Aim
No previous studies, to our knowledge, have investigated the association between psychiatrist density and suicide, accounting for individual‐ and area‐level characteristics.
Methods
We ...investigated all suicide cases in 2007‐2017 identified from the national cause‐of‐death data files, with each suicide case matched to 10 controls by age and sex and each suicide case/control assigned to one of the 355 townships across Taiwan. Our primary outcome was the odds ratio (OR) of suicide and its 95% confidence interval (CI) estimated via multilevel models, which included both individual‐ and area‐level characteristics. Townships with no psychiatrists were compared with the quartiles of townships with psychiatrists (density per 100,000 population): quartile 1 (Q1) (0.01–3.02); quartile 2 (Q2) (3.02–7.20); quartile 3 (Q3) (7.20–13.82); and quartile 4 (Q4) (>13.82).
Results
A total of 40,930 suicide cases and 409,300 age‐ and sex‐matched controls were included. We found that increased psychiatrist density was associated with decreased suicide risk (Q1: adjusted OR aOR, 0.95 95% CI, 0.90–1.01; Q2: aOR, 0.90 95% CI, 0.85–0.96; Q3: aOR, 0.89 95% CI, 0.83–0.94; Q4: aOR, 0.89 95% CI, 0.83–0.95) after adjusting for individual‐level characteristics (employment state, monthly income, physical comorbidities, and the diagnosis of psychiatric disorders) and area socioeconomic characteristics.
Conclusions
The psychiatrist density–suicide association suggests an effect of increased availability of psychiatric services on preventing suicide. Suicide prevention strategies could usefully focus on enhancing local access to psychiatric services.
Drug susceptibility (also called chemosensitivity) is an important criterion for developing a therapeutic strategy for various cancer types such as breast cancer and leukemia. Recently, functional ...assays such as high-content screening together with genomic analysis have been shown to be effective for predicting drug susceptibility, but their clinical applicability is poor since they are time-consuming (several days long), labor-intensive, and costly. Here we present a highly simple, rapid, and cost-effective liquid biopsy for
ex vivo
drug-susceptibility testing of leukemia. The method is based on an extreme-throughput (>1 million cells per second), label-free, whole-blood imaging flow cytometer with a deep convolutional autoencoder, enabling image-based identification of the drug susceptibility of every single white blood cell in whole blood within 24 hours by simply flowing a drug-treated whole blood sample as little as 500 μL into the imaging flow cytometer without labeling. Our results show that the method accurately evaluates the drug susceptibility of white blood cells from untreated patients with acute lymphoblastic leukemia. Our method holds promise for affordable precision medicine.
The drug susceptibility of leukemia cells in whole blood is evaluated by using extreme-throughput imaging flow cytometry with deep learning.
Exosomes secreted by adipose-derived stem cells (ADSC-exo) reportedly improve nerve regeneration after peripheral nerve injury. Herein, we investigated whether pretreatment of ADSCs with FK506, an ...immunosuppressive drug that enhances nerve regeneration, could secret exosomes (ADSC-F-exo) that further augment nerve regeneration. Designed exosomes were topically applied to injured nerve in a mouse model of sciatic nerve crush injury to assess the nerve regeneration efficacy. Outcomes were determined by histomorphometric analysis of semi-thin nerve sections stained with toluidine blue, mouse neurogenesis PCR array, and neurotrophin expression in distal nerve segments. Isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile potential exosomal proteins facilitating nerve regeneration. We observed that locally applied ADSC-exo and ADSC-F-exo significantly enhanced nerve regeneration after nerve crush injury. Pretreatment of ADSCs with FK506 failed to produce exosomes possessing more potent molecules for enhanced nerve regeneration. Proteomic analysis revealed that of 192 exosomal proteins detected in both ADSC-exo and ADSC-F-exo, histone deacetylases (HDACs), amyloid-beta A4 protein (APP), and integrin beta-1 (ITGB1) might be involved in enhancing nerve regeneration.
