Suicide Attempts After a Diagnosis of Polycystic Ovary Syndrome : A Cohort Study.

BACKGROUND: Limited evidence exists about suicide risk in persons with polycystic ovary syndrome (PCOS). OBJECTIVE: To assess suicide risk in persons with PCOS, accounting for psychiatric comorbid conditions and age group. DESIGN: Cohort study. SETTING: Data from the Taiwanese nationwide database from 1997 to 2012. PATIENTS: A cohort of 18 960 patients diagnosed with PCOS, each matched with control participants in a 1:10 ratio on the basis of age, psychiatric comorbid conditions, urbanization level, and income. Suicide attempts were evaluated using Cox regression models. MEASUREMENTS: Suicide risk with hazard ratios (HRs). RESULTS: Participants with PCOS had a notable 8.47-fold increase in risk for suicide attempt compared with the control group (HR, 8.47 [95% CI, 7.54 to 9.51]), after adjustment for demographic characteristics, psychiatric comorbid conditions, Charlson Comorbidity Index scores, and frequency of all-cause clinical visits. The elevated risk was evident across the adolescent (HR, 5.38 [CI, 3.93 to 7.37]), young adult (<40 years; HR, 9.15 [CI, 8.03 to 10.42]), and older adult (HR, 3.75 [CI, 2.23 to 6.28]) groups. Sensitivity analyses involving the exclusion of data from the first year or the first 3 years of observation yielded consistent results. LIMITATION: Potential underestimation of PCOS and mental disorder prevalence due to use of administrative claims data; lack of clinical data, such as body mass index and depressive symptoms; and no assessment of a confounding effect of valproic acid exposure. CONCLUSION: This study underscores the heightened risk for suicide attempt that persons with PCOS face, even after adjustment for demographics, psychiatric comorbid conditions, physical conditions, and all-cause clinical visits. This suggests the importance of routine monitoring of mental health and suicide risk in persons diagnosed with PCOS. PRIMARY FUNDING SOURCE: Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and Ministry of Science and Technology of Taiwan.

Risk of autoimmune diseases after post-traumatic stress disorder: a nationwide cohort study.

This longitudinal study aimed to investigate the risk of subsequent autoimmune disease in patients with post-traumatic stress disorder (PTSD) in Asian population. Between 2002 and 2009, we enrolled 5273 patients with PTSD and 1:4 matched controls from the National Health Insurance Database of Taiwan, and followed up the patients until December 31, 2011, or death. The investigated autoimmune diseases included thyroiditis, lupus, rheumatic arthritis, inflammatory bowel disease, Sjogren's syndrome, dermatomyositis, and polymyositis. The Cox regression model was used to estimate the risk of developing autoimmune diseases, with adjustment for demographics and psychiatric and medical comorbidities. Furthermore, we examined the psychiatric clinics utility of patients with PTSD indicating the severity of PTSD in association with autoimmune diseases. After adjusting for confounders, patients with PTSD had a 2.26-fold higher risk of developing any autoimmune diseases (reported as hazard ratios with 95% confidence intervals: 1.82-2.80) than the controls. For specific autoimmune diseases, patients with PTSD had a 2.70-fold higher risk (1.98-3.68) of thyroiditis, a 2.95-fold higher risk (1.20-7.30) of lupus, and a 6.32-fold higher risk (3.44-11.60) of Sjogren's syndrome. Moreover, the PTSD severity was associated with the risk of autoimmune diseases in a dose-dependent manner. The patient with the highest psychiatric clinics utility was associated with an 8.23-fold higher risk (6.21-10.90) of any autoimmune diseases than the controls. Patients with PTSD had an increased risk of autoimmune diseases, and such risk was associated with the severity of PTSD in a dose-dependent manner. However, the present study did not provide a direct effect between PTSD and autoimmune diseases, but rather an association. Further studies are warranted to examine the underlying pathophysiological mechanisms.

Comparing the performance of ChatGPT GPT-4, Bard, and Llama-2 in the Taiwan Psychiatric Licensing Examination and in differential diagnosis with multi-center psychiatrists.

