MeIS: DNA methylation-based immune response signatures for thyroid nodule diagnostics.

CONTEXT: Accurately distinguishing between benign thyroid nodules (BTNs) and papillary thyroid cancers (PTCs) with current conventional methods poses a significant challenge. OBJECTIVE: We identify DNA methylation markers of immune response-related genes for distinguishing BTNs and PTCs. METHODS: In this study, we analyzed a public reduced representative bisulfite sequencing (RRBS) dataset and revealed distinct methylation patterns associated with immune signals in PTCs and BTNs. Based on these findings, we developed a diagnostic classifier named as the Methylation-based Immune Response Signature (MeIS), which was composed of fifteen DNA methylation markers associated with immune response-related genes. We validated the MeIS's performance in two independent cohorts: ZS's retrospective cohort (50 PTC and 18 BTN surgery-leftover samples) and ZS's preoperative cohort (31 PTC and 30 BTN fine-needle aspiration (FNA) samples). RESULTS: The MeIS classifier demonstrated significant clinical promise, achieving AUCs of 0.96, 0.98, 0.89 and 0.90 in the training set, validation set, ZS's retrospective cohort, and ZS's preoperative cohort, respectively. For the cytologically indeterminate thyroid nodules, in the ZS's retrospective cohort, MeIS exhibited a sensitivity of 91% and a specificity of 82%; in the ZS's preoperative cohort, MeIS achieved a sensitivity of 84% and a specificity of 74%. Additionally, combining MeIS and BRAFV600E detection improved the detecting performance of cytologically indeterminate thyroid nodules, yielding sensitivities of 98% and 87%, and specificities of 82% and 74% in the ZS's retrospective cohort and ZS's preoperative cohort, respectively. CONCLUSIONS: The fifteen markers we identified can be employed to improve the diagnostic of cytologically indeterminate thyroid nodules.

Altered functional connectivity in patients with post-stroke fatigue: A resting-state fMRI study.

BACKGROUND: Post-stroke fatigue (PSF) was a common complication after stroke. This study aimed to explore the neuroimaging mechanism of PSF, which was rarely studied. METHODS: Patients with the first episode of ischemic stroke were recruited from the First Affiliated Hospital of Wenzhou Medical University between March 2021 and December 2022. The fatigue severity scale (FSS) was used to assess fatigue symptoms. PSF was diagnosed by a neurologist based on the FSS score and PSF diagnostic criteria. All the patients were scanned by resting-state functional MRI (rs-fMRI). Precuneus, the posterior node of default-mode network (pDMN), was related to fatigue. Therefore, imaging data were further analyzed by the seed-based resting-state functional connectivity (FC) approach, with the left (PCUN.L) and right precuneus (PCUN.R) being the seeds. RESULTS: A total of 70 patients with acute ischemic stroke were finally recruited, comprising 40 patients with PSF and 30 patients without PSF. Both the PCUN.L and PCUN.R seeds (pDMN) exhibited decreased FC with the prefrontal lobes located at the anterior part of DMN (aDMN), and the FC values were negatively correlated with FSS scores (both p < 0.001). These two seeds also exhibited increased FC with the right insula, and the FC values were positively correlated with FSS scores (both p < 0.05). CONCLUSION: The abnormal FC between the aDMN and pDMN was associated with PSF. Besides, the insula, related to interoception, might also play an important role in PSF.

Efficacy of scalp stimulation for multidomain cognitive impairment in patients with post-stroke cognitive impairment and dementia: A network meta-analysis and meta-regression of moderators.

