The combination of valsartan and spironolactone mitigated mitral regurgitation induced cardiac dysfunction in a novel rat model.

Despite its high prevalence, effective treatment for degenerative mitral regurgitation (MR) remains elusive. Although the mineralocorticoid-receptor antagonist spironolactone, in conjunction with renin-angiotensin system (RAS) inhibitors, has been shown to reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF), its efficacy in managing degenerative MR is uncertain. In this study, we aimed to compare the effectiveness of valsartan (a renin-angiotensin system inhibitor), spironolactone, and combination therapy in mitigating MR-induced myocardial dysfunction. Using a mini-invasive model of degenerative MR, we administered valsartan (31 mg/kg/day), spironolactone (80 mg/kg/day), or a combination of both to rats over a 4-week period. Serial echocardiography and pressure-volume loops were utilized to assess cardiac function and hemodynamics. Rats with degenerative MR treated with valsartan or spironolactone alone did not show significant improvement in myocardial dysfunction. In contrast, combination therapy resulted in significant improvement. Similarly, the pressure-volume relationship was significantly improved in rats treated with the combination therapy compared to that in rats treated with a single therapy. Mechanistically, combination therapy effectively suppressed circulating and cardiac expression of aldosterone- and apoptosis-associated proteins. Overall, combination treatment with valsartan and spironolactone significantly attenuated the degenerative MR-induced myocardial stress and dysfunction, suggesting a potential therapeutic avenue for managing degenerative MR-induced HF.

Abdominal wound length influences the postoperative serum level of interleukin-6 and recovery of flatus passage among patients with colorectal cancer.

Introduction: A mini-laparotomy for colorectal cancer (CRC) has been reported to shorten postoperative ileus (POI) and hospital stay. Interleukin-6 (IL-6) plays a role in intestinal tissue inflammation, leading to POI. This study investigated the effects of abdominal wounds and IL-6 levels on POI in patients having CRC surgery. Materials and methods: Forty-three patients with CRC underwent bowel resection. Serum samples were collected preoperatively and at 2, 24, and 48 h after surgery for cytokine quantification by ELISA. Clinical data, including time from surgery to first passage of flatus and postoperative hospital stay, demographic and pathological data, and routine blood tests, were compared statistically with abdominal wound length and the postoperative increments of cytokines (designated as Δ). Results: The length of the abdominal wound showed a significant correlation with clinical variables (length of operation time, time of first flatus passage, and length of postoperative hospital stay) and cytokine variables (IL-6(Δ2 h), IL-8(Δ2 h) and IL-10(Δ2 h). Linear regression analysis showed that the abdominal wound length significantly influenced the operation time, time of first flatus passage, and length of postoperative hospital stay (p < 0.001). The length of the abdominal wound showed a significant influence on the IL-6(Δ2 h) and IL-8(Δ2 h) (p < 0.001, respectively) but no influence on IL-10(Δ2 h). IL-6(Δ2 h), but not IL-8(Δ2 h), significantly influenced the time to first flatus passage and length of hospital stay (p = 0.007, p = 0.006, respectively). The mini-laparotomy approach (wound length <7 cm) led to significantly shortened operation time, time of first flatus passage, length of postoperative stay (p = 0.004, p = 0.003, p = 0.006, respectively) as well as reduced postoperative increment of IL-6(Δ2 h) (p = 0.015). The mini-laparotomy for anterior resection surgery significantly influenced operation time, time of first passage of flatus, length of postoperative stay, and IL-6(Δ2 h). Conclusion: Our study is the first to report the complex interaction among the length of the abdominal wound, IL-6 serum level, recovery of the first passage of flatus, and postoperative hospital stay. These results suggest that smaller abdominal wounds and smaller postoperative IL-6 increments were associated with faster recovery of flatus passage and shorter hospital stays.

Sex-specific associations between prolonged serum uric acid levels and risk of major adverse cardiovascular events.

