEW & NOTEWORTHY We demonstrate here that iPSCs derived from patients with Ebstein's anomaly and left ventricular noncompaction, when differentiated into cardiomyocytes, display significant structural and functional changes that offer insight into disease pathogenesis, including altered ER/SR and mitochondrial morphology, contractility, and calcium signaling.

Integration of Artificial Intelligence Decision Aids to Reduce Workload and Enhance Efficiency in Thyroid Nodule Management.

Importance: To optimize the integration of artificial intelligence (AI) decision aids and reduce workload in thyroid nodule management, it is critical to incorporate personalized AI into the decision-making processes of radiologists with varying levels of expertise. Objective: To develop an optimized integration of AI decision aids for reducing radiologists' workload while maintaining diagnostic performance compared with traditional AI-assisted strategy. Design, Setting, and Participants: In this diagnostic study, a retrospective set of 1754 ultrasonographic images of 1048 patients with 1754 thyroid nodules from July 1, 2018, to July 31, 2019, was used to build an optimized strategy based on how 16 junior and senior radiologists incorporated AI-assisted diagnosis results with different image features. In the prospective set of this diagnostic study, 300 ultrasonographic images of 268 patients with 300 thyroid nodules from May 1 to December 31, 2021, were used to compare the optimized strategy with the traditional all-AI strategy in terms of diagnostic performance and workload reduction. Data analyses were completed in September 2022. Main Outcomes and Measures: The retrospective set of images was used to develop an optimized integration of AI decision aids for junior and senior radiologists based on the selection of AI-assisted significant or nonsignificant features. In the prospective set of images, the diagnostic performance, time-based cost, and assisted diagnosis were compared between the optimized strategy and the traditional all-AI strategy. Results: The retrospective set included 1754 ultrasonographic images from 1048 patients (mean [SD] age, 42.1 [13.2] years; 749 women [71.5%]) with 1754 thyroid nodules (mean [SD] size, 16.4 [10.6] mm); 748 nodules (42.6%) were benign, and 1006 (57.4%) were malignant. The prospective set included 300 ultrasonographic images from 268 patients (mean [SD] age, 41.7 [14.1] years; 194 women [72.4%]) with 300 thyroid nodules (mean [SD] size, 17.2 [6.8] mm); 125 nodules (41.7%) were benign, and 175 (58.3%) were malignant. For junior radiologists, the ultrasonographic features that were not improved by AI assistance included cystic or almost completely cystic nodules, anechoic nodules, spongiform nodules, and nodules smaller than 5 mm, whereas for senior radiologists the features that were not improved by AI assistance were cystic or almost completely cystic nodules, anechoic nodules, spongiform nodules, very hypoechoic nodules, nodules taller than wide, lobulated or irregular nodules, and extrathyroidal extension. Compared with the traditional all-AI strategy, the optimized strategy was associated with increased mean task completion times for junior radiologists (reader 11, from 15.2 seconds [95% CI, 13.2-17.2 seconds] to 19.4 seconds [95% CI, 15.6-23.3 seconds]; reader 12, from 12.7 seconds [95% CI, 11.4-13.9 seconds] to 15.6 seconds [95% CI, 13.6-17.7 seconds]), but shorter times for senior radiologists (reader 14, from 19.4 seconds [95% CI, 18.1-20.7 seconds] to 16.8 seconds [95% CI, 15.3-18.3 seconds]; reader 16, from 12.5 seconds [95% CI, 12.1-12.9 seconds] to 10.0 seconds [95% CI, 9.5-10.5 seconds]). There was no significant difference in sensitivity (range, 91%-100%) or specificity (range, 94%-98%) between the 2 strategies for readers 11 to 16. Conclusions and Relevance: This diagnostic study suggests that an optimized AI strategy in thyroid nodule management may reduce diagnostic time-based costs without sacrificing diagnostic accuracy for senior radiologists, while the traditional all-AI strategy may still be more beneficial for junior radiologists.

Value of Multimodal Data From Clinical and Sonographic Parameters in Predicting Recurrence of Hepatocellular Carcinoma After Curative Treatment.

