Homeobox B4 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on endotoxin-associated acute lung injury in rats.

BACKGROUND: Alveolar capillary endothelial cell (EC) injury has a pivotal role in driving acute respiratory distress syndrome (ARDS) progression and maintaining endothelial homeostasis. A previous ex vivo study revealed that overexpression of homeobox B4 (HOXB4) in bone marrow mesenchymal stem cells (BMSCs) enhanced protection against lipopolysaccharide (LPS)-induced EC injury by activating the Wnt/ß-catenin pathway. This in vivo study was performed to verify whether BMSCs overexpressing HOXB4 exert similar protective effects on LPS-induced acute lung injury (ALI) in an animal model. METHODS: The ALI rat model was established by intraperitoneal injection of LPS. Wildtype BMSCs or BMSCs overexpressing HOXB4 were then injected via the tail vein. The lung characteristics of rats were visualized by computed tomography. Lung histopathological characteristics and collagen deposition were assessed by hematoxylin-eosin and Masson's staining, respectively, which were combined with the lung wet/dry ratio and proinflammatory factor levels in bronchoalveolar lavage fluid to further evaluate therapeutic effects. Expression of ß-catenin and VE-cadherin was assessed by western blotting and immunofluorescence. RESULTS: Compared with wildtype BMSCs, overexpression of HOXB4 optimized the therapeutic effects of BMSCs, which manifested as improvements in lung exudation and histopathological features, reduced lung collagen deposition, amelioration of lung permeability, attenuation of lung inflammation, and enhanced expression of ß-catenin and VE-cadherin proteins. CONCLUSIONS: HOXB4-overexpressing BMSCs optimized the protective effect against LPS-induced ALI by partially activating Wnt/ß-catenin signaling.

Cross-Platform Comparison of Highly Sensitive Immunoassays for Inflammatory Markers in a COVID-19 Cohort.

A variety of commercial platforms are available for the simultaneous detection of multiple cytokines and associated proteins, often employing Ab pairs to capture and detect target proteins. In this study, we comprehensively evaluated the performance of three distinct platforms: the fluorescent bead-based Luminex assay, the proximity extension-based Olink assay, and a novel proximity ligation assay platform known as Alamar NULISAseq. These assessments were conducted on human serum samples from the National Institutes of Health IMPACC study, with a focus on three essential performance metrics: detectability, correlation, and differential expression. Our results reveal several key findings. First, the Alamar platform demonstrated the highest overall detectability, followed by Olink and then Luminex. Second, the correlation of protein measurements between the Alamar and Olink platforms tended to be stronger than the correlation of either of these platforms with Luminex. Third, we observed that detectability differences across the platforms often translated to differences in differential expression findings, although high detectability did not guarantee the ability to identify meaningful biological differences. Our study provides valuable insights into the comparative performance of these assays, enhancing our understanding of their strengths and limitations when assessing complex biological samples, as exemplified by the sera from this COVID-19 cohort.

Cross-platform comparison of highly-sensitive immunoassays for inflammatory markers in a COVID-19 cohort 1.

A variety of commercial platforms are available for the simultaneous detection of multiple cytokines and associated proteins, often employing antibody pairs to capture and detect target proteins. In this study, we comprehensively evaluated the performance of three distinct platforms: the fluorescent bead-based Luminex assay, the proximity extension-based Olink assay, and a novel proximity ligation assay platform known as Alamar NULISAseq. These assessments were conducted on serum samples from the NIH IMPACC study, with a focus on three essential performance metrics: detectability, correlation, and differential expression. Our results reveal several key findings. Firstly, the Alamar platform demonstrated the highest overall detectability, followed by Olink and then Luminex. Secondly, the correlation of protein measurements between the Alamar and Olink platforms tended to be stronger than the correlation of either of these platforms with Luminex. Thirdly, we observed that detectability differences across the platforms often translated to differences in differential expression findings, although high detectability did not guarantee the ability to identify meaningful biological differences. Our study provides valuable insights into the comparative performance of these assays, enhancing our understanding of their strengths and limitations when assessing complex biological samples, as exemplified by the sera from this COVID-19 cohort.

NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing.

The blood proteome holds great promise for precision medicine but poses substantial challenges due to the low abundance of most plasma proteins and the vast dynamic range of the plasma proteome. Here we address these challenges with NUcleic acid Linked Immuno-Sandwich Assay (NULISA™), which improves the sensitivity of traditional proximity ligation assays by ~10,000-fold to attomolar level, by suppressing assay background via a dual capture and release mechanism built into oligonucleotide-conjugated antibodies. Highly multiplexed quantification of both low- and high-abundance proteins spanning a wide dynamic range is achieved by attenuating signals from abundant targets with unconjugated antibodies and next-generation sequencing of barcoded reporter DNA. A 200-plex NULISA containing 124 cytokines and chemokines and other proteins demonstrates superior sensitivity to a proximity extension assay in detecting biologically important low-abundance biomarkers in patients with autoimmune diseases and COVID-19. Fully automated NULISA makes broad and in-depth proteomic analysis easily accessible for research and diagnostic applications.

Association between ICU admission (neutrophil + monocyte)/lymphocyte ratio and 30-day mortality in patients with sepsis: a retrospective cohort study.

BACKGROUND: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. METHODS: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P = 0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P = 0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P < 0.0001). CONCLUSION: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.

Associating Multimodal Neuroimaging Abnormalities With the Transcriptome and Neurotransmitter Signatures in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is a multidimensional disease. This study proposes a new research framework that combines multimodal meta-analysis and genetic/molecular architecture to solve the consistency in neuroimaging biomarkers of schizophrenia and whether these link to molecular genetics. STUDY DESIGN: We systematically searched Web of Science, PubMed, and BrainMap for the amplitude of low-frequency fluctuations (ALFF) or fractional ALFF, regional homogeneity, regional cerebral blood flow, and voxel-based morphometry analysis studies investigating schizophrenia. The pooled-modality, single-modality, and illness duration-dependent meta-analyses were performed using the activation likelihood estimation algorithm. Subsequently, Spearman correlation and partial least squares regression analyses were conducted to assess the relationship between identified reliable convergent patterns of multimodality and neurotransmitter/transcriptome, using prior molecular imaging and brain-wide gene expression. STUDY RESULTS: In total, 203 experiments comprising 10 613 patients and 10 461 healthy controls were included. Multimodal meta-analysis showed that brain regions of significant convergence in schizophrenia were mainly distributed in the frontotemporal cortex, anterior cingulate cortex, insula, thalamus, striatum, and hippocampus. Interestingly, the analyses of illness-duration subgroups identified aberrant functional and structural evolutionary patterns: Lines from the striatum to the cortical core networks to extensive cortical and subcortical regions. Subsequently, we found that these robust multimodal neuroimaging abnormalities were associated with multiple neurobiological abnormalities, such as dopaminergic, glutamatergic, serotonergic, and GABAergic systems. CONCLUSIONS: This work links transcriptome/neurotransmitters with reliable structural and functional signatures of brain abnormalities underlying disease effects in schizophrenia, which provides novel insight into the understanding of schizophrenia pathophysiology and targeted treatments.

Association Between ICU admission (Neutrophil + Monocyte)/Lymphocyte Ratio And 30-Day Mortality in Patients with Sepsis: A Retrospective Study from MIMIC-IV.

Background: Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. Methods: A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. Results: Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44-23.67] vs. 8.71 [4.81-16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P=0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P=0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P<0.0001). Conclusion: The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.

DNA Tetrahedra-Based Delivery of MicroRNA-22 to Reduce Depressive Symptoms in Mice.