Background: While hyperuricemia has been correlated with cardiovascular (CV) diseases, further evidence is required to evaluate the implications of stable serum uric acid (sUA) levels, especially concerning low sUA. This study aimed to investigate prolonged stable sUA levels and CV events/mortality. Methods: We conducted a retrospective cohort study at a medical center using electronic medical records linked with the national claims database. Patients with at least two sUA measurements, with intervals ranging from 6 months to 4 years, were included. The mean of the first two eligible sUA measurements were analyzed, stratified by sex. Outcomes of interest comprised major adverse cardiovascular events (MACE), heart failure hospitalization, CV and all-cause mortality. Results: This study included 33,096 patients (follow-up: men 6.6 years, women 6.4 years). After multivariable adjustment, cubic spline models showed that long-term high sUA levels were consistently associated with a higher risk of MACE, heart failure hospitalization, CV and all-cause mortality. A U-shaped association was observed between sUA levels and all-cause mortality in both sexes and between sUA levels and CV mortality in women. The impact of sUA, especially lower levels, on CV events and mortality was more pronounced in women than in men. Conclusion: Long-term high sUA levels are consistently associated with increased risk of CV events and mortality. A U-shaped association between sUA levels and all-cause mortality was observed in both men and women and was pronounced in women. The findings underscore the importance of considering sUA levels, especially in women, when assessing CV risk.

Evaluating the Protective Effectiveness of Rubber Glove Materials Against Organic Solvents Upon Repeated Exposure and Decontamination.

Background: Glove reuse poses risks, as chemicals can persist even after cleaning. Decontamination methods like thermal aeration, recommended by US OSHA, vary in effectiveness. Some studies show promising results, while others emphasize the importance of considering both permeation and tensile strength changes. This research advocates for informed glove reuse, emphasizing optimal thermal aeration temperatures and providing evidence to guide users in maintaining protection efficiency. Methods: The investigation evaluated Neoprene and Nitrile gloves (22 mils). Permeation tests with toluene and acetone adhered to American Society for Testing Materials (ASTM) F739 standards. Decontamination optimization involved aeration at various temperatures. The experiment proceeded with a maximum of 22 re-exposure cycles. Tensile strength and elongation were assessed following ASTM D 412 protocols. Breakthrough time differences were statistically analyzed using t-test and ANOVA. Results: At room temperature, glove residuals decreased, and standardized breakthrough time (SBT)2 was significantly lower than SBT1, indicating reduced protection. Higher temperature decontamination accelerated residual removal, with ΔSBT (SBT2/SBT1) exceeding 100%, signifying restored protection. Tensile tests showed stable neoprene properties postdecontamination. Results underscore thermal aeration's efficacy for gloves reuse, emphasizing temperature's pivotal role. Findings recommend meticulous management strategies, especially post-breakthrough, to uphold glove-protective performance. Conclusions: Thermal aeration at 100°C for 1 hour proves effective, restoring protection without compromising glove strength. The study, covering twenty cycles, suggests safe glove reuse with proper decontamination, reducing costs significantly. However, limitations in chemical-glove combinations and exclusive focus on specific gloves caution against broad generalization. The absence of regulatory directives on glove reuse highlight the importance of informed selection and rigorous decontamination validation for workplace safety practices.

How Time Pressure Modulates Individual Differences in the Functional Connectivity of Chunk Memory in Chess Games.