OBJECTIVE: The objective of the work described here was to assess the value of the combination of pre-operative multimodal data-including clinical data, contrast-enhanced ultrasound (CEUS) information and liver stiffness measurement (LSM) based on 2-D shear wave elastography (SWE)-in predicting early (within 1 y) and late (after 1 y) recurrence of hepatocellular carcinoma (HCC) after curative treatment. METHODS: We retrospectively included 101 patients with HCC who met the Milan criteria and received curative treatment. The multimodel data from clinical parameters, LSM by 2-D SWE and CEUS enhancement patterns were collected. The association between different variables in HCC recurrence was accessed using a Cox proportional hazard model. On the basis of the independent factors of early recurrence, models with different source variables were established (Clinical Model, CEUS-Clinical Model, SWE-Clinical Model, CEUS-SWE-Clinical Model). The goodness-of-fit of models was evaluated and the performance trends of different models were calculated by time-dependent area under the curve (AUC). RESULTS: Two-dimensional SWE, CEUS enhancement patterns and clinical parameters (spleen length, multiple tumors, α-fetoprotein, albumin and prothrombin time) were independently associated with early recurrence (all p values <0.05). Multiple tumors and a decrease in albumin independently contributed to the late recurrence. The model fit of CEUS-SWE-Clinical Model was superior to other models in predicting early recurrence (all p values <0.05). The AUCs of the CEUS-Clinical Model were higher from 2 mo to 7 mo, while the SWE-Clinical Model had higher AUCs from 9 mo to 12 mo. CONCLUSION: CEUS enhancement patterns and 2-D SWE were independent predictors of HCC early recurrence as the two factors contributed to the predictive performance at different times. The multimodal model, which included diverse data in predicting early HCC recurrence, had the best goodness-of-fit.

6His-tatritin promotes antimicrobial defense via regulating immune ability and intestinal microbial community in grass carp (Ctenopharyngodon idella).

Antimicrobial peptides are small, cationic, and amphiphilic peptides found in most organisms, and many of these peptides have broad antimicrobial activity against Gram-negative, -positive bacteria and fungi. In the present study, a derivative of antimicrobial peptide Tatritin, 6His-Tatritin, was designed and expressed by Pichia pastoris using a constitutive vector pGAPZαA with the promoter of pGAP. The 6His-Tatritin had a broad-spectrum antibacterial activity based on the Oxford cup method and the micro broth dilution test. In addition, to explore the role of 6His-Tatritin in vivo, grass carps (Ctenopharyngodon idellus) were infected with Aeromonas hydrophila after they were fed with 6His-Tatritin as feed additives for 28 days. The results revealed that 6His-Tatritin could significantly up-regulate the expression levels of Hepcidin, Leap-2b, Nrf-2, CuZn-SOD and LZM (P < 0.05). In addition, 6His-Tatritin could significantly reduce the mortality (P < 0.05) and the intestinal injury of grass carps infected with bacteria. The 16S sequencing analysis showed that the structure of microbial community in intestine of fish was more diversified compared with control after treatment with 6His-Tatritin. In summary, the peptide of 6His-Tatritin could promote antimicrobial defense via regulating immune ability and intestinal microbial community in grass carp. This study provides an effective method and approach for the application of antimicrobial peptide Tatritin in aquaculture, and also provides insights into the function of antimicrobial peptides in immunity against pathogens in fish.

Causal influences of salience/cerebellar networks on dorsal attention network subserved age-related cognitive slowing.

Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18-75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

Nuclear Cell-Free DNA Predicts Adverse Events After Pediatric Cardiothoracic Surgery.

BACKGROUND: Preoperative risk stratification in cardiac surgery includes patient and procedure factors that are used in clinical decision-making. Despite these tools, unidentified factors contribute to variation in outcomes. Identification of latent physiologic risk factors may strengthen predictive models. Nuclear cell-free DNA (ncfDNA) increases with tissue injury and drops to baseline levels rapidly. The goal of this investigation is to measure and to observe ncfDNA kinetics in children undergoing heart operations with cardiopulmonary bypass (CPB), linking biomarkers, organ dysfunction, and outcomes. METHODS: This is a prospective observational study of 116 children <18 years and >3 kg undergoing operations with CPB. Plasma ncfDNA samples were collected and processed in a stepwise manner at predefined perioperative time points. The primary outcome measure was occurrence of postoperative cardiac arrest or extracorporeal membrane oxygenation. RESULTS: Data were available in 116 patients (median age, 0.9 years [range, 0-17.4 years]; median weight, 7.8 kg [range, 3.2-98 kg]). The primary outcome was met in 6 of 116 (5.2%). Risk of primary outcome was 2% with ncfDNA <20 ng/mL and 33% with ncfDNA >20 ng/mL (odds ratio, 25; CI, 3.96-158; P = .001). Elevated ncfDNA was associated with fewer hospital-free days (P < .01). CONCLUSIONS: This study analyzes ncfDNA kinetics in children undergoing operations with CPB for congenital heart disease. Elevated preoperative ncfDNA is strongly associated with postoperative arrest and extracorporeal membrane oxygenation. Further studies are needed to validate this technology as a tool to predict morbidity in children after cardiac surgical procedures.

To compare the efficacy and incidence of severe hematological adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia / 中华血液学杂志

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.