AIM: Large language models (LLMs) have been suggested to play a role in medical education and medical practice. However, the potential of their application in the psychiatric domain has not been well-studied. METHOD: In the first step, we compared the performance of ChatGPT GPT-4, Bard, and Llama-2 in the 2022 Taiwan Psychiatric Licensing Examination conducted in traditional Mandarin. In the second step, we compared the scores of these three LLMs with those of 24 experienced psychiatrists in 10 advanced clinical scenario questions designed for psychiatric differential diagnosis. RESULT: Only GPT-4 passed the 2022 Taiwan Psychiatric Licensing Examination (scoring 69 and ≥ 60 being considered a passing grade), while Bard scored 36 and Llama-2 scored 25. GPT-4 outperformed Bard and Llama-2, especially in the areas of 'Pathophysiology & Epidemiology' (χ2 = 22.4, P < 0.001) and 'Psychopharmacology & Other therapies' (χ2 = 15.8, P < 0.001). In the differential diagnosis, the mean score of the 24 experienced psychiatrists (mean 6.1, standard deviation 1.9) was higher than that of GPT-4 (5), Bard (3), and Llama-2 (1). CONCLUSION: Compared to Bard and Llama-2, GPT-4 demonstrated superior abilities in identifying psychiatric symptoms and making clinical judgments. Besides, GPT-4's ability for differential diagnosis closely approached that of the experienced psychiatrists. GPT-4 revealed a promising potential as a valuable tool in psychiatric practice among the three LLMs.

Parental mental disorders in patients with comorbid schizophrenia and obsessive-compulsive disorder: a nationwide family-link study.

Schizophrenia is highly comorbid with obsessive-compulsive disorder (OCD); both conditions share numerous pathophysiological etiologies. We, thus, examined the risk of mental disorders in the parents of probands with schizophrenia, OCD, or both conditions. Between 2001 and 2011, we enrolled a nationwide cohort of 69,813 patients with schizophrenia, OCD, or both. The control cohort included 698,130 individuals matched for demographics. Poisson regression models were employed to examine the risk of six mental disorders in their parents, including schizophrenia, bipolar disorder, depressive disorder, OCD, alcohol use disorder, and substance use disorder. We stratified patients into schizophrenia-only, OCD-only, and dual-diagnosis groups, and the dual-diagnosis group was further divided into schizophrenia-first, OCD-first, and simultaneously diagnosed groups. Compared with controls, the schizophrenia, OCD, and dual-diagnosis groups had higher risks for the six mental disorders in their parents (range of odds ratio [OR] 1.50-7.83). The sub-analysis of the dual-diagnosis group showed that the schizophrenia-first, OCD-first, and simultaneously diagnosed groups had higher odds for schizophrenia, bipolar disorder, depressive disorder, and OCD (range of OR 1.64-6.45) in their parents than the control group; the simultaneously diagnosed and OCD-first diagnosed groups had a higher odds of parental substance use disorder, while the schizophrenia-first diagnosed group had a higher odds of parental alcohol use disorder. The interrelationship between OCD and schizophrenia is linked to bipolar disorder, depressive disorder, alcohol use disorder, and substance use disorder. The results have implications for mental health policy and future research.

Effect of cranial electrotherapy stimulation as an add-on therapy on late-life generalized anxiety disorder: An open-label study.