Previous studies on the chess game demonstrated that chess experts strongly rely on the activation of memory chunks to manifest accurate decision-making. Although the chunk memory might be affected by temporal constraints, it is unclear why the performance of chess experts is not significantly dropped under time pressure. In this study, our objective is to examine the variations in cognitive neural mechanisms between chess experts and novices under time pressure. The underlying cognitive neural mechanism was carefully inspected by accessing the chess game performance between 20 local experienced and 20 inexperienced chess players with 1-minute and 5-minute time constraints. In addition, functional near-infrared spectroscopy (fNIRS) recordings were carried out for each individual from the two groups while playing a 1-minute or 5-minute chess game. It was discovered that under temporal constraints, players exhibited different patterns of functional connectivity in frontal-parietal regions, suggesting that temporal stress can enhance segmentation processes in chess games. In particular, the experienced group exhibited significantly enhanced functional connectivity networks under time pressure including the dorsolateral prefrontal cortex, inferior frontal gyrus, supramarginal gyrus, and postcentral gyrus, which demonstrated the important role of the segmentation process for experienced players under time pressure. Our study found that experienced players were able to enhance recall, reorganize, and integrate chunks to improve chess performance under time pressure.

Effects of Length of Employment and Head Nurse Leadership Style on the Clinical Competency of Staff Nurses in Taiwan.

BACKGROUND: High-quality patient care requires nurses with strong clinical competency. Thus, it is essential to examine the factors associated with clinical competency. PURPOSE: This study was designed to (a) investigate head nurse leadership, staff nurse demographics, and clinical competency; (b) examine the impact of demographics on the clinical competency of staff nurses; (c) analyze the correlation between head nurse leadership and staff nurse clinical competency; and (d) examine the effects of demographics on clinical competency after controlling for the head nurse leadership. METHODS: A cluster sampling method was used to collect data from 200 staff nurses at a national medical center in Taiwan. Questionnaires were used to gather information on head nurse leadership style and staff nurse clinical competency. Descriptive and inferential statistical analyses were conducted, including Mann-Whitney U test, Kruskal-Wallis test, Spearman's rank correlation coefficient, and multivariate analysis of covariance. RESULTS: The average score for transformational leadership style among the head nurses was 2.89, whereas transactional leadership style scored an average of 2.49. The average scores for the components of clinical competency, listed from highest to lowest, were as follows: patient care (3.35), professionalism (3.28), communication skills (3.18), management (2.84), and knowledge (2.73). In addition, statistically significant differences were found in clinical competency based on demographic factors, including age, marital status, educational level, job title, and length of employment. Also, a statistically significant, positive correlation between the head nurse transformational leadership style and nurse clinical competency was found. The main effect of length of employment on the five competency components was statistically significant after controlling for transformational leadership. Furthermore, post hoc analysis of covariance revealed a significant effect of length of employment on patient care, knowledge, communication skills, and management. CONCLUSIONS: The findings of this study indicate transformational leadership and employment length impact the clinical competency of staff nurses, particularly in terms of patient care, communication skills, management, and knowledge. Providing education and training in leadership and management to current and prospective head nurses may be expected to enhance clinical competency in staff nurses and create a more nurturing work environment. Moreover, targeted training may help current head nurses gain insight into their leadership styles and acquire skills to promote transformational leadership. In addition, leadership development may help equip prospective head nurses with critical competencies before assuming leadership responsibilities.

Ultrahigh frequency transcutaneous electrical nerve stimulation for neuropathic pain alleviation and neuromodulation.

A challenging complication in patients with peripheral compressive neuropathy is neuropathic pain. Excessive neuroinflammation at the injury site worsens neuropathic pain and impairs function. Currently, non-invasive modulation techniques like transcutaneous electrical nerve stimulation (TENS) have shown therapeutic promise with positive results. However, the underlying regulatory molecular mechanism for pain relief remains complex and unexplored. This study aimed to validate the therapeutic effect of ultrahigh frequency (UHF)-TENS in chronic constriction injury of the rat sciatic nerve. Alleviation of mechanical allodynia was achieved through the application of UHF-TENS, lasting for 3 days after one session of therapy and 4 days after two sessions, without causing additional damage to the myelinated axon structure. The entire tissue collection schedule was divided into four time points: nerve exposure surgery, 7 days after nerve ligation, and 1 and 5 days after one session of UHF therapy. Significant reductions in pain-related neuropeptides, MEK, c-Myc, c-FOS, COX2, and substance P, were observed in the injured DRG neurons after UHF therapy. RNA sequencing of differential gene expression in sensory neurons revealed significant downregulation in Cables, Pik3r1, Vps4b, Tlr7, and Ezh2 after UHF therapy, while upregulation was observed in Nfkbie and Cln3. UHF-TENS effectively and safely relieved neuropathic pain without causing further nerve damage. The decreased production of pain-related neuropeptides within the DRG provided the therapeutic benefit. Possible molecular mechanisms behind UHF-TENS may result from the modulation of the NF-κB complex, toll-like receptor-7, and phosphoinositide 3-kinase/Akt signaling pathways. These results suggest the neuromodulatory effects of UHF-TENS in rat sciatic nerve chronic constriction injury, including alleviation of neuropathic pain, amelioration of pain-related neuropeptides, and regulation of neuroinflammatory gene expression. In combination with the regulation of related neuroinflammatory genes, UHF-TENS could become a new modality for enhancing the treatment of neuropathic pain in the future.

