Association Between Use of Sodium-Glucose Cotransporter-2 Inhibitors or Angiotensin Receptor-Neprilysin Inhibitor and the Risk of Atherosclerotic Cardiovascular Disease With Coexisting Diabetes and Heart Failure.

PURPOSE: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. METHODS: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. RESULTS: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. CONCLUSION: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions.

Antibiotic heliomycin and its water-soluble 4-aminomethylated derivative provoke cell death in T24 bladder cancer cells by targeting sirtuin 1 (SIRT1).

Bladder cancer is one of the most frequent cancers among males, and a poor survival rate reflects problems with aggressiveness and chemo-resistance. Accumulating evidence indicates that SIRT1 is involved in bladder cancer tumorigenesis and is positively associated with chemo-resistance and poor prognosis. We recently synthesized water-soluble chemical derivatives of heliomycin, an antibiotic from Streptomyces resistomycificus, and demonstrated that they possess anticancer properties. In this present study, we used the cellular thermal shift assay (CETSA) in T24 bladder cancer cells to show that heliomycin (designated compound (H1)) and its 4-(tert-butylamino)methyl derivative (HD2) directly engaged with SIRT1 in the native cellular environment, whereas another derivative (HD3) did not. Upon binding, heliomycin downregulated SIRT1 protein expression without altering its transcript level, and subsequently induced autophagy. Interestingly, the derivative (HD2) triggered apoptosis. The interaction between SIRT1 protein and heliomycin or its derivatives was also speculated by a molecular docking simulation, suggesting heliomycin (H1) and derivative (HD2) acting with the different binding modes to SIRT1. Given the increased water-solubility, hydrogen bonds were found on Ala262 and Ile347 residues in the docked complex of derivative (HD2) to produce more steady interaction and initiate signaling pathways that were not observed in the case of heliomycin. Meanwhile, it is evident that derivative (HD3) did not engage with SIRT1 by CETSA or molecular docking studies, nor did it downregulate SIRT1 expression. Taken together, these findings clearly show that SIRT1 is targeted and downregulated by heliomycin and its water-soluble 4-aminomethylated derivative (HD2) possibly through autophagic and/or proteasomal degradation, leading to cell death and growth suppression of T24 bladder cancer cells.

Risk of Retinopathy of Prematurity in Preterm Births with Respiratory Distress Syndrome: A Population-Based Cohort Study in Taiwan.

BACKGROUND: Respiratory distress syndrome (RDS) is a risk factor that plays an important role in retinopathy in preterm infants. We used population data of infants to investigate this relationship. This study evaluated whether respiratory distress syndrome was associated with an increased incidence of ROP in preterm infants. METHODS: From the National Health Insurance claims data of Taiwan in the 2000-2009 period, preterm infants were identified to establish a RDS cohort (N = 7573) and a comparison cohort without RDS (N = 11428). We followed each infant for one year to identify incident retinopathy of prematurity (ROP) for comparison between the two cohorts. The RDS cohort for comparisons of hazard ratio (HR) with 95% confidence interval (CI) were calculated. RESULTS: Low birth weight, an extended stay in the neonatal intensive care unit (NICU), female gender, and RDS were factors associated with an increased incidence of ROP. The ROP incidence was 2.5-fold higher in RDS children than in control (30.3 versus 11.9 per 100 person-years), with an adjusted HR (aHR) of 1.28 (95% CI = 1.18-1.39). The incidence increased as the birth weight decreased in both cohorts, but the RDS cohort to the comparison cohort aHR decreased as the birth weight decreased, not significant for groups with birth weights less than 1500g. The aHR for RDS children was the highest for infants with a normal birth weight: 3.33 (95% CI = 2.09-5.31). Among infants with RDS, the ROP incidence increased to 51.0 per 100 person-years in those who underwent invasive ventilation, or to 76.3 per 100 person-years for NICU stay for ≥30 days. CONCLUSION: Preterm infants with RDS are at an elevated risk of developing ROP, not limited to those with low birth weights.

Population-Based Study on Cancer Incidence in Pharmacist: A Cohort Study in Taiwan.