INTRODUCTION: Cranial electrotherapy stimulation (CES) is beneficial in reducing anxiety in psychiatric patients. However, no studies have reported on elderly patients with generalized anxiety disorders (GAD). This study aimed to determine the efficacy and safety of a 6-week CES intervention for late-life GAD. MATERIALS AND METHODS: This single-arm pilot study assessed 6-week CES treatment (Alpha-Stim AID) for late-life GAD and 4-week follow-up post intervention. The Hamilton Rating Scale for Anxiety (HAMA) and Beck Anxiety Inventory (BAI) were used as baseline and outcome measures at weeks 4, 6, and 10, respectively. Treatment response was defined as 50 % or more reduction of the HAMA score and remission was defined as a of score ≤7 on the HAMA. Other measures included depression, sleep quality, and quality of life assessment. RESULTS: We included participants (n = 27) aged 68.0 ± 5.0 years, 81.5 % of whom were female. Fifteen (55.6 %), 18 (66.7 %), and 15 (55.6 %) patients were concurrently treated with antidepressants, BZDs, and antipsychotics, respectively. Intention-to-treat (ITT) analysis revealed a significant decrease in HAMA scores from baseline (20.96 ± 3.30) to week 6 (12.26 ± 7.09) and one-month (12.85 ± 7.08) follow-up at W10 (all p < 0.001). The response and remission rates were 33.3 %, 40.7 %, and 48.1 % and 25.9 %, 29.6 %, and 25.9 % at W4, W6, and W10, respectively. The CES improved depression and sleep conditions as measured by the Beck Depression Inventory-II and Pittsburgh Sleep Quality Index. CONCLUSION: CES clinically reduces symptoms of anxiety and depression and may improve sleep quality in late-life GAD. Future randomized controlled study is needed.

Effectiveness of Electroencephalography Neurofeedback for Improving Working Memory and Episodic Memory in the Elderly: A Meta-Analysis.

Background and Objective: Existing evidence indicates the potential benefits of electroencephalography neurofeedback (NFB) training for cognitive function. This study aims to comprehensively review all available evidence investigating the effectiveness of NFB on working memory (WM) and episodic memory (EM) in the elderly population. Material and Methods: A systematic search was conducted across five databases to identify clinical trials examining the impact of NFB on memory function in healthy elderly individuals or those with mild cognitive impairment (MCI). The co-primary outcomes focused on changes in WM and EM. Data synthesis was performed using a random-effects meta-analysis. Results: Fourteen clinical trials (n = 284) were included in the analysis. The findings revealed that NFB was associated with improved WM (k = 11, reported as Hedges' g = 0.665, 95% confidence [CI] = 0.473 to 0.858, p < 0.001) and EM (k = 12, 0.595, 0.333 to 0.856, p < 0.001) in the elderly, with moderate effect sizes. Subgroup analyses demonstrated that NFB had a positive impact on both WM and EM, not only in the healthy population (WM: k = 7, 0.495, 0.213 to 0.778, p = 0.001; EM: k = 6, 0.729, 0.483 to 0.976, p < 0.001) but also in those with MCI (WM: k = 6, 0.812, 0.549 to 1.074, p < 0.001; EM: k = 6, 0.503, 0.088 to 0.919, p = 0.018). Additionally, sufficient training time (totaling more than 300 min) was associated with a significant improvement in WM (k = 6, 0.743, 0.510 to 0.976, p < 0.001) and EM (k = 7, 0.516, 0.156 to 0.876, p = 0.005); however, such benefits were not observed in groups with inadequate training time. Conclusions: The results suggest that NFB is associated with enhancement of both WM and EM in both healthy and MCI elderly individuals, particularly when adequate training time (exceeding 300 min) is provided. These findings underscore the potential of NFB in dementia prevention or rehabilitation.

Ramelteon for delirium prevention in hospitalized patients: An updated meta-analysis and trial sequential analysis of randomized controlled trials.

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta-analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all-cause mortality, and all-cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo-controlled randomized controlled trials (n = 587) were included. This updated meta-analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29-0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09-0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14-0.82; I2 = 44.24%) but not in the non-elderly and non-multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between-group differences were found in the secondary outcomes. The current meta-analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients.

Risk of parental major psychiatric disorders in patients with comorbid autism spectrum disorder and attention deficit hyperactivity disorder: A population-based family-link study.

