Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of ß-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

Costs and Cardiovascular Benefits of a Fourth-Generation Synchronous Telehealth Program on Mortality and Cardiovascular Outcomes for Patients With Atrial Fibrillation: Retrospective Cohort Study.

BACKGROUND: The prevalence of atrial fibrillation (AF) continues to increase in modern aging society. Patients with AF are at high risk for multiple adverse cardiovascular events, including heart failure, stroke, and mortality. Improved medical care is needed for patients with AF to enhance their quality of life and limit their medical resource utilization. With advances in the internet and technology, telehealth programs are now widely used in medical care. A fourth-generation telehealth program offers synchronous and continuous medical attention in response to physiological parameters measured at home. Although we have previously shown the benefits of this telehealth program for some patients with a high risk of cardiovascular disease, its benefits for patients with AF remains uncertain. OBJECTIVE: This study aims to investigate the benefits of participating in a fourth-generation telehealth program for patients with AF in relation to cardiovascular outcomes. METHODS: This was a retrospective cohort study. We retrospectively searched the medical records database of a tertiary medical center in Northern Taiwan between January 2007 and December 2017. We screened 5062 patients with cardiovascular disease and enrolled 537 patients with AF, of which 279 participated in the telehealth program and 258 did not. Bias was reduced using the inverse probability of treatment weighting adjustment based on the propensity score. Outcomes were collected and analyzed, including all-cause readmission, admission for heart failure, acute coronary syndrome, ischemic stroke, systemic embolism, bleeding events, all-cause mortality, and cardiovascular death within the follow-up period. Total medical expenses and medical costs in different departments were also compared. Subgroup analyses were conducted on ischemic stroke stratified by several subgroup variables. RESULTS: The mean follow-up period was 3.0 (SD 1.7) years for the telehealth group and 3.4 (SD 1.9) years for the control group. After inverse probability of treatment weighting adjustment, the patients in the telehealth program had significantly fewer ischemic strokes (2.0 vs 4.5 events per 100 person-years; subdistribution hazard ratio [SHR] 0.45, 95% CI 0.22-0.92) and cardiovascular deaths (2.5 vs 5.9 events per 100 person-years; SHR 0.43, 95% CI 0.18-0.99) at the follow-up. The telehealth program particularly benefited patients comorbid with vascular disease (SHR 0.11, 95% CI 0.02-0.53 vs SHR 1.16, 95% CI 0.44-3.09; P=.01 for interaction). The total medical expenses during follow-up were similar in the telehealth and control groups. CONCLUSIONS: This study demonstrated the benefits of participating in the fourth-generation telehealth program for patients with AF by significantly reducing their ischemic stroke risk while spending the same amount on medical expenses.

Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

BACKGROUND: Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common cardiac conditions with high mortality risks, which can be improved through early intervention. Telehealth services, which allow for remote monitoring of patient conditions, have been proven to improve the health management of chronic diseases, but the effects on MR and TR progression are unknown. OBJECTIVE: This study aimed to explore whether patients receiving telehealth services have less MR and TR progression compared with a control group. We also aimed to identify the determinants of MR and TR progression. METHODS: This single-center retrospective study conducted at the National Taiwan University Hospital compared MR and TR progression (defined as either progression to moderate or greater MR and TR or MR and TR progression by ≥2 grades during the study period) between the telehealth and control groups. Patients had a minimum of 2 transthoracic echocardiograms at least 6 months apart; baseline mild-moderate MR and TR or lower; and no prior surgeries on the mitral or tricuspid valve. Telehealth patients were defined as those who received telehealth services for at least 28 days within 3 months of baseline. Basic demographics, baseline blood pressure measurements, prescribed medication, and Charlson Comorbidity Index components were obtained for all patients. RESULTS: A total of 1081 patients (n=226 in the telehealth group and n=855 in the control group) were included in the study analyses. The telehealth group showed significantly lower baseline systolic blood pressure (P<.001), higher Charlson Comorbidity Index (P=.02), higher prevalence of prior myocardial infarction (P=.01) and heart failure (P<.001), higher beta-blocker (P=.03) and diuretic (P=.04) use, and lower nitrate use (P=.04). Both groups showed similar cardiac remodeling conditions at baseline. Telehealth was found to be neutral for both MR (hazard ratio 1.10, 95% CI 0.80-1.52; P=.52) and TR (hazard ratio 1.27, 95% CI 0.92-1.74; P=.14) progression. Determinants for moderate or greater MR progression included older age, female sex, diuretic use, larger left atrial dimension, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction. Determinants of moderate or greater TR progression included older age, female sex, diuretic use, presence of atrial fibrillation, LA dimension, left ventricular end-systolic dimension, and lower left ventricular ejection fraction; statin use was found to be protective. CONCLUSIONS: This is the first study to assess the association between telehealth services and the progression of MR and TR. Telehealth patients, who had more comorbidities, displayed similar MR and TR progression versus control patients, indicating that telehealth may slow MR and TR progression. Determinants of MR and TR progression included easy-to-measure traditional echo parameters of cardiac function, older age, female sex, and atrial fibrillation, which can be incorporated into a telehealth platform and advanced alert system, improving patient outcomes through personalized care.