Psychiatric disorders in term-born children with marginally low birth weight: a population-based study.

BACKGROUND: Marginally low birth weight (MLBW) is defined as a birth weight of 2000 ~ 2499 g. Inconsistent findings have been reported on whether children with low birth weight had higher rates of neurological, attention, or cognitive symptoms. No studies have explored the occurrence of clinically diagnosed psychiatric disorders in term- born MLBW infants. We aimed to investigate the risk of subsequent psychiatric disorders in term-born children with MLBW. METHODS: This is a nationwide retrospective cohort study, by analysing the data from Taiwan's National Health Insurance Research Database from 2008 to 2018. The study population includes propensity-score-matched term-born infants with MLBW and those without MLBW (birth weight ≥ 2500 g). Cox proportional hazard analysis was used after adjustment for potential demographic and perinatal comorbidity confounders. Incidence rates and hazard ratios (HR) of 11 psychiatric clinical diagnoses were evaluated. RESULTS: A total of 53,276 term-born MLBW infants and 1,323,930 term-born infants without MLBW were included in the study. After propensity score matching for demographic variables and perinatal comorbidities, we determined that the term-born MLBW infants (n = 50,060) were more likely to have attention deficit and hyperactivity disorder (HR = 1.26, 95% confidence interval (CI) [1.20, 1.33]), autism spectrum disorder (HR = 1.26, 95% CI [1.14, 1.40]), conduct disorder (HR = 1.25, 95% CI [1.03, 1.51]), emotional disturbance (HR: = 1.13, 95% CI [1.02, 1.26]), or specific developmental delays (HR = 1.38, 95% CI [1.33, 1.43]) than term-born infants without MLBW (n = 50,060). CONCLUSION: MLBW was significantly associated with the risk of subsequent psychiatric disorder development among term-born infants. The study findings demonstrate that further attention to mental health and neurodevelopment issues may be necessary in term-born children with MLBW. However, possibilities of misclassification in exposures or outcomes, and risks of residual and unmeasured confounding should be concerned when interpreting our data.

Ivabradine could not decrease mitral regurgitation triggered atrial fibrosis and fibrillation compared with carvedilol.

BACKGROUND: Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta-blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta-blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. METHODS AND RESULTS: Using a novel echo-guided mini-invasive surgery, MR was created in 12-weeks-old Sprague-Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two-week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR-induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR-induced chamber dilatation (end-systolic volume and end-diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end-systolic pressure-volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01). CONCLUSIONS: Although both ivabradine and carvedilol, at least in part, mitigated MR-induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR-induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings.

Transpulmonary Expression of Exosomal microRNAs in Idiopathic and Congenital Heart Disease-Related Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)-related PAH. METHODS AND RESULTS: During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD-related PAH. Next-generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR-21, miR-139-5p, miR-155-5p, let-7f-5p, miR-328-3p, miR-330-3p, and miR-103a-3p in patients with CHD-related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR-21 exhibited the highest expression in patients with CHD-related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD-related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR-21. Suppressing miR-21 rescued the shear stress-induced downregulation of the RAS/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to a mitigation of apoptosis. CONCLUSIONS: Our study identified a pronounced expression of transpulmonary exosomal miR-21, particularly in patients with CHD-related PAH, through next-generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR-21 in the pathophysiology of PAH.