Cancer is increasing in rate globally and is leading cause of death among no communicable chronic diseases (NCDs) after cardiovascular disease (CVD). Most of the research focuses on the risk of occupational injury, job stress, mental illness, substance abuse and workplace safety in physicians and nurses. However, fewer studies have investigated the risk of cancer in pharmacists. We compared the matched general population to investigate the risk of cancer in pharmacists in Taiwan. Data were obtained from the Health and Welfare Data Science Center of the Ministry of Health and Welfare in Taiwan. We established a pharmacist group that included 11,568 pharmacists and selected a 4-fold comparison (n = 46,272) for the non-clinics comparison group, frequency being matched by age, gender and Charlson Comorbidity Index (CCI) score. The pharmacists had a lower but non-significant risk of all cancer (Adjusted hazard ratio [aHR] = 0.96; 95% confidence interval [CI] = 0.85-1.07) compared with the general population. Female pharmacists had a higher risk of cancer than male pharmacists ([aHR] = 1.23; 95% CI = 1.06-1.43). Pharmacists had higher risks of breast cancer in females (aHR = 1.68; 95% CI = 1.35-2.08) and of prostate cancer in males (aHR = 2.18; 95% CI = 1.35-2.08) when compared with the general population. Occupational risk factors could play a role, but they were not evaluated. These epidemiological findings require additional studies to clarify cancer risk mechanisms in pharmacists.

Vaccination distribution by community pharmacists under the COVID-19 vaccine appointment system in Taiwan.

Pharmacists play a critical role in implementing and promoting public health policies, particularly during pandemics, thanks to their exceptional skills, knowledge, expertise, and accessibility to the public. This study aimed to increase the roll-out of COVID-19 vaccines in a coordinated manner to ensure equal accessibility to all Taiwanese residents. A total of 3301 health insurance special pharmacies, equivalent to 80% of all community pharmacies in Taiwan, are assisting the public in scheduling vaccines. Once pharmacists had ensured adequate vaccine availability, vaccinations were scheduled depending on the time of registration on the platform for vaccination appointments. The roll-out of this program saw a significant number of people register and receive the vaccine throughout the country, and the number of individuals who received both a first and second dose increased significantly. Community pharmacy-based distribution of the vaccine to the public signifies the novel and innovative involvement of pharmacists in government initiatives to promote public health. Our study shows that community pharmacies can potentially enhance the efficiency and equitable distribution of health supplies and resources, particularly during pandemics.

Stroke risk associated with NSAIDs uses in women with dysmenorrhea: A population-based cohort study.

OBJECTIVE: Dysmenorrhea is among the most common type of gynecological problem, affecting young women across the globe. This study assessed the comparative risk of stroke associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and non-NSAIDs in women with dysmenorrhea while taking into account the following factors such as age, history of pregnancy, NSAIDs uses and its duration of use, and selected comorbidities. METHODOLOGY: We used a quantitative research approach based on a comparative case-control study design. The study data was selected from the Longitudinal Health Insurance Database (LHID) 2000, of the Taiwan National Health Research Institutes. Among the estimated 23.4 million insured Taiwanese, who were covered by the Taiwan health insurance system, in the 2000 registry of beneficiaries, one million individuals were randomly selected from the database. A total of 24,955 females suffering from dysmenorrhea were selected for the study. Out of those 3238 (13%) participated in the study group and 21,717 (87%) were randomly distributed into the controls group. Women in the age range, 15-49 years, who did not have any history of stroke, hysterectomy, and/or ovariectomy, were included in the study. A comparative proportional distribution analysis was used for data analysis. RESULTS: Age and use of NSAIDs and its duration of usage were factors associated with an increased incidence of stroke. The stroke incidence rate was 12.77 per 10,000 person-years, and 1.83-fold higher in NSAIDs use cohort than in comparisons with adjusted hazard ratio (aHR) of 1.47 (95% CI = 0.93-2.32). Among women with dysmenorrhea use of NSAIDs, the stroke incidence increased to 2.29-fold (aHR 95% CI = 1.36-3.84) in those use for ≧24 days per month and to 0.51-fold (aHR 95% CI = 0.13-2.10) in those use for 6-12 days per month. CONCLUSIONS: Women with dysmenorrhea who use NSAIDs have a higher risk of stroke. Especially young women, the risk of stroke is further increased, and the longer the medication, the higher the risk of stroke. Every woman with symptoms of dysmenorrhea deserves specialized outpatient treatment and care.