Major depressive disorder (MDD) is a common illness with an increasing lifetime prevalence. Thus, an increasing number of studies have investigated the association between MDD and microRNAs (miRNAs), which are a novel approach for treating depression. However, the therapeutic potential of miRNA-based strategies has several limitations. To overcome these limitations, DNA tetrahedra (TDNs) have been used as piggyback materials. In this study, we successfully used TDNs as carriers of miRNA-22-3p (miR-22-3p) and synthesized a novel DNA nanocomplex (TDN-miR-22-3p), which was used in a lipopolysaccharide (LPS)-induced depression cell model. The results suggest that miR-22-3p may regulate inflammation by regulating phosphatase and tensin homologue (PTEN), an important regulatory molecule in the PI3K/AKT pathway, and downregulating the expression of NLRP3. We further validated the role of TDN-miR-22-3p in vivo using an LPS-induced animal model of depression. The results indicate that it ameliorated depression-like behavior and attenuated the expression of inflammation-related factors in mice. This study demonstrates the establishment of a straightforward and efficacious miRNA delivery system and the potential of TDNs as therapeutic vectors and tools for mechanistic studies. To the best of our knowledge, this is the first study to use TDNs in combination with miRNAs to treat depression.

Multiple sclerosis lesion segmentation: revisiting weighting mechanisms for federated learning.

Background and introduction: Federated learning (FL) has been widely employed for medical image analysis to facilitate multi-client collaborative learning without sharing raw data. Despite great success, FL's applications remain suboptimal in neuroimage analysis tasks such as lesion segmentation in multiple sclerosis (MS), due to variance in lesion characteristics imparted by different scanners and acquisition parameters. Methods: In this work, we propose the first FL MS lesion segmentation framework via two effective re-weighting mechanisms. Specifically, a learnable weight is assigned to each local node during the aggregation process, based on its segmentation performance. In addition, the segmentation loss function in each client is also re-weighted according to the lesion volume for the data during training. Results: The proposed method has been validated on two FL MS segmentation scenarios using public and clinical datasets. Specifically, the case-wise and voxel-wise Dice score of the proposed method under the first public dataset is 65.20 and 74.30, respectively. On the second in-house dataset, the case-wise and voxel-wise Dice score is 53.66, and 62.31, respectively. Discussions and conclusions: The Comparison experiments on two FL MS segmentation scenarios using public and clinical datasets have demonstrated the effectiveness of the proposed method by significantly outperforming other FL methods. Furthermore, the segmentation performance of FL incorporating our proposed aggregation mechanism can achieve comparable performance to that from centralized training with all the raw data.

NULISA: a novel proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing.

The blood proteome holds great promise for precision medicine but poses substantial challenges due to the low abundance of most plasma proteins and the vast dynamic range across the proteome. We report a novel proteomic technology - NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) - that incorporates a dual capture and release mechanism to suppress the assay background and improves the sensitivity of the proximity ligation assay by over 10,000-fold to the attomolar level. It utilizes pairs of antibodies conjugated to DNA oligonucleotides that enable immunocomplex purification and generate reporter DNA containing target- and sample-specific barcodes for a next-generation sequencing-based, highly multiplexed readout. A 200-plex NULISA targeting 124 cytokines and chemokines and 80 other immune response-related proteins demonstrated superior sensitivity for detecting low-abundance proteins and high concordance with other immunoassays. The ultrahigh sensitivity allowed the detection of previously difficult-to-detect, but biologically important, low-abundance biomarkers in patients with autoimmune diseases and COVID-19. Fully automated NULISA addresses longstanding challenges in proteomic analysis of liquid biopsies and makes broad and in-depth proteomic analysis accessible to the general research community and future diagnostic applications.

Overexpression of FoxM1 optimizes the therapeutic effect of bone marrow mesenchymal stem cells on acute respiratory distress syndrome.