BACKGROUND: Scalp stimulation has gained more traction for post-stroke cognitive impairment and dementia (PSCID); the interaction between stimulation targets and parameters influences the response to the stimulation. However, the most efficacious treatment for improving different domains of cognitive impairment remains unknown. OBJECTIVE: We aimed to conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of various scalp stimulation protocols used in PSCID treatment. METHODS: Randomized controlled trials of scalp stimulation in patients with PSCID were searched in eight databases over the past 20 years. Standardized mean differences (SMDs) for global and subdomain cognitive scores were pooled in Bayesian NMA. Moderators were examined using meta-regression analysis. RESULTS: A total of 90 trials, with 6199 patients, were included. Low-frequency repetitive transcranial magnetic stimulation (rTMS) over the unaffected dorsolateral prefrontal cortex (DLPFC) was highly suggested for alleviating global severity (SMD = 1.11, 95% CI (0.64, 1.57)). High-frequency rTMS over the left DLPFC was recommended for language use (1.85 (1.18, 2.52)), executive function (0.85 (0.36, 1.33)), orientation deficits (0.59 (0.07, 1.13)), and attention (0.85 (0.27, 1.43)). Anodal transcranial direct current stimulation over the affected DLPFC (2.03 (0.72, 3.34)) was recommended for treating memory impairment. Meta-regression analyses showed significant associations within attention, language and orientation. CONCLUSION: Overall, different cognitive domains have different optimal scalp stimulation prescriptions, and activating the affected key brain regions and inhibiting the unaffected area is still the most effective treatment.

FTO Knockdown-Mediated Maturation of miR-383-5p Inhibits Malignant Advancement of Pancreatic Cancer by Targeting ITGA3.

m6A demethylase FTO is confirmed to be involved in pancreatic cancer progression. FTO regulates miRNA processing. To investigate the regulatory effect of FTO on miR-383-5p and its role in pancreatic cancer. The expression of miR-383-5p, ITGA3, and FTO was predicted using bioinformatic analysis in tissues and was measured using qPCR in cells. Cell biological functions were investigated using MTT assay, Transwell assay, sphere formation assay, and qPCR. The targeting relationship between miR-383-5p and ITGA3 was evaluated using the dual-luciferase reporter assay. The effect of FTO on miR-383-5p processing was evaluated using RIP and MeRIP assay. FTO expression was upregulated in pancreatic cancer and silencing of FTO promoted the processing of miR-383-5p in an m6A-dependent manner. m6A-modified miRNA processing was recognized by IGF2BP1. Downregulation of miR-383-5p reversed FTO knockdown-induced inhibition of cellular processes. The FTO/miR-383-5p/ITGA3 axis facilitated cell viability, metastasis, and stemness in pancreatic cancer.

Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-ß1 signaling pathway.

BACKGROUND: Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood. METHODS: hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-ß1 in exosomes were evaluated by Western blot. RESULTS: Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-ß1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-ß1 in exosomes, and the results showed that exosomes had high expression of TGF-ß1. CONCLUSION: By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-ß1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TßR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.

Xuanfei Baidu decoction in the treatment of coronavirus disease 2019 (COVID-19): Efficacy and potential mechanisms.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and become a major global public health concern. Although novel investigational COVID-19 antiviral candidates such as the Pfizer agent PAXLOVID™, molnupiravir, baricitinib, remdesivir, and favipiravir are currently used to treat patients with COVID-19, there is still a critical need for the development of additional treatments, as the recommended therapeutic options are frequently ineffective against SARS-CoV-2. The efficacy and safety of vaccines remain uncertain, particularly with the emergence of several variants. All 10 versions of the National Health Commission's diagnosis and treatment guidelines for COVID-19 recommend using traditional Chinese medicine. Xuanfei Baidu Decoction (XFBD) is one of the "three Chinese medicines and three Chinese prescriptions" recommended for COVID-19. This review summarizes the clinical evidence and potential mechanisms of action of XFBD for COVID-19 treatment. With XFBD, patients with COVID-19 experience improved clinical symptoms, shorter hospital stay, prevention of the progression of their symptoms from mild to moderate and severe symptoms, and reduced mortality in critically ill patients. The mechanisms of action may be associated with its direct antiviral, anti-inflammatory, immunomodulatory, antioxidative, and antimicrobial properties. High-quality clinical and experimental studies are needed to further explore the clinical efficacy and underlying mechanisms of XFBD in COVID-19 treatment.