Correction: Effect of Telehealth Services on Mitral and Tricuspid Regurgitation Progression: Retrospective Study.

[This corrects the article DOI: 10.2196/47947.].

Nutrient status regulates MED19a phase separation for ORESARA1-dependent senescence.

The mediator complex is highly conserved in eukgaryotes and is integral for transcriptional responses. Mediator subunits associate with signal-responsive transcription factors (TF) to activate expression of specific signal-responsive genes. As the key TF of Arabidopsis thaliana senescence, ORESARA1 (ORE1) is required for nitrogen deficiency (-N) induced senescence; however, the mediator subunit that associates with ORE1 remains unknown. Here, we show that Arabidopsis MED19a associates with ORE1 to activate -N senescence-responsive genes. Disordered MED19a forms inducible nuclear condensates under -N that is regulated by decreasing MED19a lysine acetylation. MED19a carboxyl terminus (cMED19a) harbors a mixed-charged intrinsically disordered region (MC-IDR) required for ORE1 interaction and liquid-liquid phase separation (LLPS). Plant and human cMED19 are sufficient to form heterotypic condensates with ORE1. Human cMED19 MC-IDR, but not yeast cMED19 IDR, partially complements med19a suggesting functional conservation in evolutionarily distant eukaryotes. Phylogenetic analysis of eukaryotic cMED19 revealed that the MC-IDR could arise through convergent evolution. Our result of MED19 MC-IDR suggests that plant MED19 is regulated by phase separation during stress responses.

The Costs and Cardiovascular Benefits in Patients With Peripheral Artery Disease From a Fourth-Generation Synchronous Telehealth Program: Retrospective Cohort Study.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk for major cardiovascular events, including myocardial infarction, stroke, and hospitalization for heart failure. We have previously shown the clinical efficacy of a fourth-generation synchronous telehealth program for some patients, but the costs and cardiovascular benefits of the program for PAD patients remain unknown. OBJECTIVE: The telehealth program is now widely used by higher-risk cardiovascular patients to prevent further cardiovascular events. This study investigated whether patients with PAD would also have better cardiovascular outcomes after participating in the fourth-generation synchronous telehealth program. METHODS: This was a retrospective cohort study. We screened 5062 patients with cardiovascular diseases who were treated at National Taiwan University Hospital and then enrolled 391 patients with a diagnosis of PAD. Of these patients, 162 took part in the telehealth program, while 229 did not and thus served as control patients. Inverse probability of treatment weighting (IPTW) based on the propensity score was used to mitigate possible selection bias. Follow-up outcomes included heart failure hospitalization, acute coronary syndrome, stroke, and all-cause readmission during the 1-year follow-up period and through the last follow-up. RESULTS: The mean follow-up duration was 3.1 (SD 1.8) years for the patients who participated in the telehealth program and 3.2 (SD 1.8) for the control group. The telehealth program patients exhibited lower risk of ischemic stroke than did the control group in the first year after IPTW (0.9% vs 3.5%; hazard ratio [HR] 0.24; 95% CI 0.07-0.80). The 1-year composite endpoint of vascular accident, including acute coronary syndrome and stroke, was also significantly lower in the telehealth program group after IPTW (2.4% vs 5.2%; HR 0.46; 95% CI 0.21-0.997). At the end of the follow-up, the telehealth program group continued to exhibit a significantly lower rate of ischemic stroke than did the control group after IPTW (0.9% vs 3.5%; HR 0.52, 95% CI 0.28-0.93). Furthermore, the medical costs of the telehealth program patients were not higher than those of the control group, whether in terms of outpatient, emergency department, hospitalization, or total costs. CONCLUSIONS: The PAD patients who participated in the fourth-generation synchronous telehealth program exhibited lower risk of ischemic stroke events over both mid- and long-term follow-up periods. However, larger-scale and prospective randomized clinical trials are needed to confirm our findings.

Assessment of the Relationship Between Ambient Temperature and Home Blood Pressure in Patients From a Web-Based Synchronous Telehealth Care Program: Retrospective Study.

BACKGROUND: Decreased ambient temperature significantly increases office blood pressure, but few studies have evaluated the effect of ambient temperature on home blood pressure. OBJECTIVE: We aimed to investigate the relationship between short-term ambient temperature exposure and home blood pressure. METHODS: We recruited patients with chronic cardiovascular diseases from a telehealth care program at a university-affiliated hospital. Blood pressure was measured at home by patients or their caregivers. We obtained hourly meteorological data for Taipei (temperature, relative humidity, and wind speed) for the same time period from the Central Weather Bureau, Taiwan. RESULTS: From 2009 to 2013, we enrolled a total of 253 patients. Mean patient age was 70.28 (SD 13.79) years, and 66.0% (167/253) of patients were male. We collected a total of 110,715 home blood pressure measurements. Ambient temperature had a negative linear effect on all 3 home blood pressure parameters after adjusting for demographic and clinical factors and antihypertensive agents. A 1°C decrease was associated with a 0.5492-mm Hg increase in mean blood pressure, a 0.6841-mm Hg increase in systolic blood pressure, and a 0.2709-mm Hg increase in diastolic blood pressure. This temperature effect on home blood pressure was less prominent in patients with diabetes or hypertension. Antihypertensive agents modified this negative effect of temperature on home blood pressure to some extent, and angiotensin receptor blockers had the most favorable results. CONCLUSIONS: Short-term exposure to low ambient temperature significantly increased home blood pressure in patients with chronic cardiovascular diseases. Antihypertensive agents may modify this effect.