Medical Costs of Stroke Care Between Women With and Without Dysmenorrhea: A Population-Based Comparison.

Objective: This study investigated the medical care costs of stroke type between age-matched cohorts with and without dysmenorrhea using the National Health Insurance Research Database (NHIRD). Methods: We collected all 66,048 women with dysmenorrhea and 66,048 women without dysmenorrhea whose age (15-44-year-old) and index year (from 1997 to 2013) were matched for comparison. We assessed the incidence and compared the risk of stroke and stroke subtype in two cohorts. The proportional distributions of stroke subtypes by age between the two cohorts were compared among the women with stroke, and their hospitalization rate was also estimated. In addition, medical cost, length of stay, and the medical cost within 30 days after stroke were compared between the two cohorts. Results: The stroke risk in dysmenorrhea was greater than comparisons (HR = 1.26, 95% CI = 1.11-1.42). Proportionally, hemorrhagic stroke (HS) significantly decreased with age in both cohorts, whereas ischemic stroke (IS) significantly increased with age when both cohorts were combined. The dysmenorrhea cohort had a higher portion of transient cerebral ischemia (TIA) stroke than comparisons (31.3 vs. 24.2%, p = 0.01) and a lower risk of hospitalization for IS (OR = 0.48, 95% CI = 0.21-0.69). Among the four-stroke subtypes, the cost of care for TIA was the least (US$157 ± 254). The average cost for stroke care was not significantly different between women with and without dysmenorrhea. Conclusion: The hospitalization rate and medical costs of TIA are lower than other types. All women should prevent and treat TIA as soon as possible to avoid recurrence or progression to major stroke events and reduce medical costs, regardless of whether they have dysmenorrhea.

Population-based study on birth outcomes among women with hypertensive disorders of pregnancy and gestational diabetes mellitus.

To evaluate birth outcomes in women with hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM), we used insurance data of Taiwan to evaluate 11 adverse neonatal outcomes of infants born to women with HDP (N = 7775) and with both HDP and GDM (HDP/GDM) (N = 1946), comparing to women with neither disorder (N = 19,442), matched by age. The impacts of preeclampsia/eclampsia were also evaluated. Results showed that Caesarean section delivery was near 1.7-fold greater in the HDP/GDM and HDP groups than in comparisons. The preterm delivery rates were more than threefold greater in HDP/GDM group and HDP group than in comparisons with adjusted odds ratios (aORs) of 4.84 (95% confidence interval (CI) 4.34-5.40) and 3.92 (95% CI 3.65-4.21), respectively, followed by jaundice (aORs 2.95 (95% CI 2.63-3.33) and 1.90 (95% CI 1.76-2.06)), and small gestation age (SGA) (aORs 6.57 (95% CI 5.56-7.75) and 5.81 (95% CI 5.15-6.55)). Incidence rates of birth trauma, patent ductus arteriosus, atrial septal defect, respiratory distress syndrome, and neonatal hypoglycemia were also higher in the HDP/GDM and HDP groups than in the comparison group. Most adverse outcomes increased further in women with preeclampsia or eclampsia. In conclusion, women with HDP are at elevated risks of adverse neonatal outcomes. Risks of most adverse outcomes increase further for women with both HDP and GDM. Preeclampsia or eclampsia may also contribute to these outcomes to higher risk levels. Every pregnant woman with these conditions deserves specialized prenatal care.

Risk of mental illness after the diagnosis of occupational injury or disease: a retrospective cohort study.