Examining the impacts of public transit on healthy aging through a natural experiment: study protocols and lessons learned from the Active El Paso project.

This paper describes protocols and experiences from a seven-year natural-experiment study in El Paso, Texas, a border city of predominantly Latino/Hispanic population. The study focuses on how Bus Rapid Transit (BRT) impacts physical activity and thus plays a role in alleviating obesity and related chronic diseases that impact healthy aging. Our protocols describe a longitudinal and case-comparison study, which compared residents exposed to new BRT stations with those who were not. This paper also introduces lessons and experiences to overcome the following challenges: delays in the BRT opening (the main intervention), the COVID-19 pandemic, methodological challenges, participant recruitment and retention, and predatory survey takers. Our transdisciplinary approach was pivotal in addressing these challenges. We also proposed and tested multi-level intervention strategies to reduce modifiable barriers to transit use. Our most important takeaway for researchers, practitioners, and policy makers is the importance of being flexible and ready to adapt to new circumstances. Future natural-experiment researchers need to become more versatile in an increasingly volatile and uncertain world.

Cross-platform comparisons for targeted bisulfite sequencing of MGISEQ-2000 and NovaSeq6000.

BACKGROUND: An accurate and reproducible next-generation sequencing platform is essential to identify malignancy-related abnormal DNA methylation changes and translate them into clinical applications including cancer detection, prognosis, and surveillance. However, high-quality DNA methylation sequencing has been challenging because poor sequence diversity of the bisulfite-converted libraries severely impairs sequencing quality and yield. In this study, we tested MGISEQ-2000 Sequencer's capability of DNA methylation sequencing with a published non-invasive pancreatic cancer detection assay, using NovaSeq6000 as the benchmark. RESULTS: We sequenced a series of synthetic cell-free DNA (cfDNA) samples with different tumor fractions and found MGISEQ-2000 yielded data with similar quality as NovaSeq6000. The methylation levels measured by MGISEQ-2000 demonstrated high consistency with NovaSeq6000. Moreover, MGISEQ-2000 showed a comparable analytic sensitivity with NovaSeq6000, suggesting its potential for clinical detection. As to evaluate the clinical performance of MGISEQ-2000, we sequenced 24 clinical samples and predicted the pathology of the samples with a clinical diagnosis model, PDACatch classifier. The clinical model performance of MGISEQ-2000's data was highly consistent with that of NovaSeq6000's data, with the area under the curve of 1. We also tested the model's robustness with MGISEQ-2000's data when reducing the sequencing depth. The results showed that MGISEQ-2000's data showed matching robustness of the PDACatch classifier with NovaSeq6000's data. CONCLUSIONS: Taken together, MGISEQ-2000 demonstrated similar data quality, consistency of the methylation levels, comparable analytic sensitivity, and matching clinical performance, supporting its application in future non-invasive early cancer detection investigations by detecting distinct methylation patterns of cfDNAs.

Moving to an Activity-Friendly Community Can Increase Physical Activity.

BACKGROUND: Creating activity-friendly communities (AFCs) is an important strategy to increase physical activity (PA). While cross-sectional links between community environments and PA are well documented, their causal relationships remain insufficiently explored. METHODS: Using the accelerometer and survey data collected from adults who moved to an AFC (cases) and similar non-AFC-residing adults who did not move (comparisons), this pre-post, case-comparison study examines if moving to an AFC increases PA. Data came from 115 participants (cases = 37, comparisons = 78) from Austin, Texas, who completed 2 waves of 1-weeklong data collection. Difference-in-difference analyses and fixed-effect models were used to test the significance of the pre-post differences in moderate-to-vigorous PA (MVPA) between cases and comparisons, for the full sample and the subsample of 37 pairs matched in key covariates using the Propensity Score Matching method. RESULTS: Average treatment effect generated based on Propensity Score Matching and difference-in-difference showed that moving to this AFC led to an average of 10.88 additional minutes of daily MVPA (76.16 weekly minutes, P = .015). Fixed-effect models echoed the result with an increase of 10.39 minutes of daily MVPA after moving to the AFC. We also found that case participants who were less active at baseline and had higher income increased their MVPA more than their counterparts. CONCLUSIONS: This study showed that, among our study sample, moving to an AFC increased residents' PA significantly when compared to their premove level and the comparison group. This causal evidence suggests the potential of AFCs as sustainable interventions for PA promotion.