OBJECTIVE: Few studies have investigated the parental risk of major psychiatric disorders among patients with comorbid autism spectrum disorder and attention deficit hyperactivity disorder. This study examined the differences in such risk among patients with autism spectrum disorder-only, with attention deficit hyperactivity disorder-only and both conditions. METHODS: Between 2001 and 2011, we enrolled 132,624 patients with autism spectrum disorder or attention deficit hyperactivity disorder and 1:10 matched controls for age, sex and demographics from the National Health Insurance Database of Taiwan. Poisson regression models were used to examine the risk of five major psychiatric disorders in the patients' parents compared with those of the controls, including schizophrenia, bipolar disorder, major depressive disorder, alcohol use disorder, and substance use disorder. Patients were classified into the autism spectrum disorder-only, attention deficit hyperactivity disorder-only and dual-diagnosis groups. RESULTS: The parents of attention deficit hyperactivity disorder-only and dual-diagnosis groups had a higher likelihood to be diagnosed with (odds ratios [95% confidence intervals]) schizophrenia (attention deficit hyperactivity disorder: 1.48 [1.39, 1.57]; dual: 1.79 [1.45, 1.20]), bipolar disorder (attention deficit hyperactivity disorder: 1.91 [1.82, 2.01]; dual: 1.81 [1.51, 2.17]), major depressive disorder (attention deficit hyperactivity disorder: 1.94 [1.89, 2.00]; dual: 1.99 [1.81, 2.20]), alcohol use disorder (attention deficit hyperactivity disorder: 1.39 [1.33, 1.45]; dual: 1.20 [1.01, 1.42]) and substance use disorder (attention deficit hyperactivity disorder: 1.66 [1.59, 1.73]; dual: 1.34 [1.13, 1.58]) than the controls. In contrast, the parents of autism spectrum disorder-only group had a higher likelihood to be diagnosed with schizophrenia (1.77 [1.46, 2.15]) and major depressive disorder (1.45 [1.32, 1.61]) and a lower likelihood to be diagnosed with alcohol use disorder (0.68 [0.55, 0.84]) than the controls. CONCLUSION: The autism spectrum disorder-only group had a different parental incidence of major psychiatric disorders than the attention deficit hyperactivity disorder-only and dual-diagnosis groups. Our findings have implications for clinical practice and future genetic research.

Comparisons of Quality, Correctness, and Similarity Between ChatGPT-Generated and Human-Written Abstracts for Basic Research: Cross-Sectional Study.

BACKGROUND: ChatGPT may act as a research assistant to help organize the direction of thinking and summarize research findings. However, few studies have examined the quality, similarity (abstracts being similar to the original one), and accuracy of the abstracts generated by ChatGPT when researchers provide full-text basic research papers. OBJECTIVE: We aimed to assess the applicability of an artificial intelligence (AI) model in generating abstracts for basic preclinical research. METHODS: We selected 30 basic research papers from Nature, Genome Biology, and Biological Psychiatry. Excluding abstracts, we inputted the full text into ChatPDF, an application of a language model based on ChatGPT, and we prompted it to generate abstracts with the same style as used in the original papers. A total of 8 experts were invited to evaluate the quality of these abstracts (based on a Likert scale of 0-10) and identify which abstracts were generated by ChatPDF, using a blind approach. These abstracts were also evaluated for their similarity to the original abstracts and the accuracy of the AI content. RESULTS: The quality of ChatGPT-generated abstracts was lower than that of the actual abstracts (10-point Likert scale: mean 4.72, SD 2.09 vs mean 8.09, SD 1.03; P<.001). The difference in quality was significant in the unstructured format (mean difference -4.33; 95% CI -4.79 to -3.86; P<.001) but minimal in the 4-subheading structured format (mean difference -2.33; 95% CI -2.79 to -1.86). Among the 30 ChatGPT-generated abstracts, 3 showed wrong conclusions, and 10 were identified as AI content. The mean percentage of similarity between the original and the generated abstracts was not high (2.10%-4.40%). The blinded reviewers achieved a 93% (224/240) accuracy rate in guessing which abstracts were written using ChatGPT. CONCLUSIONS: Using ChatGPT to generate a scientific abstract may not lead to issues of similarity when using real full texts written by humans. However, the quality of the ChatGPT-generated abstracts was suboptimal, and their accuracy was not 100%.