BACKGROUND: Injury of alveolar epithelial cells and capillary endothelial cells is crucial in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) are a promising cell source for ALI/ARDS treatment. Overexpression of Fork head box protein M1 (FoxM1) facilitates MSC differentiation into alveolar type II (AT II) cells in vitro. Moreover, FoxM1 has been shown to repair the endothelial barrier. Therefore, this study explored whether overexpression of FoxM1 promotes the therapeutic effect of bone marrow-derived MSCs (BMSCs) on ARDS by differentiation of BMSCs into AT II cells or a paracrine mechanism. METHODS: A septic ALI model was established in mice by intraperitoneal administration of lipopolysaccharide. The protective effect of BMSCs-FoxM1 on ALI was explored by detecting pathological variations in the lung, total protein concentration in bronchoalveolar lavage fluid (BALF), wet/dry (W/D) lung weight ratio, oxidative stress levels, cytokine levels, and retention of BMSCs in the lung. In addition, we assessed whether FoxM1 overexpression promoted the therapeutic effect of BMSCs on ALI/ARDS by differentiating into AT II cells using SPC-/- mice. Furthermore, the protective effect of BMSCs-FoxM1 on lipopolysaccharide-induced endothelial cell (EC) injury was explored by detecting EC proliferation, apoptosis, scratch wounds, tube formation, permeability, and oxidative stress, and analyzing whether the Wnt/ß-catenin pathway contributes to the regulatory mechanism in vitro using a pathway inhibitor. RESULTS: Compared with BMSCs-Vector, treatment with BMSCs-FoxM1 significantly decreased the W/D lung weight ratio, total BALF protein level, lung injury score, oxidative stress, and cytokine levels. With the detected track of BMSCs-FoxM1, we observed a low residency rate and short duration of residency in the lung. Notably, SPC was not expressed in SPC-/- mice injected with BMSCs-FoxM1. Furthermore, BMSCs-FoxM1 enhanced EC proliferation, migration, and tube formation; inhibited EC apoptosis and inflammation; and maintained vascular integrity through activation of the Wnt/ß-catenin pathway, which was partially reversed by XAV-939. CONCLUSION: Overexpression of FoxM1 enhanced the therapeutic effect of BMSCs on ARDS, possibly through a paracrine mechanism rather than by promoting BMSC differentiation into AT II cells in vivo, and prevented LPS-induced EC barrier disruption partially through activating the Wnt/ß-catenin signaling pathway in vitro.

Overexpression of FoxM1 Enhanced the Protective Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Lipopolysaccharide-Induced Acute Lung Injury through the Activation of Wnt/ß-Catenin Signaling.

Background: Mesenchymal stem cell- (MSC-) based cell and gene therapies have made remarkable progress in alleviating acute lung injury/acute respiratory distress syndrome (ALI/ARDS). However, the benefits of Forkhead box protein M1 (FoxM1) gene-modified MSCs in the treatment of ALI have not been studied. Methods: We evaluated the therapeutic effects of FoxM1-modified MSCs in ALI mice induced by lipopolysaccharide (LPS) by quantifying the survival rate, lung weight ratio (wet/dry), and contents of bronchoalveolar lavage fluid. In addition, microcomputed tomography, histopathology, Evans Blue assay, and quantification of apoptosis were performed. We also explored the underlying mechanism by assessing Wnt/ß-catenin signaling following the treatment of mice with FoxM1-modified MSCs utilizing the Wnt/ß-catenin inhibitor XAV-939. Results: Compared with unmodified MSCs, transplantation of FoxM1-modified MSCs improved survival and vascular permeability; reduced total cell counts, leukocyte counts, total protein concentrations, and inflammatory cytokines in BALF; attenuated lung pathological impairments and fibrosis; and inhibited apoptosis in LPS-induced ALI/ARDS mice. Furthermore, FoxM1-modified MSCs maintained vascular integrity during ALI/ARDS by upregulating Wnt/ß-catenin signaling, which was partly reversed via a pathway inhibitor. Conclusion: Overexpression of FoxM1 optimizes the treatment action of MSCs on ALI/ARDS by inhibiting inflammation and apoptosis and restoring vascular integrity partially through Wnt/ß-catenin signaling pathway stimulation.

Intrinsic Therapeutic Link between Recuperative Cerebellar Con-Nectivity and Psychiatry Symptom in Schizophrenia Patients with Comorbidity of Metabolic Syndrome.