Enhanced dominance of soil moisture stress on vegetation growth in Eurasian drylands.

Despite the mounting attention being paid to vegetation growth and their driving forces for water-limited ecosystems, the relative contributions of atmospheric and soil moisture dryness stress on vegetation growth are an ongoing debate. Here we comprehensively compare the impacts of high vapor pressure deficit (VPD) and low soil water content (SWC) on vegetation growth in Eurasian drylands during 1982-2014. The analysis indicates a gradual decoupling between atmospheric dryness and soil dryness over this period, as the former has expanded faster than the latter. Moreover, the VPD-SWC relation and VPD-greenness relation are both non-linear, while the SWC-greenness relation is near-linear. The loosened coupling between VPD and SWC, the non-linear correlations among VPD-SWC-greenness and the expanded area extent in which SWC acts as the dominant stress factor all provide compelling evidence that SWC is a more influential stressor than VPD on vegetation growth in Eurasian drylands. In addition, a set of 11 Earth system models projected a continuously growing constraint of SWC stress on vegetation growth towards 2100. Our results are vital to dryland ecosystems management and drought mitigation in Eurasia.

Immune-check blocking combination multiple cytokines shown curative potential in mice tumor model.

OBJECTIVE: In order to ensure the stable transcription of target genes, we constructed a eukaryotic high expression vector carrying an immune-check inhibitor PD-1v and a variety of cytokines, and studied their effects on activating immune response to inhibit tumor growth. METHODS: A novel eukaryotic expression plasmid vector named pT7AMPCE containing T7RNA polymerase, T7 promoter, internal ribosome entry site (IRES), and poly A tailing signal was constructed by T4 DNA ligase, on which homologous recombination was used to clone and construct the vector carrying PD-1v, IL-2/15, IL-12, GM-CSF, and GFP. In vitro transfection of CT26 cells was performed, and the protein expression of PD-1v, IL-12 and GM-CSF was detected by Western blot and ELISA after 48 h. Mice were subcutaneously inoculated with CT26-IRFP tumor cells in the rib abdomen, and the tumor tissues were injected with PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids for treatment during the experimental period. The efficacy of the treatment was evaluated by assay tumor size and survival time of tumor-bearing mice during the experiment. Expression levels of IFN-γ, TNF, IL-4, IL-2, and IL-5 in mouse blood were measured using the CBA method. Tumor tissues were extracted and immune cell infiltration in tumor tissues was detected by HE staining and the IHC method. RESULTS: The recombinant plasmids carrying PD-1v, IL-2/15, IL-12, and GM-CSF were successfully constructed, and the Western blot and ELISA results showed that PD-1v, IL-12, and GM-CSF were expressed in the supernatant of CT26 cells 48 h after in vitro cell transfection. The combined application of PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids significantly inhibited tumor growth in mice, and the tumor growth rate was significantly lower than that in the blank control group and GFP plasmid control group (p < 0.05). Cytometric bead array data suggested that the combination of PD-1v and various cytokines can effectively activate immune cells. HE and IHC analysis revealed plenty of immune cell infiltrates in the tumor tissue, and a large proportion of tumor cells showed the necrotic phenotype in the combination treatment group. CONCLUSION: The combination of immune check blockade and multiple cytokine therapy can significantly activate the body's immune response and inhibit tumor growth.