Sporadic Alzheimer’s disease (sAD) is the most common type of neurodegenerative disease. Recent studies show that detectable impairment of brain glucose metabolism occurs years before onset of AD ...symptoms, and the dysregulated O‐GlcNAc levels likely arisen from impaired glucose metabolism correlates with AD pathogenesis. So far, the mechanism of sAD and the role of OGN in AD pathology remained largely unknown due to a lack of human sAD model. We have established a human sAD model in which the pathological features are reproduced by glucose deficiency that better represents sAD as a metabolic disease. We generated human cortical neurons from human induced pluripotent stem cell and treated mature neuron with glucose reduction media to study the effect of low glucose on the degenerative status of neuron. Fluoro JADE C staining and cell viability assays reveals low glucose treatment at 2mM leads to dramatic increases of degeneration cell on day 3 and 5 of treatment and decreased cell viability on day 7. Interestingly, western blotting and immunofluorescent staining results demonstrate that long‐term low glucose treatment induces two major AD features in cortical neuron, including accumulation of abnormal hyperphosphorylated tau and increasing amyloid beta production. In addition, glucose deficiency also causes decreased neurite coverage, synapse loss, and neuron network activity disruption detected by immunofluorescent staining and multi‐electrode array electrophysiological analyses. Furthermore, we find that O‐GlcNAc levels are significantly reduced soon after low glucose treatment and last till the end of experiment. Artificially increasing O‐GlcNAc level by thiamet‐G (TMG) in low glucose treated neurons, rescues low glucose‐induced AD phenotypes. Moreover, our data show that O‐GlcNAc dysregulation results in mitochondrial dysfunction, which occurs before any other degenerative phenotype appeared, and may be one of the underlying mechanisms of sAD onset and pathogenesis. Taken together, we established a human sAD model that mimics the main features of AD pathogenesis, which agrees with clinical observations of sAD patients. Therefore, this platform can serve as a tool to better understand molecular processes involved in sAD. Our results also suggest that dysregulated O‐GlcNAc levels by glucose deficiency is involved in the onset and progression of sAD.
Board corruption and loan contracts Chen, Robin; Huang, Chia‐Wei; Lin, Chih‐Yung
Journal of business finance & accounting,
October-November 2022, Letnik:
49, Številka:
9-10
Journal Article
Recenzirano
In this study, we examine the effects of board corruption on the financing costs of firms. We construct an index of perceived corruption that uses the average level of corruption that is linked to a ...director's surname. The evidence shows that lending banks attach higher spreads and stricter covenants to the loan contracts of firms with high perceived board corruption. Specifically, when the perceived board corruption increases after mergers and acquisitions, firms are charged higher loan spreads. Further analysis shows that the effects of board corruption on financing costs become stronger when firms have weak governance mechanisms. These results show that banks recognize board corruption as a source of agency problem with borrowers when they make lending decisions.
Background: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint ...inhibitor (ICI) therapy. Objectives: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). Methods: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. Results: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8 + LAG3 + cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. Conclusions: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
This study estimated the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) according to cardiometabolic risk factors. The long-term impacts of MASLD on all-cause and ...cardiometabolic-specific mortality were evaluated.
We enrolled 343 816 adults aged ≥30 years who participated in a health screening program from 1997 through 2013. MASLD was identified on the basis of abdominal ultrasonography and metabolic profiles. The participants were further categorized by liver enzyme elevation. Baseline cardiometabolic comorbidities were classified on the basis of self-reported medication use and clinical seromarkers. All-cause and cardiometabolic-specific deaths were determined through computerized data linkage with nationwide death certifications until December 31, 2020.