Dapagliflozin protects against doxorubicin-induced nephrotoxicity associated with nitric oxide pathway-A translational study.

Doxorubicin (Dox) is a potent anticancer agent, but its associated organ toxicity, including nephrotoxicity, restricts clinical applications. Dapagliflozin (DAPA), a sodium-glucose cotransporter-2 inhibitor, has been shown to slow the progression of kidney disease in patients with and without diabetes. However, the effect of DAPA to counteract Dox-induced nephrotoxicity remains uncertain. Therefore, in this study, we aimed to elucidate the effects of DAPA in mitigating Dox-induced nephrotoxicity. We analyzed the Taiwan National Health Insurance Database to evaluate the incidence of renal failure among breast cancer patients receiving Dox treatment compared to those without. After adjusting for age and comorbidities, we found that the risk of renal failure was significantly higher in Dox-treated patients (incidence rate ratio, 2.45; confidence interval, 1.41-4.26; p = 0.0014). In a parallel study, we orally administered DAPA to Sprague-Dawley rats for 6 weeks, followed by Dox for 4 weeks. DAPA ameliorated Dox-induced glomerular atrophy, renal fibrosis, and dysfunction. Furthermore, DAPA effectively suppressed Dox-induced apoptosis and reactive oxygen species production. On a cellular level, DAPA in HK-2 cells mitigated Dox-mediated suppression of the endothelial NOS pathway and reduced Dox-induced activities of reactive oxygen species and apoptosis-associated proteins. DAPA improved Dox-induced apoptosis and renal dysfunction, suggesting its potential utility in preventing nephrotoxicity in patients with cancer undergoing Dox treatment.

Enhanced Optical Transmission through a Hybrid Bull's Eye Structure Integrated with a Silicon Hemisphere.

In this work, we demonstrate a novel structure that can generate extraordinary optical transmission with a silicon hemisphere placed on a conventional bull's eye structure. There is a single subwavelength aperture surrounded by concentric periodic grooves on a substrate. The extraordinary optical transmission in this work is realized by the coupling of the surface plasmon polaritons in the periodic grooves and the localized electromagnetic field generated by the Mie resonance in the silicon hemisphere. The maximum normalized-to-area transmission peak can reach up to 662 with a decreasing device area and size. The electromagnetic field distribution at different geometry parameters is analyzed to clarify the mechanisms of the work in this paper. Additionally, the use of dielectric material in the aperture can avoid ohmic losses of metal material compared with the conventional one, which may suggest that a wider range of bull's-eye-structure applications is possible.

Eradicating Helicobacter pylori via 13C-urea breath screening to prevent gastric cancer in indigenous communities: a population-based study and development of a family index-case method.