Association between Antibiotic Exposure and the Risk of Rash in Children with Infectious Mononucleosis: a Multicenter, Retrospective Cohort Study.

Present evidence suggests that the administration of antibiotics, particularly aminopenicillins, may increase the risk of rash in children with infectious mononucleosis (IM). This retrospective, multicenter cohort study of children with IM was conducted to explore the association between antibiotic exposure in IM children and the risk of rash. A robust error generalized linear regression was performed to address the potential cluster effect, as well as confounding factors such as age and sex. A total of 767 children (aged from 0 to 18 years) with IM from 14 hospitals in Guizhou Province were included in the final analysis. The regression analysis implied that exposure to antibiotics was associated with a significantly increased incidence of overall rash in IM children (adjusted odds ratio [AOR], 1.47; 95% confidence interval [CI], ~1.04 to 2.08; P = 0.029). Of 92 overall rash cases, 43 were probably related to antibiotic exposure: two cases (4.08%) in the amoxicillin-treated group and 41 (8.15%) in the group treated with other antibiotics. Regression analysis indicated that the risk of rash induced by amoxicillin in IM children was similar to that induced by other penicillins (AOR, 1.12; 95% CI, ~0.13 to 9.67), cephalosporins (AOR, 2.45; 95% CI, ~0.43 to 14.02), or macrolides (AOR, 0.91; 95% CI, ~0.15 to 5.43). Antibiotic exposure may be associated with an increased risk of overall rash in IM children, but amoxicillin was not found to be associated with any increased risk of rash during IM compared to other antibiotics. We suggest that clinicians be vigilant against the occurrence of rash in IM children receiving antibiotic therapy, rather than indiscriminately avoiding prescribing amoxicillin.

Cell-free DNA methylation biomarker for the diagnosis of papillary thyroid carcinoma.

BACKGROUND: Cell-free DNA (cfDNA) is being explored as biomarker for non-invasive diagnosis of cancer. We aimed to establish a cfDNA-based DNA methylation marker panel to differentially diagnose papillary thyroid carcinoma (PTC) from benign thyroid nodule (BTN). METHODS: 220 PTC- and 188 BTN patients were enrolled. Methylation markers of PTC were identified from patients' tissue and plasma by reduced representation bisulfite sequencing and methylation haplotype analyses. They were combined with PTC markers from literatures and were tested on additional PTC and BTN samples to verify PTC-detecting ability using targeted methylation sequencing. Top markers were developed into ThyMet and were tested in 113 PTC and 88 BTN cases to train and validate a PTC-plasma classifier. Integration of ThyMet and thyroid ultrasonography was explored to improve accuracy. FINDINGS: From 859 potential PTC plasma-discriminating markers that include 81 markers identified by us, the top 98 most PTC plasma-discriminating markers were selected for ThyMet. A 6-marker ThyMet classifier for PTC plasma was trained. In validation it achieved an Area Under the Curve (AUC) of 0.828, similar to thyroid ultrasonography (0.833) but at higher specificity (0.722 and 0.625 for ThyMet and ultrasonography, respectively). A combinatorial classifier by them, ThyMet-US, improved AUC to 0.923 (sensitivity = 0.957, specificity = 0.708). INTERPRETATION: The ThyMet classifier improved the specificity of differentiating PTC from BTN over ultrasonography. The combinatorial ThyMet-US classifier may be effective in preoperative diagnosis of PTC. FUNDING: This work was supported by the grants from National Natural Science Foundation of China (82072956 and 81772850).

Corrigendum: Modulations of static and dynamic functional connectivity among brain networks by electroacupuncture in post-stroke aphasia.

[This corrects the article DOI: 10.3389/fneur.2022.956931.].

Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients.

Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, ß-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA.

Predictors of functional dependence at one year in acute ischemic stroke with large vessel occlusion.