Risk of Major Mental Disorder after Severe Bacterial Infections in Children and Adolescents: A Nationwide Longitudinal Study.

INTRODUCTION: Evidence has suggested an association between bacterial infection and increased risk of subsequent major mental disorders (MMDs). Whether such association varies with different pathogens remains unclear. We aimed to investigate the risk of subsequent MMDs after exposure to bacterial pathogens in children and adolescents. METHODS: Between 1997 and 2012, we enrolled a nationwide cohort of 14,024 children and adolescents with hospitalized bacterial infection, and noninfected controls were 1:4 matched for demographics. There were 11 investigated pathogens, namely, Streptococcus, Staphylococcus, Pseudomonas, Klebsiella, Hemophilus, Mycoplasma, Tuberculosis, Meningococcus, Escherichia, Chlamydia, and Scrub typhus. The primary outcomes were the subsequent risk of seven MMDs, namely, autism spectrum disorder (ASD), attention-deficiency hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic disorder, schizophrenia, bipolar disorder, and depressive disorder. The secondary outcomes were the subsequent risk of exposure to psychotropic medications. RESULTS: Pooled bacterial infection was associated with increased risk of the six MMDs - ASD (reported as hazard ratios with 95% confidence intervals: 13.80; 7.40-25.75), ADHD (6.93; 5.98-8.03), OCD (3.93; 1.76-8.76), tic disorder (6.19; 4.44-8.64), bipolar disorder (2.50; 1.28-4.86), and depressive disorder (1.93; 1.48-2.51) - and exposure to four psychotropic medications, including ADHD drugs (11.81; 9.72-14.35), antidepressants (2.96; 2.45-3.57), mood stabilizers (4.51; 2.83-7.19), and atypical antipsychotics (4.23; 3.00-5.96) compared to controls. The associations among MMDs and specific pathogens varied. Importantly, Streptococcus was associated with the most MMDs (six MMDs), and ADHD was associated with eight bacterial pathogen infections. CONCLUSIONS: After bacterial infection, the risk of MMDs increased in children and adolescents compared to controls, and such associations varied with different pathogens. Future studies are warranted to validate our study findings and investigate the potential mechanisms.

Attention deficit hyperactivity disorder and risk of migraine: A nationwide longitudinal study.

OBJECTIVE: This study explored the risk of migraine in children, adolescents, and young adults with attention deficit hyperactivity disorder (ADHD) and its association with ADHD medications. BACKGROUND: The prevalence of migraine peaks between the ages of 35 and 39 years. Recent studies have reported a positive association between ADHD and migraine. METHODS: This longitudinal case-cohort study was conducted using data from the Taiwan National Health Insurance Database. Between 2001 and 2009, we enrolled 81,441 participants with ADHD and a 1:1-matched control cohort for age, sex, and physical and psychiatric comorbidities. All participants had no diagnosis of migraine before enrollment and were followed up to the end of 2011. We examined the risk of newly diagnosed migraine among patients with ADHD and matched controls after adjusting for demographics and physical/psychiatric comorbidities. RESULTS: Patients with ADHD had a higher incidence of migraine than those in the control group (462/81441 [0.6%] vs. 212/81441 [0.3%] patients, p < 0.001). After adjusting for potential confounders, the hazard ratio (HR) was 1.92 (95% CI, 1.64-2.34) for migraine in patients with ADHD versus controls. The subgroup analyses stratified by age showed the HRs were 2.01 (95% CI, 1.63-2.49), 1.94 (95% CI, 1.35-2.79), and 1.31 (95% CI, 0.58-2.98) for children (<12 years old), adolescents (12-17), and young adults (18-29), respectively, versus controls. When stratified by sex, the HR was 1.97 (95% CI, 1.58-2.46) for men and 1.94 (95% CI, 1.44-2.62) for women versus controls. The cumulative daily dose of ADHD medications was not associated with the risk of migraine. CONCLUSION: Children and adolescents with ADHD were associated with an increased risk of migraine compared with matched controls. The increased risk was not observed in young adults with ADHD. Further studies are required to examine the mechanisms between migraine and ADHD.