OBJECTIVE: Screening and eradication of Helicobacter pylori help reduce disparities in the incidence of gastric cancer. We aimed to evaluate its acceptability and feasibility in the indigenous communities and develop a family index-case method to roll out this programme. DESIGN: We enrolled residents aged 20-60 years from Taiwanese indigenous communities to receive a course of test, treat, retest and re-treat initial treatment failures with the 13C-urea breath tests and four-drug antibiotic treatments. We also invited the family members of a participant (constituting an index case) to join the programme and evaluated whether the infection rate would be higher in the positive index cases. RESULTS: Between 24 September 2018 and 31 December 2021, 15 057 participants (8852 indigenous and 6205 non-indigenous) were enrolled, with a participation rate of 80.0% (15 057 of 18 821 invitees). The positivity rate was 44.1% (95% CI 43.3% to 44.9%). In the proof-of-concept study with 72 indigenous families (258 participants), family members of a positive index case had 1.98 times (95% CI 1.03 to 3.80) higher prevalence of H. pylori than those of a negative index case. The results were replicated in the mass screening setting (1.95 times, 95% CI 1.61 to 2.36) when 1115 indigenous and 555 non-indigenous families were included (4157 participants). Of the 6643 testing positive, 5493 (82.6%) received treatment. According to intention-to-treat and per-protocol analyses, the eradication rates were 91.7% (89.1% to 94.3%) and 92.1% (89.2% to 95.0%), respectively, after one to two courses of treatment. The rate of adverse effects leading to treatment discontinuation was low at 1.2% (0.9% to 1.5%). CONCLUSION: A high participation rate, a high eradication rate of H. pylori and an efficient rollout method indicate that a primary prevention strategy is acceptable and feasible in indigenous communities. TRIAL REGISTRATION NUMBER: NCT03900910.

Occlusion preconditioned mice are resilient to hypobaric hypoxia-induced myocarditis and arrhythmias due to enhanced immunomodulation, metabolic homeostasis, and antioxidants defense.

Background: Sea-level residents experience altitude sickness when they hike or visit altitudes above ~2,500 m due to the hypobaric hypoxia (HH) conditions at such places. HH has been shown to drive cardiac inflammation in both ventricles by inducing maladaptive metabolic reprogramming of macrophages, which evokes aggravated proinflammatory responses, promoting myocarditis, fibrotic remodeling, arrhythmias, heart failure, and sudden deaths. The use of salidroside or altitude preconditioning (AP) before visiting high altitudes has been extensively shown to exert cardioprotective effects. Even so, both therapeutic interventions have geographical limitations and/or are inaccessible/unavailable to the majority of the population as drawbacks. Meanwhile, occlusion preconditioning (OP) has been extensively demonstrated to prevent hypoxia-induced cardiomyocyte damage by triggering endogenous cardioprotective cascades to mitigate myocardial damage. Herein, with the notion that OP can be conveniently applied anywhere, we sought to explore it as an alternative therapeutic intervention for preventing HH-induced myocarditis, remodeling, and arrhythmias. Methods: OP intervention (6 cycles of 5 min occlusion with 200 mmHg for 5 min and 5 min reperfusion at 0 mmHg - applying to alternate hindlimb daily for 7 consecutive days) was performed, and its impact on cardiac electric activity, immunoregulation, myocardial remodeling, metabolic homeostasis, oxidative stress responses, and behavioral outcomes were assessed before and after exposure to HH in mice. In humans, before and after the application of OP intervention (6 cycles of 5 min occlusion with 130% of systolic pressure and 5 min reperfusion at 0 mmHg - applying to alternate upper limb daily for 6 consecutive days), all subjects were assessed by cardiopulmonary exercise testing (CPET). Results: Comparing the outcomes of OP to AP intervention, we observed that similar to the latter, OP preserved cardiac electric activity, mitigated maladaptive myocardial remodeling, induced adaptive immunomodulation and metabolic homeostasis in the heart, enhanced antioxidant defenses, and conferred resistance against HH-induce anxiety-related behavior. Additionally, OP enhanced respiratory and oxygen-carrying capacity, metabolic homeostasis, and endurance in humans. Conclusions: Overall, these findings demonstrate that OP is a potent alternative therapeutic intervention for preventing hypoxia-induced myocarditis, cardiac remodeling, arrhythmias, and cardiometabolic disorders and could potentially ameliorate the progression of other inflammatory, metabolic, and oxidative stress-related diseases.

DNMT1 Mediates Chronic Pain-Related Depression by Inhibiting GABAergic Neuronal Activation in the Central Amygdala.