The overall prevalence of MASLD was 36.4%. Among patients with MASLD, 35.9% had abnormal liver enzyme levels. Compared with patients without MASLD, abnormal liver enzymes were positively associated with cardiometabolic comorbidities in patients with MASLD (P
< 0.001). After follow-up, patients with MASLD had a 9%-29% higher risk of all-cause, cardiovascular-related, or diabetes-related mortality. In the groups with MASLD and elevated and normal liver enzyme levels, the multivariate-adjusted hazard ratios for cardiovascular deaths were 1.14 (1.05-1.25) and 1.10 (1.03-1.17), respectively, and those for diabetes deaths were 1.42 (1.05-1.93) and 1.24 (0.98-1.57), respectively, compared with those in the non-MASLD group (P
< 0.001).
Individuals with MASLD and elevated liver enzyme levels exhibited significantly higher risks of all-cause and cardiometabolic deaths and should be monitored and given consultation on cardiometabolic modifications.
Platelets are anucleate cells in blood whose principal function is to stop bleeding by forming aggregates for hemostatic reactions. In addition to their participation in physiological hemostasis, ...platelet aggregates are also involved in pathological thrombosis and play an important role in inflammation, atherosclerosis, and cancer metastasis. The aggregation of platelets is elicited by various agonists, but these platelet aggregates have long been considered indistinguishable and impossible to classify. Here we present an intelligent method for classifying them by agonist type. It is based on a convolutional neural network trained by high-throughput imaging flow cytometry of blood cells to identify and differentiate subtle yet appreciable morphological features of platelet aggregates activated by different types of agonists. The method is a powerful tool for studying the underlying mechanism of platelet aggregation and is expected to open a window on an entirely new class of clinical diagnostics, pharmacometrics, and therapeutics.
Exosomes secreted by adipose-derived stem cells (ADSCs) enhance angiogenesis and wound healing. However, in clinical settings, wounds may be infected by various bacteria or pathogens. We investigated ...whether human ADSCs stimulated with lipopolysaccharide (LPS) secrete exosomes (ADSC-LPS-exo) that augment the angiogenesis of human umbilical vein endothelial cells (HUVECs). ExoQuick-TC exosome precipitation solution was used to purify exosomes from human ADSC culture media in the presence or absence of 1 µg/mL LPS treatment for 24 h. The uptake of ADSC-LPS-exo significantly induced the activation of cAMP response element binding protein (CREB), activating protein 1 (AP-1), and nuclear factor-κB (NF-κB) signaling pathways and increased the migration of and tube formation in HUVECs. RNA interference with CREB, AP-1, or NF-κB1 significantly reduced the migration of and tube formation in HUVECs treated with ADSC-LPS-exo. An experiment with an antibody array for 25 angiogenesis-related proteins revealed that only interleukin-8 expression was significantly upregulated in HUVECs treated with ADSC-LPS-exo. In addition, proteomic analysis revealed that eukaryotic translation initiation factor 4E, amyloid beta A4 protein, integrin beta-1, and ras-related C3 botulinum toxin substrate 1 may be potential candidates involved in ADSC-LPS-exo-mediated enhanced angiogenesis.
Combining the strength of flow cytometry with fluorescence imaging and digital image analysis, imaging flow cytometry is a powerful tool in diverse fields including cancer biology, immunology, drug ...discovery, microbiology, and metabolic engineering. It enables measurements and statistical analyses of chemical, structural, and morphological phenotypes of numerous living cells to provide systematic insights into biological processes. However, its utility is constrained by its requirement of fluorescent labeling for phenotyping. Here we present label-free chemical imaging flow cytometry to overcome the issue. It builds on a pulse pair-resolved wavelength-switchable Stokes laser for the fastest-to-date multicolor stimulated Raman scattering (SRS) microscopy of fast-flowing cells on a 3D acoustic focusing microfluidic chip, enabling an unprecedented throughput of up to ∼140 cells/s. To show its broad utility, we use the SRS imaging flow cytometry with the aid of deep learning to study the metabolic heterogeneity of microalgal cells and perform marker-free cancer detection in blood.
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