Analysis of dust monitoring results of dust exposure enterprises in Shenxian from 2017 to 2020 / 中华劳动卫生职业病杂志

Objective: In order to understand the dust concentration in the workplace of dust exposure enterprises in Shenxian. To evaluate the degree of occupational hazard factors of dust exposure enterprises. And provide basis for the formulation of occupational protection standards and management system of dust exposure enterprises. Methods: In February 2022, the dust concentration monitoring data of 89 dust exposure enterprises from 2017 to 2020 by the Shenxian Center for Disease Control and Prevention were collected, and the qualified rates of dust concentration detection of dust exposure enterprises in different years, dust types and enterprise sizes were analyzed. Results: A total of 89 dust enterprises were monitored from 2017 to 2020, 2132 dust samples were collected, and 1818 qualified samples were taken, with a total qualified rate of 85.3%. From 2017 to 2020, the dust detection qualified rates showed a year-by-year increase trend, 78.7% (447/568), 84.1% (471/560), 88.6% (418/472) and 90.6% (482/532), respectively, with statistically significant differences (χ(2)=36.27, P=0.003). The differences in the qualified rates of dust detection samples of silicon dust (66.1%, 41/62), grain dust (86.7%, 1549/1786), cotton dust (84.1%, 106/126) and wood dust (77.2%, 122/158) were statistically significant (χ(2)=29.66, P=0.002). The qualified rate of dust samples in large and medium-sized enterprises (95.1%, 1194/1256) was higher than that of small-sized enterprises (71.2%, 624/876), and the difference was statistically significant (χ(2)=1584.40, P=0.001) . Conclusion: The qualified rate of dust concentration monitoring results of dust exposure enterprises in Shenxian showed an increase trend year by year, while the pualified rate of dust concentration monitoring in small-sized enterprises was low, and the occupational hazard of silica dust was still severe.

Simulation Palynologists for Pollinosis Prevention: A Progressive Learning of Pollen Localization and Classification for Whole Slide Images.

Existing API approaches usually independently leverage detection or classification models to distinguish allergic pollens from Whole Slide Images (WSIs). However, palynologists tend to identify pollen grains in a progressive learning manner instead of the above one-stage straightforward way. They generally focus on two pivotal problems during pollen identification. (1) Localization: where are the pollen grains located? (2) Classification: which categories do these pollen grains belong to? To perfectly mimic the manual observation process of the palynologists, we propose a progressive method integrating pollen localization and classification to achieve allergic pollen identification from WSIs. Specifically, data preprocessing is first used to cut WSIs into specific patches and filter out blank background patches. Subsequently, we present the multi-scale detection model to locate coarse-grained pollen regions (targeting at "pollen localization problem") and the multi-classifiers combination to determine the fine-grained category of allergic pollens (targeting at "pollen classification problem"). Extensive experimental results have demonstrated the feasibility and effectiveness of our proposed method.

Development and validation of tools for predicting the risk of death and ICU admission of non-HIV-infected patients with Pneumocystis jirovecii pneumonia.

Introduction: The mortality rate of non-HIV-infected Pneumocystis jirovecii pneumonia (PCP) is high. This research aimed to develop and validate two clinical tools for predicting the risk of death and intensive care unit (ICU) admission in non-HIV-infected patients with PCP to reduce mortality. Methods: A retrospective study was conducted at Peking Union Medical College Hospital between 2012 and 2021. All proven and probable non-HIV-infected patients with PCP were included. The least absolute shrinkage and selection operator method and multivariable logistic regression analysis were used to select the high-risk prognostic parameters. In the validation, the receiver operating characteristic curve and concordance index were used to quantify the discrimination performance. Calibration curves were constructed to assess the predictive consistency compared with the actual observations. A likelihood ratio test was used to compare the tool and CURB-65 score. Results: In total, 508 patients were enrolled in the study. The tool for predicting death included eight factors: age, chronic lung disease, respiratory rate, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), cytomegalovirus infection, shock, and invasive mechanical ventilation. The tool for predicting ICU admission composed of the following factors: respiratory rate, dyspnea, lung moist rales, LDH, BUN, C-reactive protein/albumin ratio, and pleural effusion. In external validation, the two clinical models performed well, showing good AUCs (0.915 and 0.880) and fit calibration plots. Compared with the CURB-65 score, our tool was more informative and had a higher predictive ability (AUC: 0.880 vs. 0.557) for predicting the risk of ICU admission. Conclusion: In conclusion, we developed and validated tools to predict death and ICU admission risks of non-HIV patients with PCP. Based on the information from the tools, clinicians can tailor appropriate therapy plans and use appropriate monitoring levels for high-risk patients, eventually reducing the mortality of those with PCP.