Potyviral Gene-Silencing Suppressor HCPro Interacts with Salicylic Acid (SA)-Binding Protein 3 to Weaken SA-Mediated Defense Responses.

The viral infection process is a battle between host defense response and pathogen antagonizing action. Several studies have established a tight link between the viral RNA silencing suppressor (RSS) and the repression of salicylic acid (SA)-mediated defense responses, nonetheless host factors directly linking an RSS and the SA pathway remains unidentified. From yeast two-hybrid analysis, we identified an interaction between the potyviral RSS helper-component proteinase (HCPro) and SA-binding protein SABP3. Co-localization and bimolecular fluorescence complementation analyses validated the direct in vivo interaction between Turnip mosaic virus (TuMV) HCPro and the Arabidopsis homologue of SABP3, AtCA1. Additionally, transient expression of TuMV HCPro demonstrated its ability to act as a negative regulator of AtCA1. When the plants of the AtCA1 knockout mutant line were inoculated with TuMV, our results indicated that AtCA1 is essential to restrict viral spreading and accumulation, induce SA accumulation, and trigger the SA pathway. Unexpectedly, the AtCA1 overexpression line also displayed a similar phenotype, suggesting that the constitutive expression of AtCA1 antagonizes the SA pathway. Taken together, our results depict AtCA1 as an essential regulator of SA defense responses. Moreover, the interaction of potyviral HCPro with this regulator compromises the SA pathway to weaken host defense responses and facilitate viral infection.

A noncoding RNA transcribed from the AGAMOUS (AG) second intron binds to CURLY LEAF and represses AG expression in leaves.

Dispersed H3K27 trimethylation (H3K27me3) of the AGAMOUS (AG) genomic locus is mediated by CURLY LEAF (CLF), a component of the Polycomb Repressive Complex (PRC) 2. Previous reports have shown that the AG second intron, which confers AG tissue-specific expression, harbors sequences targeted by several positive and negative regulators. Using RACE reverse transcription polymerase chain reaction, we found that the AG intron 2 encodes several noncoding RNAs. RNAi experiment showed that incRNA4 is needed for CLF repressive activity. AG-incRNA4RNAi lines showed increased leaf AG mRNA levels associated with a decrease of H3K27me3 levels; these plants displayed AG overexpression phenotypes. Genetic and biochemical analyses demonstrated that the AG-incRNA4 can associate with CLF to repress AG expression in leaf tissues through H3K27me3-mediated repression and to autoregulate its own expression level. The mechanism of AG-incRNA4-mediated repression may be relevant to investigations on tissue-specific expression of Arabidopsis MADS-box genes.

Effect of Contract Compliance Rate to a Fourth-Generation Telehealth Program on the Risk of Hospitalization in Patients With Chronic Kidney Disease: Retrospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is prevalent in Taiwan and it is associated with high all-cause mortality. We have shown in a previous paper that a fourth-generation telehealth program is associated with lower all-cause mortality compared to usual care with a hazard ratio of 0.866 (95% CI 0.837-0.896). OBJECTIVE: This study aimed to evaluate the effect of renal function status on hospitalization among patients receiving this program and to evaluate the relationship between contract compliance rate to the program and risk of hospitalization in patients with CKD. METHODS: We retrospectively analyzed 715 patients receiving the telehealth care program. Contract compliance rate was defined as the percentage of days covered by the telehealth service before hospitalization. Patients were stratified into three groups according to renal function status: (1) normal renal function, (2) CKD, or (3) end-stage renal disease (ESRD) and on maintenance dialysis. The outcome measurements were first cardiovascular and all-cause hospitalizations. The association between contract compliance rate, renal function status, and hospitalization risk was analyzed with a Cox proportional hazards model with time-dependent covariates. RESULTS: The median follow-up duration was 694 days (IQR 338-1163). Contract compliance rate had a triphasic relationship with cardiovascular and all-cause hospitalizations. Patients with low or very high contract compliance rates were associated with a higher risk of hospitalization. Patients with CKD or ESRD were also associated with a higher risk of hospitalization. Moreover, we observed a significant interaction between the effects of renal function status and contract compliance rate on the risk of hospitalization: patients with ESRD, who were on dialysis, had an increased risk of hospitalization at a lower contract compliance rate, compared with patients with normal renal function or CKD. CONCLUSIONS: Our study showed that there was a triphasic relationship between contract compliance rate to the telehealth program and risk of hospitalization. Renal function status was associated with risk of hospitalization among these patients, and there was a significant interaction with contract compliance rate.