Risk of retinal disease in patients with bipolar disorder: A nationwide cohort study.

AIMS: Patients with brain diseases have been associated with several retinal abnormalities. This study aimed to assess the risk of retinal diseases in patients with bipolar disorder (BD). METHODS: This nationwide cohort of 73,271 patients with BD was enrolled between 2001 and 2009. To identify newly diagnosed retinal diseases, the patients were followed to the end of 2011. The control group included 293,084 patients, matched for demographic characteristics and medical and ophthalmological comorbidities. The Kaplan-Meier method was used to estimate incidence rates of retinal diseases. Cox regression was applied to calculate the hazard ratios (HRs) with 95% confidence intervals (CIs) after adjusting for confounders. RESULTS: Patients with BD had higher incidence rates of any retinal disease than the controls (1.27% vs 0.48%, P < 0.001), and retinal diseases were diagnosed at a young age (54.23 years [±12.68 years] vs 57.01 years [±13.12 years], P < 0.001). After adjusting for demographic characteristics, physical and ophthalmological comorbidities, and medications, the HR was 3.24 (95% CI, 2.18-4.82) for retinal detachment, 2.35 (95% CI, 1.83-3.03) for primary retinopathy, 2.26 (95% CI, 1.91-2.68) for diabetes retinopathy, 2.39 (95% CI, 1.49-3.82) for hypertensive retinopathy, and 3.46 (95% CI, 2.45-4.89) for retinal vascular complications in patients with BD vs controls. The cumulative daily dose of bipolar medications was not associated with the incidence of any retinal disease. CONCLUSION: Patients with BD were associated with a higher risk of retinal detachment, primary retinopathy, diabetes retinopathy, hypertensive retinopathy, and retinal vascular complications than the controls. Further studies are needed to examine the mechanisms mediating these retinal diseases in patients with BD.

Diagnostic progression to schizophrenia: A nationwide cohort study of 11 170 adolescents and young adults with autism spectrum disorder.

AIMS: Previous studies have suggested an increased risk of developing schizophrenia later in life in children with autism spectrum disorder (ASD). This study aims to investigate the diagnosis stability and the potential predictors for progression to schizophrenia in ASD. METHODS: We recruited 11 170 adolescents (10-19 years) and young adults (20-29 years) with ASD between 2001 and 2010. They were followed up to the end of 2011 to identify newly diagnosed schizophrenia. The Kaplan-Meier method and Cox regression with age as a time scale were employed to estimate incidence rates and the significance of candidate predictors. RESULTS: The progression rate from ASD to schizophrenia was 10.26% for 10 years of follow-up. Among 860 progressors, 580 (67.44%) occurred within the first 3 years after a diagnosis of ASD. The identified predictors were age (reported as hazard ratio with 95% confidence interval: 1.13; 1.11-1.15), depressive disorder (1.36; 1.09-1.69), alcohol use disorder (3.05; 2.14-4.35), substance use disorder (1.91; 1.18-3.09), cluster A personality disorder (2.95; 1.79-4.84), cluster B personality disorder (1.86; 1.05-3.28), and a family history of schizophrenia (2.12; 1.65-2.74). CONCLUSION: More than two-thirds of the progressors developed schizophrenia within the first 3 years. Demographic characteristics, physical and psychiatric comorbidities, and psychiatric family history were significant predictors of progression.

Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19.

BACKGROUND: Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. RESULTS: In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. CONCLUSIONS: These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

Involvement of collagen XVII in pluripotency gene expression and metabolic reprogramming of lung cancer stem cells.

BACKGROUND: Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms. METHODS: The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients. RESULTS: We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin-332 through FAK-PI3K/AKT-GSB3ß/ß-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients. CONCULSIONS: These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment.

High metabolic rate and stem cell characteristics of esophageal cancer stem-like cells depend on the Hsp27-AKT-HK2 pathway.