BACKGROUND: In China, the current status of clinical treatment of eLVO and the factors affecting its long-term prognosis are unclear. OBJECTIVE: This study aims to explore the predictive factors of functional outcomes at one year in patients of acute ischemic stroke with emergent large vessel occlusion (eLVO). METHODS: We retrospectively collected 536 patients who underwent treatments for eLVO. Primary outcomes included one-year functional outcomes and delayed functional independence (DFI). The logistic regression was performed to predict the primary outcome. RESULTS: 431 (85%) survivors participated in the one-year follow-up. In the multivariate logistic analysis adjusted for baseline characteristics, the following factors were found to be significant predictors of functional dependence at one year: old age (aOR = 1.042, 95% CI=1.01-1.076, p = 0.011), low Alberta stroke program early CT score (ASPECTS) (aOR = 0.791, 95% CI=0.671-0.933, p = 0.005), unsuccessful reperfusion (aOR = 0.168, 95% CI=0.048-0.586, p = 0.005), poor medication compliance (aOR = 0.022, 95% CI=0.007-0.072, p < 0.001), and complicated with stroke-associated pneumonia (SAP) (aOR = 2.269, 95% CI=1.103-4.670, p = 0.026). We also found that men (aOR = 3.947, 95% CI=1.15-13.549, p = 0.029) had better medication adherence (aOR = 14.077, 95% CI=1.736-114.157, p = 0.013), and going to rehabilitation centers (aOR = 5.197, 95% CI=1.474-18.327, p = 0.010) were independent predictors of DFI. CONCLUSION: The significant predictors of functional dependence at one year were: old age, low ASPECTS, unsuccessful reperfusion, poor medication adherence, and combination with SAP. Men, good medication adherence, and going to rehabilitation centers contributed to getting delayed functional independence.

Lactate Dehydrogenase Predicts Hemorrhagic Transformation in Patients with Acute Ischemic Stroke.

INTRODUCTION: Hemorrhagic transformation (HT) is a severe but frequent complication of acute ischemic stroke (AIS). This study aimed to evaluate the relationship between serum lactate dehydrogenase (LDH) levels and HT. METHODS: We retrospectively included 542 AIS patients with HT and 1,091 age- and gender-matched patients without HT. Demographic and clinical data were obtained from medical records, and blood samples were obtained within 24 h after admission. The characteristics of the groups were compared. With the receiver operating characteristic (ROC) curve analysis, we assessed the discriminating capacity of LDH levels in predicting HT in patients with AIS. The logistic regression model was used to determine the connection between LDH and HT. RESULTS: The HT group had considerably higher LDH levels than the non-HT group (263.0 [216.0-323.3] U/L versus 178.0 [162.0-195.0] U/L, p < 0.001). We also observed that the levels of LDH in the parenchymal hemorrhage subgroup were significantly higher than those in the hemorrhagic infarction subgroup (281.0 [230.0-340.0] U/L versus 258.0 [209.0-311.0] U/L, p < 0.001). The area under the ROC curve of LDH was 0.890 (95% confidence level [CI] 0.874-0.905, p < 0.001). Besides, logistic regression revealed that high LDH levels (LDH >215 U/L) showed a higher risk of HT (odds ratio = 10.958, 95% CI 7.964-15.078, p < 0.001). CONCLUSION: High LDH levels were linked with an increased risk of HT in AIS patients. Practical measures should be considered in patients with increased LDH levels (LDH >215 U/L).

Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4.