OBJECTIVES: As studies on mental disorders in victims of occupational injury or disease are limited, this study aims to evaluate the risk of, and factors associated with, the development of mental illness in patients with occupational injury or disease using insurance claims data from Taiwan. METHODS: This retrospective cohort study analyzed insurance records in Taiwan to identify 18,285 adults who experienced occupational injury or disease in 2002-2013 and 18,285 adults without occupational injury or disease who were matched by propensity score. The risks of mental disorders during a follow-up period of up to 2 years were estimated and compared between the two cohorts. RESULTS: After controlling for other variables, the odds of mental illness in patients with occupational injury or disease was significantly higher compared to patients without occupational injury or disease. Additional factors associated with higher odds of mental disorders included female gender, age ≥ 30 years (vs. 20-29 years), Charlson comorbidity index ≥ 1, occupation category of labor union member, soldier, insured by social security, religious group member (vs. private or government employee), lower premium-based monthly salary (≤ 576 US$), treatment at a district hospital or clinic (vs. medical center), treatment at a publically-owned or consortium-owned hospital (vs. private hospital), and central or southeast geographic location (vs. Taipei). The main types of mental illness were anxiety disorder (2.79%) and other psychoses (3.29%). CONCLUSION: The risk of mental illness slightly increased during the 2-year period after the diagnosis of occupational injury or disease.

The pharmaceutical practice of mask distribution by pharmacists in Taiwan's community pharmacies under the Mask Real-Name System, in response to the COVID-19 outbreak.

BACKGROUND: Pharmacists hold to their promise to foster, implement and promote the health of the population and to prevent disease, given their knowledge, skills, and proximity to the locals. The objective of this study was to foster equality and cost-effectiveness in the distribution and sale of masks to all Taiwanese citizens, in response to the COVID-19 pandemic. METHODS: All 6336 special community pharmacies participating in the NHI (National Health Insurance) served as mask-selling sites. Access to masks by citizens was determined and controlled, based on the weekly rationing of the number of purchasable masks per citizen and the last digit of their NHI card number. Masks were available on different weekdays for holders of cards ending with odd and even numbers, except on Sundays, when everyone was eligible to buy a mask. RESULTS: Implementing the program has provided equal access to masks for all citizens across Taiwan. It has stabilized the pricing of masks and mitigated the public's anxiety of a perceived likely market shortage. CONCLUSION: The community pharmacy-based approach to the distribution of prevention face masks to citizens represents a new and innovative engagement of pharmacists in public health promotion and protection initiatives. Community pharmacies can greatly improve the efficiency, reliability, and cost-saving of the distribution of public health resources to local communities, especially in the face of an epidemic.

Sleepiness and injury risk in emergency medical service workers in Taiwan.

BACKGROUND: Insufficient sleep is a common health and safety risk factor in high-impact workplaces where workers are required to take rotating shifts. However, studies on sleepiness-related risks and incidents, particularly among emergency medical services (EMS) workers are limited. OBJECTIVE: This study sought to investigate the prevalence of sleepiness and related workplace incidents among EMS workers. METHODS: This study utilized a cross-sectional survey design on a convenient sample of 500 EMS workers from 41 EMS squads across Taiwan. Data were collected using structured online questionnaires on workplace sleepiness and related safety incidents based on the Epworth Sleepiness Scale (ESS) and a modified 25-item EMS Safety Inventory respectively. RESULTS: With a response rate of 79.8% (n = 399), 36.9% of the respondents were identified as having mild daytime sleepiness, while 39.2% of the respondents were identified as having excessive daytime sleepiness. Multivariate analysis indicated that not only was working on rotating shifts the main cause of the high ESS scores among EMS workers, but also that higher ESS scores increased their risk of sustaining a workplace injury. Furthermore, ill-at-work incidents were associated with an increased risk of workplace-related injuries. CONCLUSION: Overall, the findings indicated a correlation among working on rotation shifts, the prevalence of sleepiness, and a higher risk of workplace injury among EMS workers.

Stroke risks in women with dysmenorrhea by age and stroke subtype.