Tumor progression with chemoresistance and local recurrence is commonly happened during treatment of esophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSC) may respond for tumor progression. However, there are few reports regarding metabolism of esophageal CSCs with clinical correlation. In this work, we demonstrated that ESCC cell lines in spheroid culture display CSC phenotypes, including increased ALDH activity, chemoresistance and tumor initiation, which are dependent on Hsp27 activation. Esophageal CSCs also exhibit reprogrammed metabolic features particularly higher glycolysis and oxidative phosphorylation, which are regulated via the Hsp27-AKT-HK2 pathway. Moreover, HK2 is required for maintenance of CSC phenotypes. Inhibition of CSC metabolism reduces cell growth and tumor formation. Clinically, patients who underwent surgical resection for esophageal cancer, and displayed overexpression of both Hsp27 and HK2, had the worst prognosis of all expression types. In conclusion, stem cells features and aberrant metabolic reprogramming of esophageal CSCs depend on the Hsp27-AKT-HK2 pathway. Targeting Hsp27 and HK2 could be novel therapeutic strategy for treating esophageal cancer and warrants further investigation.

Particulate Matter Increases the Severity of Bleomycin-Induced Pulmonary Fibrosis through KC-Mediated Neutrophil Chemotaxis.

BACKGROUND: Although particular matter (PM) increases incidence and severity of idiopathic pulmonary fibrosis, the underlying mechanism remains elusive. METHODS: The effects of PM were evaluated in a murine model of bleomycin-induced pulmonary fibrosis. Mice were divided into four groups, receiving: (1) Saline (control), (2) bleomycin, (3) PM, or (4) bleomycin plus PM (Bleo+PM). Additional groups of Bleo+PM mice were treated with sivelestat (an inhibitor of neutrophil elastase) or reparixin (a C-X-C motif chemokine receptor 2 antagonist), or were genetically modified with keratinocyte chemoattractant (KC) deletion. RESULTS: Pulmonary fibrosis was not observed in the control or PM groups. Bleomycin induced pulmonary fibrosis within 14 days. The Bleo+PM group showed worse pulmonary fibrosis when compared to the bleomycin group. Analyses of immune cell profile and chemokine/cytokine concentrations at day 2-bronchoalveolar lavage fluid (BALF) revealed that the Bleo+PM group had increased neutrophil number and elastase level and KC concentration compared to the bleomycin group. Neutrophil elastase activated the Smad2/Smad3/α-SMA pathway to induce collagen deposition, while sivelestat abrogated the increased severity of pulmonary fibrosis caused by PM. Chemotaxis assay revealed that BALF of the Bleo+PM group recruited neutrophil, which was dependent on KC. Further, genetic KC deletion or pharmaceutical inhibition of KC binding to CXCR2 with reparixin ameliorated the PM-induced increased severity of pulmonary fibrosis. CONCLUSIONS: These data provide evidence that the PM-induced increased severity of pulmonary fibrosis depends on KC-mediated neutrophil chemotaxis and give additional mechanic insight that will aid in the development of therapeutic strategies.

IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation.

Tumors are influenced by a microenvironment rich in inflammatory cytokines, growth factors and chemokines, which may promote tumor growth. Interleukin-6 (IL-6) is a multifunctional cytokine and known as a regulator of immune and inflammation responses. IL-6 has also been reported to be associated with tumor progression and chemoresistance in different types of cancers. In our study, we demonstrated that IL-6 enriches the properties of lung cancer stem-like cells in A549 lung cancer cells cultured in spheroid medium. IL-6 also promotes sphere formation and stem-like properties of A549 cells by enhancing cell proliferation. Methylation-specific polymerase chain reaction (PCR) was performed and revealed that IL-6 increased methylation of p53 and p21 in A549 cancer cells. Western blot analysis and quantitative real-time PCR demonstrated that IL-6 increased the expression of DNA methyltransferase 1 (DNMT1) in A549 cells cultured in spheroid medium, but not the expression of DNMT3a or DNMT3b. Knockdown of DNMT1 eliminated IL-6-mediated hypermethylation of cell cycle regulators and enrichment of lung cancer stem-like properties. In conclusion, our study, for the first time, shows that the IL-6/JAK2/STAT3 pathway upregulates DNMT1 and enhances cancer initiation and lung cancer stem cell (CSC) proliferation by downregulation of p53 and p21 resulting from DNA hypermethylation. Upon blockage of the IL-6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs was reduced and their formation of spheres and ability to initiate tumor growth were decreased. These data suggest that targeting of the IL-6/JAK2/STAT3 signaling pathway and DNMT1 may become important strategies for treating lung cancer.