Cytochrome P450 3A4 (CYP3A4) is one of the major drug metabolizing enzymes in the human body and metabolizes ∼30-50% of clinically used drugs. Inhibition of CYP3A4 must always be considered in the development of new drugs. Time-dependent inhibition (TDI) is an important P450 inhibition type that could cause undesired drug-drug interactions. Therefore, identification of CYP3A4 TDI by a rapid convenient way is of great importance to any new drug discovery effort. Here, we report the development of in silico classification models for prediction of potential CYP3A4 time-dependent inhibitors. On the basis of the CYP3A4 TDI data set that we manually collected from literature and databases, both conventional machine learning and deep learning models were constructed. The comparisons of different sampling strategies, molecular representations, and machine-learning algorithms showed the benefits of a balanced data set and the deep-learning model featured by GraphConv. The generalization ability of the best model was tested by screening an external data set, and the prediction results were validated by biological experiments. In addition, several structural alerts that are relevant to CYP3A4 time-dependent inhibitors were identified via information gain and frequency analysis. We anticipate that our effort would be useful for identification of potential CYP3A4 time-dependent inhibitors in drug discovery and design.

The HALP (hemoglobin, albumin, lymphocyte, and platelet) score is associated with early-onset post-stroke cognitive impairment.

BACKGROUND: The HALP score (hemoglobin, albumin, lymphocyte, and platelet) is a novel indicator that measures systemic inflammation and nutritional status. The goal of this study was to look into the relationship between the HALP score and post-stroke cognitive impairment (PSCI) in people who had an acute ischemic stroke (AIS). METHODS: A total of 592 individuals with ischemic stroke were included in the research, and the PSCI (n = 382) and non-PSCI (n = 210) groups were determined using the Mini-Mental State Examination scale 2 weeks following the stroke. HALP score was computed by the formula: hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L) / platelets (/L), and was split into three layers according to the tertiles. The connection between the HALP and cognitive results was investigated by binary logistic regression. RESULTS: The PSCI group's HALP score was much lower than the non-PSCI group's (p < 0.001). The HALP score was divided into three layers: T1 ≤ 34.0, T2 34.1-49.4, and T3 ≥ 49.5, respectively. In the binary regression analysis, taking the T3 layer as the reference, the T1 layer showed the highest risk of PSCI after adjusting for confounding factors (odds ratio (OR) = 1.965, 95% confidence interval (CI) = 1.237-3.122, p = 0.004), while there was no increased risk of PSCI in the T2 layer (OR = 1.538, 95%CI = 0.983-2.404, p = 0.059). CONCLUSION: Low HALP score at admission was found to be correlated with early-onset PSCI and may help clinicians in the early identification of high-risk patients.

Association Between the Serum Iron and Acute Cognitive Impairment After Stroke: A Cross-Sectional Study.

BACKGROUND: Complications such as cognitive impairment are common in stroke victims. The goal of this study was to see if there was a link between blood iron levels and post-stroke cognitive impairment (PSCI) within 2 weeks after stroke. METHODS: A total of 313 patients with ischemic stroke were recruited and separated into two groups: PSCI (n = 202) and non-PSCI (n = 111). The Mini-mental state examination scale was used to evaluate the cognitive status within 2 weeks after stroke (acute phase). The serum iron levels were divided into 4 layers: Q1 ≤ 11.7 µmol/L, Q2 11.8-15.1 µmol/, Q3 15.2-19.3 µmol/L, Q4 ≥ 19.4 µmol/L, respectively. The connection between serum iron and PSCI was then investigated further using binary logistic regression, which was adjusted for confounders. RESULTS: The difference in serum iron levels between the PSCI and non-PSCI group was initially conducted by the Mann-Whitney test, and a significant difference was found (14.5 (11.0-17.8) vs. 16.9 (13.7-21.8), p < .001), with no confounders being adjusted. After adjusting for confounding factors, the binary regression analysis showed that the Q4 layer showed the lowest risk of PSCI, with the Q1 layer being the reference. (odds ratio (OR) = 0.297, 95% confidence interval (CI) = 0.136-0.649, p = 0.002). CONCLUSION: A decreased risk of early-onset PSCI was linked to high serum iron levels. Low serum iron levels were found to be a risk factor for acute cognitive impairment following stroke, which could help physicians identify and take intervention measures early to reduce the risk of cognitive impairment after stroke.