BACKGROUND: Dysmenorrhea and stroke are health problems affecting women worldwide in their day-to-day lives; however, there is limited knowledge of the stroke risk in women with dysmenorrhea, and there have been no studies assessing the specific distribution of stroke subtypes. This case-control study assessed stroke subtypes by age and the role of comorbidities in women with dysmenorrhea. METHODS AND FINDINGS: Data obtained between 1997 and 2013 from Taiwan's health insurance database identified 514 stroke cases and 31,201 non-stroke controls in women with dysmenorrhea aged 15-49 years. Proportional distributions of subtypes and odds ratios (ORs) of stroke associated with comorbidities by age and subtype were measured. We found that the stroke risk in dysmenorrheal patients increased with age, and that hypertension was nine-fold more prevalent in the stroke cases than in the controls and was associated with an adjusted OR of 4.53 (95% confidence interval (CI) = 3.46-5.92) for all stroke cases. Moreover, the proportion of hemorrhagic stroke was greater than that of ischemic stroke in younger dysmenorrheal patients between 15-24 years old (50.5% vs. 11.4%), whereas this was reversed in those aged 30-49 years old (16.1% vs. 21.0%). Overall, 25.3% of the stroke cases consisted of transient cerebral ischemia and 31.3% were other acute but ill-defined cerebrovascular diseases, in which the prevalence increased with age for both types of strokes. Hypertension was the comorbidity with the highest OR associated with each subtype stroke; diabetes, hyperlipidemia, arrhythmia, and thyroid disease were also comorbidities that were significantly associated with ill-defined cerebrovascular diseases. CONCLUSIONS: The stroke type varies by age in dysmenorrheal patients, and hypertension is the most important comorbidity associated with all types of stroke; therefore, more attention for stroke prevention must be paid to women with dysmenorrhea, particularly when combined with comorbidities.

Capsaicin Targets tNOX (ENOX2) to Inhibit G1 Cyclin/CDK Complex, as Assessed by the Cellular Thermal Shift Assay (CETSA).

Capsaicin (8-methyl-N-vanillyl-6-noneamide), which is an active component in red chili peppers, is used as a chemopreventive agent that shows favorable cytotoxicity against cancer cells. Accumulating evidence indicates that capsaicin preferentially inhibits a tumor-associated NADH oxidase (tNOX, ENOX2) that is ubiquitously expressed in cancer but not in non-transformed cells. This attenuates cancer cell growth by inducing apoptosis. The capsaicin-mediated inhibition of tNOX was recently shown to prolong the cell cycle. However, the molecular events underlying this regulation have not yet been investigated. In the present study, we used a cellular thermal shift assay (CETSA) to detect "target engagement" of capsaicin and its consequent impact on cell cycle progression. Our results indicated that capsaicin engaged with tNOX and triggered the proteasomal degradation of tNOX, which leads to the inhibition of NAD+-dependent SIRT1 deacetylase. Ultimately, the acetylation levels of c-Myc and p53 were enhanced, which suppressed the activation of G1 cyclin/Cyclin-dependent kinase complexes and triggered cell cycle arrest in cancer cells. The results obtained when tNOX was overexpressed in non-cancer cells validated its importance in cell cycle progression. These findings provide the first molecular insights into the regulatory role of tNOX and the anti-proliferative property of capsaicin in regulating the cell cycle of bladder cancer cells.

Capsaicin attenuates cell migration via SIRT1 targeting and inhibition to enhance cortactin and ß-catenin acetylation in bladder cancer cells.

We have studied the chemopreventive property of capsaicin, a major active component in chili pepper, and found that it exhibited apoptotic activity against various lines of cancer cells. Interestingly, accumulating data has revealed that, in addition to cytotoxicity, capsaicin also plays regulatory role on cell migration and invasion. However, its effect on cell migration is paradoxical and not completely understood. Here, we set out to elucidate the molecular events underlying capsaicin-inhibited cell migration in bladder cancer cells. Our results show that the capsaicin-reduced cell migration was associated with down-regulation of sirtuin 1 (SIRT1) deacetylase, possibly through proteasome-mediated protein degradation. More importantly, we employed a cellular thermal shift assay (CETSA) to demonstrate that there was a direct binding between capsaicin and SIRT1. The engagement with capsaicin and protein degradation diminished the deacetylase of SIRT1, which in turn, enhanced acetylation of cortactin and ß-catenin to decrease MMP-2 and MMP-9 activation, resulting in cell migration impairment in bladder cancer cells.

Associations between urate-lowering therapy and the risk of type 2 diabetes mellitus.