BACKGROUND: Chronic pain can induce depressive emotion. DNA methyltransferases (DNMTs) have been shown to be involved in the development of chronic pain and depression. However, the role and mechanism of DNMTs in chronic pain-induced depression are not well understood. METHODS: In well-established spared nerve injury (SNI)-induced chronic pain-related depression models, the expression of DNMTs and the functional roles and underlying mechanisms of DNMT1 in central amygdala (CeA) GABAergic (gamma-aminobutyric acidergic) neurons were investigated using molecular, pharmacological, electrophysiological, optogenetic, and chemogenetic techniques and behavioral tests. RESULTS: DNMT1, but not DNMT3a or DNMT3b, was upregulated in the CeA of rats with SNI-induced chronic pain-depression. Inhibition of DNMT1 by 5-Aza or viral knockdown of DNMT1 in GABAergic neurons in the CeA effectively ameliorated the depression-like behaviors induced by chronic pain. The DNMT1 action was associated with methylation at the CpG-rich Gad1 promoter and GAD67 downregulation, leading to a decrease of GABAergic neuronal activity. Optogenetic activation of GABAergic neurons in the CeA improved SNI-induced depression-like behaviors. Moreover, optogenetic or chemogenetic inhibition of GABAergic neurons in the CeA reversed DNMT1 knockdown-induced improvement of depression-like behaviors in SNI mice. CONCLUSIONS: Our findings suggest that DNMT1 is involved in the development of chronic pain-related depression by epigenetic repression of GAD67, leading to the inhibition of GABAergic neuronal activation. This study indicates that DNMT1 could be a potential target for the treatment of chronic pain-related depression.

Secular-Trend Analysis of the Incidence Rate of Lung Squamous Cell Carcinoma in Taiwan.

Lung cancer is the leading cause of cancer deaths worldwide, and squamous cell carcinoma (SQC) is Taiwan's second most common lung carcinoma histotype. This study aimed to investigate changes in the long-term trend of the SQC incidence rate in Taiwan. SQC cases between 1985 and 2019 were adopted from Taiwan's Cancer Registry System; the age-adjusted incidence rate was calculated using the World Standard Population in 2000. The long-term trends of the age, period, and birth cohort effect of SQC incidence rates were estimated using the SEER Age-Period-Cohort Web Tool. The results revealed that the incidence of lung carcinoma in Taiwan increased, while the incidence of SQC exhibited a slight decrease during this study period. The age rate ratio (ARR) of the incidence rate in men declined gradually, and the period effect changed more slowly for women than men. The cohort effect formed a bimodal curve. The annual percentage change results for women indicated that the ARR decreased from 1.652 (95% confidence interval (CI): 1.422, 1.9192) at 30 to 34 years to 0.559 (95% CI: 0.4988, 0.6265) at 75 to 79 years; the period effect decreased from 1.2204 (95% CI: 1.1148, 1.336) in 1995 to 1999 to 0.608 (95% CI: 0.5515, 0.6704) in 2015 to 2019, with a greater decline in the later period. The cohort effect was unimodal, with the SQC risk value peaking in the 1915 birth cohort and exhibiting a steady decline thereafter. The results of this study suggest that a decrease in the smoking rate may be the reason for the decline in the incidence of SQC, and we observed a similar trend between SQC and the smoking rate in men.

LncRNA XR_351665 Contributes to Chronic Pain-Induced Depression by Upregulating DNMT1 via Sponging miR-152-3p.