Components of metabolic syndrome might be predictors of the therapeutic outcome of psychiatric symptom in schizophrenia, whereas clinical results are inconsistent and an intrinsic therapeutic link between weaker psychiatric symptoms and emergent metabolic syndrome remains unclear. This study aims to reveal the relationship and illustrate potential mechanism by exploring the alteration of cerebellar functional connectivity (FC) in schizophrenia patients with comorbidity metabolic syndrome. Thirty-six schizophrenia patients with comorbidity of metabolic syndrome (SCZ-MetS), 45 schizophrenia patients without metabolic syndrome (SCZ-nMetS) and 39 healthy controls (HC) were recruited in this study. We constructed FC map of cerebello-cortical circuit and used moderation effect analysis to reveal complicated relationship among FC, psychiatric symptom and metabolic disturbance. Components of metabolic syndrome were significantly correlated with positive symptom score and negative symptom score. Importantly, the dysconnectivity between cognitive module of cerebellum and left middle frontal gyrus in SCZ-nMetS was recuperative increased in SCZ-MetS, and was significantly correlated with general symptom score. Finally, we observed significant moderation effect of body mass index on this correlation. The present findings further supported the potential relationship between emergence of metabolic syndrome and weaker psychiatric symptom, and provided neuroimaging evidence. The mechanism of intrinsic therapeutic link involved functional change of cerebello-cortical circuit.

Aspirin-Loaded Cross-Linked Lipoic Acid Nanodrug Prevents Postoperative Tumor Recurrence by Residual Cancer Cell Killing and Inflammatory Microenvironment Improvement.

In addition to residual cancer cells, the surgery resection-induced hyperinflammatory microenvironment is a key factor that leads to postsurgical cancer recurrence. Herein, we developed a dual-functional nanodrug Asp@cLANVs for postsurgical recurrence inhibition by loading the classical anti-inflammatory drug aspirin (Asp) into cross-linked lipoic acid nanovesicles (cLANVs). The Asp@cLANVs can not only kill residual cancer cells at the doses comparable to common cytotoxic drugs by synergistic interaction between Asp and cLANVs, but also improve the postsurgical inflammatory microenvironment by their strongly synergistic anti-inflammation activity between Asp and cLANVs. Using mice bearing partially removed NCI-H460 tumors, we found that Asp@cLANVs gave a much lower recurrence rate (33.3%) compared with the first-line cytotoxic drug cisplatin (100%), and no mice died for at least 60 days after Asp@cLANV treatment while no mouse survived beyond day 43 in the cisplatin group. This dual-functional nanodrug constructs the first example that combines residual cancer cell killing and postoperative inflammation microenvironment improvement to suppress postsurgical cancer recurrence.

An oligomeric hyaluronic acid-GX1 molecular target drug with polyvalent targeting to CD44 and VEGF receptors.

The off-target toxicity of molecular targeted drug hinders its clinical transformation. Herein, we report a new molecular targeted drug oHA-GX1 constructed by oligomeric hyaluronan (oHA) and peptide GX1 (CGNSNPKSC). The oHA-GX1 can not only suppress the tumor growth by interacting with overexpressed VEGF and CD44 receptors inside tumor tissues, but also reduce the likelihood of off-target toxicity due to the multiple VEGF and CD44 receptors binding sites. The cytotoxicity study shows that the IC50oHA-GX1 against co-SGC-7901 and co-HUVEC cells fell in the range of common cytotoxic drugs. The animal experiment results reveal that the tumor inhibition rate of oHA-GX1 (100 mg/kg) against SGC-7901 tumor-bearing mice were 78.4 %, which was comparable to that of front-line chemotherapy drugs. Also, the cytotoxicity study on normal cells, hemolysis test, hemagglutination assay and the acute toxicity test demonstrate that oHA-GX1 exhibited excellent biosafety. This molecular targeted drug that utilizes the multiple receptor-binding sites to get rid of the side effects caused by off-target paves a new direction for the discovery of anticancer drugs with high efficacy and low adverse effects.

Prognostic factors of hearing outcome in patients with chronic suppurative otitis media following tympanoplasty: a retrospective cohort study.