Protective effect of breastfeeding on Kawasaki disease: A systemic review and meta-analysis.

BACKGROUND: Previous research has indicated a negative correlation between exclusive breastfeeding and the incidence of Kawasaki disease (KD). However, the validation of this discovery through meta-analytical studies has been lacking. Furthermore, uncertainties persist regarding whether breastfeeding reduces the risk of coronary artery lesions (CAL) or resistance to intravenous immunoglobulin (IVIG). METHODS: A systematic exploration of the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, and ClinicalTrials.gov databases was conducted to identify longitudinal or randomized controlled trials investigating the efficacy of breastfeeding in preventing KD. The primary focus was on the incidence of KD, with secondary emphasis placed on the incidence of CAL and IVIG resistance. Data were pooled using a frequentist-restricted maximum-likelihood random-effects model. RESULTS: Of the 179 potentially eligible studies identified, five (n = 1,982,634) were included. The analysis revealed a significantly lower risk of KD (expressed as odds ratio, with 95% confidence intervals and p-values) in comparisons between exclusive breastfeeding and formula feeding (0.62, 0.43-0.91, p = 0.014), exclusive breastfeeding/partial breastfeeding and formula feeding (0.66, 0.46- 0.96, p = 0.03), and exclusive breastfeeding and partial breastfeeding/formula feeding (0.81, 0.74- 0.90, p < 0.01). However, no significant difference was observed in the risk of developing KD when comparing partial breastfeeding to formula feeding exclusively. Regarding secondary outcomes, no statistically significant difference was found in the risk of CAL or IVIG resistance across any comparison formats. CONCLUSIONS: Our study suggests that breastfeeding correlated with a reduced risk of KD but not with a reduced risk of CAL or IVIG resistance. These findings advocate for the implementation of breastfeeding policies in clinical practice.

Factors associated with cognitive function in patient with Alzheimer's disease with newly prescribed acetylcholinesterase inhibitors: A 1-year retrospective cohort study.

Objective: We aimed to examine the factors associated with treatment outcomes in patients with Alzheimer's disease (AD) after 1 year of acetylcholinesterase inhibitors (AChEI) treatment. Method: We obtained electronic medical records from a medical center in Southern Taiwan between January 2015 and September 2021. Participants aged ≥60 who were newly diagnosed with AD and had been prescribed AChEIs were included. Cognitive assessments were performed before the AChEIs were prescribed and at the 1 year follow-up. Cognition progressors were defined as a Mini-Mental State Examination decline of >3 or a Clinical Dementia Rating decline of ≥1 after 1 year of AChEI treatment. The relationship between the baseline characteristics and cognitive status after follow-up was investigated using logistic regression analysis after adjusting for potential confounders. Results: A total of 1370 patients were included in our study (mean age, 79.86 ± 8.14 years). After adjustment, the body mass index (BMI) was found to be significantly lower in the progressor group [adjusted odds ratio (AOR): 0.970, 95% confidence intervals (95% CIs): 0.943 to 0.997, P = 0.033]. The usage of antipsychotics was significantly higher in the progressor group (AOR: 1.599, 95% CIs: 1.202 to 2.202, P = 0.001). The usage of benzodiazepine receptor agonists also tended to be significantly higher in the progressor group (AOR: 1.290, 95% CIs: 0.996 to 1.697, p = 0.054). Conclusion: These results suggest that patients with AD who receive 1 year of AChEI treatment and have a lower BMI or concurrent treatment with antipsychotics and benzodiazepine receptor agonists are more likely to suffer from cognitive decline.