BACKGROUND: Gout is independently associated with increased risk of type 2 diabetes mellitus (T2DM). Urate-lowering therapy (ULT) might be beneficial in lowering the risks of T2DM. Therefore, we conducted a nested case-control study to evaluate the associations between ULT and T2DM. METHODS: This study retrieved the data of 29,765 gout patients from the period of 1998-2010 by using data from Taiwan's National Health Insurance Research Database. Controls (n = 59,530) were matched at a 1:2 ratio by age, sex, and region. Multivariate Cox proportional hazards regression were performed to examine the dose-dependent relationship between ULT and T2DM. RESULTS: The adjusted Hazard ratio (HR) for the association of T2DM with allopurinol or benzbromarone exposure was 1.17 (95% confidence interval (CI) 1.07-1.28) and1.09 (95% CI 1.03-1.15), respectively. The HR for the cumulative allopurinol dose was 0.87 (95% CI 0.71-1.07) for patients with dose ≤1.3 mg/day and was 1.31 (95% CI 1.13-1.52) for those with a dose >15.2 mg/day. Similarly, the HR for the cumulative benzbromarone dose was 0.85(95% CI 0.75-0.96) for patients with a dose ≤1.3 mg/day and 1.42 (95% CI 1.30-1.55) for patients with a dose>9.4 mg/day, respectively. Moreover, the average exposure dose of >100 mg/day for allopurinol and >100 mg/day for benzbromarone was associated with a 1.28-fold (95% CI 1.11-1.48) and 1.47-fold (95% CI 1.23-1.76) T2DM risk respectively. The HR for patients in aged >50 years group with cumulative dose ≤1.3 mg/day of allopurinol or benzbromarone had lower risk of T2DM (HR = 0.74, 95% CI 0.58-0.94 for allopurinol; HR = 0.79, 95% CI 0.69-0.90 for benzbromarone). CONCLUSION: Gout patients with prolonged ULT and a high dose of ULT were associated with a significant increase in T2DM risk. Although gout patients with age greater than 50 years and a lower dose of ULT may be beneficial in lowering T2DM risk, further clinical studies need to be confirmed these associations.

Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives.

A series of 4-aminomethyl derivatives of heliomycin 1 was prepared using the Mannich reaction. The modification significantly improved aqueous solubility of the initially poorly soluble antibiotic. Testing the antiproliferative efficacy revealed a potent activity of heliomycin as well as its new derivatives on a panel of mammalian tumor cells including drug resistant variants. In contrast to 1 the new derivatives 7a, 7l, 7p generated a high level of ROS associated with induction of apoptosis in T24 bladder cancer cells. Introduction of 4-aminomethyl moiety increased the affinity to DNA and the ability to inhibit topoisomerase 1 making 7p the most promising candidate for further preclinical evaluation. Thus, aminomethylation is the first-in-class successful transformation of the antibiotic 1 resulting in an improved water solubility of derivatives and promising properties in search of novel anticancer drug candidates.

Investigating spousal concordance of diabetes through statistical analysis and data mining.

OBJECTIVE: Spousal clustering of diabetes merits attention. Whether old-age vulnerability or a shared family environment determines the concordance of diabetes is also uncertain. This study investigated the spousal concordance of diabetes and compared the risk of diabetes concordance between couples and noncouples by using nationally representative data. METHODS: A total of 22,572 individuals identified from the 2002-2013 National Health Insurance Research Database of Taiwan constituted 5,643 couples and 5,643 noncouples through 1:1 dual propensity score matching (PSM). Factors associated with concordance in both spouses with diabetes were analyzed at the individual level. The risk of diabetes concordance between couples and noncouples was compared at the couple level. Logistic regression was the main statistical method. Statistical data were analyzed using SAS 9.4. C&RT and Apriori of data mining conducted in IBM SPSS Modeler 13 served as a supplement to statistics. RESULTS: High odds of the spousal concordance of diabetes were associated with old age, middle levels of urbanization, and high comorbidities (all P < 0.05). The dual PSM analysis revealed that the risk of diabetes concordance was significantly higher in couples (5.19%) than in noncouples (0.09%; OR = 61.743, P < 0.0001). CONCLUSIONS: A high concordance rate of diabetes in couples may indicate the influences of assortative mating and shared environment. Diabetes in a spouse implicates its risk in the partner. Family-based diabetes care that emphasizes the screening of couples at risk of diabetes by using the identified risk factors is suggested in prospective clinical practice interventions.