Background: Research on the factors affecting the functional outcome of tympanoplasty in chronic suppurative otitis media (CSOM) is limited. This study aimed to investigate the prognostic factors of hearing outcome in CSOM patients following tympanoplasty. The multivariate logistic regression analysis is used to evaluate the influence of demographic, audiological, clinical and disease factors on the postoperative prognosis of CSOM. Methods: A total of 179 CSOM patients who received surgery between January 2016 and December 2019 were retrospectively included. The inclusion criteria are mainly based on clinical classification of otitis media and surgical classification guidelines [2012]. These patients were divided into an effective group (n=132) and a non-effective group (n=47) according to their postoperative air-bone gap (ABG) value. Multivariate analysis was performed according to the pure tone hearing results 1 week before operation and 4 weeks after operation. Results: The type of preoperative hearing impairment, middle ear cholesteatoma, ossicular chain status, tympanic perforation site, repair material, tympanum sclerosis, and surgical methods were significantly different between the effective and non-effective groups (all P<0.01). The speech reception threshold (SRT) (36.88±15.54 vs. 27.68±13.75, P<0.001) and ABG (18.53±9.30 vs. 10.89±5.07, P<0.001) values were markedly reduced after surgery in the effective group but not in the non-effective group. Furthermore, the postoperative decreases in the SRT (9.20±9.69 vs. 2.021±7.34, P<0.001) and ABG (7.64±8.57 vs. 0.45±7.322, P<0.001) values were considerably higher in the effective group than the non-effective group. After multivariate logistic regression analysis, we found that the type of preoperative hearing impairment [P=0.031; odds ratio (OR) =2.378], ossicular chain status (P=0.002; OR =4.430). Conclusions: Our research shows that the curative effect of conductive deafness before operation is 2.378 times better than that of mixed deafness, the curative effect of complete and unfixed ossicular chain before operation is 1.080 times better than that of interrupted ossicular chain, and the curative effect of complete ossicular chain but fixed ossicular chain is 4.430 times better than that of interrupted ossicular chain. Our findings may help to predict the postoperative prognosis of patients, thus facilitating the development of corresponding treatment strategies.

Efficacy of administrative intervention for neurosurgical patients with off-label use of alprostadil lipid microsphere.

As an adjuvant drug, alprostadil lipid microsphere injection (Lipo-PGE1) is one of the best-selling drugs in China in recent years. However, the off-label use of Lipo-PGE1 is very common. This study aimed to investigate the use of Lipo-PGE1 and evaluate the clinical effects and economic benefits after administrative intervention on inappropriate use of Lipo-PGE1 in neurosurgical patients in a Chinese tertiary hospital. Administrative interventions were implemented from January to December 2018 by reducing the procurement volume of Lipo-PGE1, judging the rationality of medical records, and establishing reward and punishment mechanisms. Administrative interventions significantly decreased prescription rate (49.98% vs 22.49%), utilization (22,311 DDDs vs 8334 DDDs), drug use density (43.52 DDDs/TID vs 15.84 DDDs/TID), total expenditure (3.58 million RMB vs 1.30 million RMB), and average expenditure (2025.04 RMB vs 1466.49 RMB) of Lipo-PGE1. To our delight, these intervention effects were maintained or even better in the 1-year post-intervention period. Moreover, in the intervention and post-intervention phases, the Lipo-PGE1 use for no indications as well as inappropriate drug dose, frequency, menstruum type, combination, and contraindication were markedly reduced. Besides, the mean costs (P < 0.001), and mean duration (P < 0.001) of Lipo-PGE1 were also obviously decreased. The administrative intervention obviously reduced the off-label use of Lipo-PGE1. However, there still remains a number of inappropriate uses of Lipo-PGE1. To further improve the rational use of Lipo-PGE1, combination of administrative intervention and real-time clinical pharmacists intervention should be implemented.

Reconfiguration of Functional Dynamics in Cortico-Thalamo-Cerebellar Circuit in Schizophrenia Following High-Frequency Repeated Transcranial Magnetic Stimulation.