Chronic pain is frequently comorbid with depression. However, the mechanisms underlying chronic pain-induced depression remain unclear. Here, we found that DNA methyltransferase 1 (DNMT1) was upregulated in the central amygdala (CeA) of spared nerve injury (SNI)-induced chronic pain-depression rats, and knockdown of DNMT1 could improve the depression-like behaviors in SNI rats. Additionally, a panel of differentially expressed lncRNAs, including 38 upregulated and 12 downregulated lncRNAs, were identified by microarray analysis. Bioinformatics analysis suggested that the upregulated lncRNA XR_351665 was the upstream molecule to regulate DNMT1 expression. The knockdown of XR_351665 significantly alleviated the depression-like behaviors in SNI rats, whereas overexpression of XR_351665 induced the depression-like behaviors in naïve rats. Further mechanism-related researches uncovered that XR_351665 functioned as a competing endogenous RNA (ceRNA) to upregulate DNMT1 by competitively sponging miR-152-3p, and subsequently promoted the development of chronic pain-induced depression. Our findings suggest that lncRNA XR_351665 is involved in the development of chronic pain-induced depression by upregulating DNMT1 via sponging miR-152-3p. These data provide novel insight into understanding the pathogenesis of chronic pain-induced depression and identify a potential therapeutic target. PERSPECTIVE: LncRNA XR_351665 in CeA functions as a ceRNA to block the inhibitory effect of miR-152-3p on DNMT1 and contributes to the development of chronic pain-induced depression. These data suggest that manipulation of XR_351665/miR-152-3p/DNMT1 axis may be a potential method to attenuate chronic pain-induced depression.

Effectiveness of statins for the primary prevention of cardiovascular disease in the Asian elderly population.

BACKGROUND: Population aging is a global trend, and the elderly have a higher risk of atherosclerotic cardiovascular disease (ASCVD) and related mortality. Statins have been observed to reduce cardiovascular events in patients with ASCVD. However, compared with secondary prevention, the benefits of statins for primary prevention are undetermined among the elderly. AIMS: This study aimed to evaluate the effectiveness of statins in an elderly population without a history of cardiovascular disease (CVD). METHODS: The study was carried out using the National Taiwan University Hospital Integrated Medical Database and the National Health Insurance Research Database in Taiwan. Patients aged 65 years and older without a history of CVD were identified between 1 February 2008 and 31 December 2015. New statin users were 1:4 matched to nonusers based on certain variables. The risks of major adverse cardiovascular events (MACEs) and all-cause mortality were estimated using Cox proportional hazards models. Further, we applied marginal structural models to account for time-varying low-density lipoprotein cholesterol (LDL-C) levels. RESULTS: A total of 2761 new statin users and 9503 nonusers were selected after matching; the mean age was 71.8 years, and 63% were women. At a median follow-up of 4.8 years, statin use was associated with reduced risk of MACEs (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.52-0.98) and mortality (HR: 0.72, 95% CI: 0.55-0.93) when accounting for time-varying LDL-C. No significant differences in effect were detected between subgroups. CONCLUSION: Statin use could be beneficial for the primary prevention of CVD in elderly Asians.

An Index to Assess Overwork-Related Adverse Effects on Employees Under the Occupational Safety and Health Act in Taiwan.

Background: The present study aimed to digitally evaluate the risk of overwork-related adverse effects (OrAEs) among employees from various occupational categories in Taiwan. Methods: Anonymous data of employees from seven companies/factories providing occupational health services were analyzed. The studied population comprised 5505 employees, and the data analyzed included employment duration, working hours, shift work schedules, and health checkup results. The risk for OrAEs was assessed by an index, Karo index (0-4, the larger the value, the higher the risk for OrAEs) obtained using a risk matrix made up of cardiocerebral and occupational risk factors. Karo index values of 3 and 4 were categorized as at high risk for OrAEs (h-OrAEs). Results: The 5505 employees had an average employment duration of 8.5 years and a mean age of 39.4 years. The prevalence rates for h-OrAEs of the seven companies/factories ranged from 3.9% to 34.2%. There were significant differences in prevalence rates for h-OrAEs between employees of retail stores and high-tech manufacturing factories. Multivariate analysis results indicated that workers of high-tech manufacturing factories had significantly higher risk for h-OrAEs compared with retail store workers. Conclusion: In terms of satisfying health risk management and legal requirements in Taiwan, the newly issued Karo index, which covers a wide range of occupational risk factors, can serve as an assessment and a warning tool for managing the risk of OrAEs in workplaces. To reduce risks for h-OrAEs, active and prudent control of cerebrocardiovascular risks and working hours is recommended.