Capsaicin Inhibits Multiple Bladder Cancer Cell Phenotypes by Inhibiting Tumor-Associated NADH Oxidase (tNOX) and Sirtuin1 (SIRT1).

Bladder cancer is one of the most frequent cancers among males, and its poor survival rate reflects problems with aggressiveness and chemo-resistance. Recent interest has focused on the use of chemopreventatives (nontoxic natural agents that may suppress cancer progression) to induce targeted apoptosis for cancer therapy. Capsaicin, which has anti-cancer properties, is one such agent. It is known to preferentially inhibit a tumor-associated NADH oxidase (tNOX) that is preferentially expressed in cancer/transformed cells. Here, we set out to elucidate the correlation between tNOX expression and the inhibitory effects of capsaicin in human bladder cancer cells. We showed that capsaicin downregulates tNOX expression and decreases bladder cancer cell growth by enhancing apoptosis. Moreover, capsaicin was found to reduce the expression levels of several proteins involved in cell cycle progression, in association with increases in the cell doubling time and enhanced cell cycle arrest. Capsaicin was also shown to inhibit the activation of ERK, thereby reducing the phosphorylation of paxillin and FAK, which leads to decreased cell migration. Finally, our results indicate that RNA interference-mediated tNOX depletion enhances spontaneous apoptosis, prolongs cell cycle progression, and reduces cell migration and the epithelial-mesenchymal transition. We also observed a downregulation of sirtuin 1 (SIRT1) in these tNOX-knockdown cells, a deacetylase that is important in multiple cellular functions. Taken together, our results indicate that capsaicin inhibits the growth of bladder cancer cells by inhibiting tNOX and SIRT1 and thereby reducing proliferation, attenuating migration, and prolonging cell cycle progression.

Melatonin Supplementation for Children With Atopic Dermatitis and Sleep Disturbance: A Randomized Clinical Trial.

IMPORTANCE: Sleep disturbance is common in children with atopic dermatitis (AD), but effective clinical management for this problem is lacking. Reduced levels of nocturnal melatonin were found to be associated with sleep disturbance and increased disease severity in children with AD. Melatonin also has sleep-inducing and anti-inflammatory properties and therefore might be useful for the management of AD. OBJECTIVE: To evaluate the effectiveness of melatonin supplementation for improving the sleep disturbance and severity of disease in children with AD. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial used a double-blind, placebo-controlled crossover design to study 73 children and adolescents aged 1 to 18 years with physician-diagnosed AD involving at least 5% of the total body surface area. The study was conducted at the pediatric department of a large tertiary care hospital in Taiwan from August 1, 2012, through January 31, 2013. Forty-eight children were randomized 1:1 to melatonin or placebo treatment, and 38 of these (79%) completed the cross-over period of the trial. Final follow-up occurred on April 13, 2013, and data were analyzed from January 27 to April 25, 2014. Analyses were based on intention to treat. INTERVENTIONS: Melatonin, 3 mg/d, or placebo for 4 weeks followed by a 2-week washout period and then crossover to the alternate treatment for 4 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was AD severity evaluated using the Scoring Atopic Dermatitis (SCORAD) index, with scores ranging from 0 to 103 and greater scores indicating worse symptoms. Secondary outcomes included sleep variables measured by actigraphy, subjective change in sleep and dermatitis, sleep variables measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, and serum IgE levels. RESULTS: After melatonin treatment among the 48 children included in the study, the SCORAD index decreased by 9.1 compared with after placebo (95% CI, -13.7 to -4.6; P < .001), from a mean (SD) of 49.1 (24.3) to 40.2 (20.9). Moreover, the sleep-onset latency shortened by 21.4 minutes after melatonin treatment compared with after placebo (95% CI, -38.6 to -4.2; P = .02). The improvement in the SCORAD index did not correlate significantly with the change in sleep-onset latency (r = -0.04; P = .85). No patient withdrew owing to adverse events, and no adverse event was reported throughout the study. CONCLUSIONS AND RELEVANCE: Melatonin supplementation is a safe and effective way to improve the sleep-onset latency and disease severity in children with AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01638234.