Schizophrenia is a serious mental illness characterized by a disconnection between brain regions. Transcranial magnetic stimulation is a non-invasive brain intervention technique that can be used as a new and safe treatment option for patients with schizophrenia with drug-refractory symptoms, such as negative symptoms and cognitive impairment. However, the therapeutic effects of transcranial magnetic stimulation remain unclear and would be investigated using non-invasive tools, such as functional connectivity (FC). A longitudinal design was adopted to investigate the alteration in FC dynamics using a dynamic functional connectivity (dFC) approach in patients with schizophrenia following high-frequency repeated transcranial magnetic stimulation (rTMS) with the target at the left dorsolateral prefrontal cortex (DLPFC). Two groups of schizophrenia inpatients were recruited. One group received a 4-week high-frequency rTMS together with antipsychotic drugs (TSZ, n = 27), while the other group only received antipsychotic drugs (DSZ, n = 26). Resting-state functional magnetic resonance imaging (fMRI) and psychiatric symptoms were obtained from the patients with schizophrenia twice at baseline (t1) and after 4-week treatment (t2). The dynamics was evaluated using voxel- and region-wise FC temporal variability resulting from fMRI data. The pattern classification technique was used to verify the clinical application value of FC temporal variability. For the voxel-wise FC temporary variability, the repeated measures ANCOVA analysis showed significant treatment × time interaction effects on the FC temporary variability between the left DLPFC and several regions, including the thalamus, cerebellum, precuneus, and precentral gyrus, which are mainly located within the cortico-thalamo-cerebellar circuit (CTCC). For the ROI-wise FC temporary variability, our results found a significant interaction effect on the FC among CTCC. rTMS intervention led to a reduced FC temporary variability. In addition, higher alteration in FC temporal variability between left DLPFC and right posterior parietal thalamus predicted a higher remission ratio of negative symptom scores, indicating that the decrease of FC temporal variability between the brain regions was associated with the remission of schizophrenia severity. The support vector regression (SVR) results suggested that the baseline pattern of FC temporary variability between the regions in CTCC could predict the efficacy of high-frequency rTMS intervention on negative symptoms in schizophrenia. These findings confirm the potential relationship between the reduction in whole-brain functional dynamics induced by high-frequency rTMS and the improvement in psychiatric scores, suggesting that high-frequency rTMS affects psychiatric symptoms by coordinating the heterogeneity of activity between the brain regions. Future studies would examine the clinical utility of using functional dynamics patterns between specific brain regions as a biomarker to predict the treatment response of high-frequency rTMS.

Impact of the COVID-19 pandemic on psychological distress and biological rhythm in China's general population: A path analysis model.

OBJECTIVE: When facing major emergency public accidents, men and women may react differently. Our research aimed to assess the influence of gender difference on social support, information preference, biological rhythm, psychological distress, and the possible interaction among these factors during the COVID-19 pandemic. METHODS: In this cross-sectional study, 3,237 respondents aged 12 years and older finished the online survey. Levels of social support, information preference, biological rhythm, and psychological distress were assessed using validated scales. A path analysis was conducted to explore possible associations among these variables. RESULTS: The path analysis indicated that women with high levels of social support had a lower possibility of biological rhythm disorders and lower levels of somatization symptoms of psychological distress during the COVID-19 pandemic. The influence of social support on somatization symptoms was exerted via biological rhythm. Women tended to believe both negative and positive information, while men preferred more extreme information. CONCLUSION: Our results highlighted gender difference in study variables during the COVID-19 pandemic and the importance of social support in alleviating psychological distress and biological rhythm disorders. Moreover, we confirmed that information preference differed significantly by somatization symptoms of psychological distress, suggesting extra efforts to provide more individualized epidemic information. Longitudinal research is required to further explore casual inferences.

Bio-Inspired Autonomous Learning Algorithm With Application to Mobile Robot Obstacle Avoidance.

Spiking Neural Networks (SNNs) are often considered the third generation of Artificial Neural Networks (ANNs), owing to their high information processing capability and the accurate simulation of biological neural network behaviors. Though the research for SNNs has been quite active in recent years, there are still some challenges to applying SNNs to various potential applications, especially for robot control. In this study, a biologically inspired autonomous learning algorithm based on reward modulated spike-timing-dependent plasticity is proposed, where a novel rewarding generation mechanism is used to generate the reward signals for both learning and decision-making processes. The proposed learning algorithm is evaluated by a mobile robot obstacle avoidance task and experimental results show that the mobile robot with the proposed algorithm exhibits a good learning ability. The robot can successfully avoid obstacles in the environment after some learning trials. This provides an alternative method to design and apply the bio-inspired robot with autonomous learning capability in the typical robotic task scenario.