Highly substituted benzo[b]furan synthesis through substituent migration.

An unusual benzofuran synthesis from 2,6-disubstituted phenols and alkynyl sulfoxides is disclosed. Various highly substituted benzofurans were synthesized via the charge-accelerated [3,3]-sigmatropic rearrangement and subsequent substituent migration. Multiaryl-substituted benzofurans and fully substituted benzofurans were prepared on the basis of the unique reaction mechanism.

Oral SSTR5 Antagonist SCO-240 for Growth Hormone Stimulation: A Phase I Single-Dose Study in Healthy Individuals.

Somatostatin inhibits endocrine and exocrine secretion in various tissues by acting on five somatostatin receptor subtypes (SSTR1-5). The clinical effects of SSTR5 antagonism remain unknown. Herein, we evaluated the effects of SCO-240, an oral SSTR5 antagonist, in healthy individuals. This randomized, single-center, double-blind, placebo-controlled, phase I study included healthy Japanese and White individuals. The effects of ascending single oral doses of SCO-240 were evaluated in healthy individuals. The main outcome measures were safety, tolerability, pharmacokinetics, and pharmacodynamics (gallbladder contractions and levels of serum insulin and plasma glucagon-like peptide-1 (GLP-1)). The levels of pituitary hormones were evaluated in our exploratory analysis. The results indicated that SCO-240 was safe and well-tolerated at all tested doses. Oral SCO-240 was readily absorbed, with its systemic exposure increasing in a dose-dependent manner. The median time to maximum concentration and mean terminal half-life of SCO-240 were 3-4 and 10.2-12.6 hours, respectively, in the ascending dose section. No clinically meaningful changes in SCO-240 pharmacokinetic profiles were observed between fed and fasted or between Japanese and White individuals. No increase in gallbladder contractions or levels of insulin and GLP-1 were detected. SCO-240 induced robust growth hormone (GH) secretion without altering the levels of other pituitary hormones. In conclusion, the study is the first to demonstrate that SSTR5 antagonism stimulates GH secretion in humans. SCO-240 was safe and well-tolerated and exhibited once-daily oral dosing potential. The robust effects of SCO-240 on GH secretion suggest that it may be a treatment option for GH-related disorders.

Facile synthesis of dibenzothiophene S-oxides from sulfinate esters.

An efficient method to prepare dibenzothiophene S-oxides is disclosed. Suzuki-Miyaura cross-coupling of 2-bromoaryl sulfinate esters with arylboronic acids selectively at the bromo group followed by electrophilic cyclization of the resulting sulfinate ester moiety provides diverse dibenzothiophene S-oxides. Further transformations including Pummerer-type C-H propargylation and aryne reactions realize to synthesize highly functionalized dibenzothiophene derivatives.

Psychological distress is affected by fear of COVID-19 via lifestyle disruption and leisure restriction among older adults in Japan: a cross-sectional study.

Introduction: Engaging in social activities is an essential component of a healthy lifestyle for community-dwelling older adults. Critically, as with past disasters, there is concern about the effects of long-term activity restrictions due to the coronavirus disease 2019 (COVID-19) pandemic on health of older adults. However, the precise associations between fear of COVID-19, lifestyle satisfaction, leisure activities, and psychological distress are unclear. Objective: The purpose of this study was to comprehensively determine the associations between fear of COVID-19, lifestyle satisfaction, leisure engagement, and psychological distress among community-dwelling older adults in the context of the ongoing COVID-19 pandemic. Materials and methods: A questionnaire survey administered by mail was conducted from October 1 to October 15, 2021. The questionnaire included the Fear of COVID-19 Scale, the Lifestyle Satisfaction Scale, the Leisure Activity Scale for Contemporary Older Adults, and the Kessler Psychological Distress Scale-6. Based on previous studies, we developed a hypothetical model for the association between fear of COVID-19, lifestyle satisfaction, leisure engagement, and psychological distress and performed structural equation modeling to assess the relationships between these variables. Results: Participants included 301 Japanese citizens (23.6% male, 76.4% female), with a mean age of 76.7 ± 4.58 years. Goodness-of-fit from structural equation modeling was generally good. Analysis of standardized coefficients revealed a significant positive relationship between fear of COVID-19 and psychological distress (ß = 0.33, p < 0.001) and lifestyle satisfaction and leisure activities (ß = 0.35, p < 0.001). We further observed a significant negative relationship between fear of COVID-19 and lifestyle satisfaction (ß = -0.23, p < 0.001) and between leisure activities and psychological distress (ß = -0.33, p < 0.001). Conclusion: Fear of COVID-19 is significantly associated with psychological distress, both directly and via its effects on lifestyle satisfaction and leisure activities. That is, not only did fear of COVID-19 directly impact psychological distress of participants, it also affected psychological distress through lifestyle disruption and leisure restriction. This results may be used to better understand how a national emergency that substantially restricts daily life, such as COVID-19 or an earthquake disaster, can affect the psychological health and wellbeing of older, community-dwelling adults.

Facile synthesis of sulfinate esters from aryl iodides via direct oxidation of thioesters.

A practical method to synthesize sulfinate esters from aryl iodides is disclosed. Direct oxidation of thioesters prepared by copper-catalyzed C-S formation of aryl iodides realized the efficient synthesis of sulfinate esters. Due to the good accessibility of aryl iodides, a wide variety of sulfinate esters were prepared from easily available starting materials such as carboxylic acids and anilines.

Synthesis of benzo[b]furans from alkynyl sulfoxides and phenols by the interrupted Pummerer reaction.

The interrupted Pummerer reaction of alkynyl sulfoxides with phenols is disclosed. A wide range of benzo[b]furans were efficiently synthesized through unexplored electrophilic activation of the electron-deficient alkynyl sulfinyl group. Based on the good availability of alkynyl sulfoxides, we successfully prepared various functionalized benzo[b]furans from readily available alkynes, thiosulfonates, and phenols.

Liquid chromatography-mass spectrometry measurements of blood diphosphoinositol pentakisphosphate levels.

Diphosphoinositol pentakisphosphate (InsP7) is an inositol pyrophosphate generated by inositol hexakisphosphate kinases (IP6Ks) that regulate diverse biological functions in cells. To date, we have a limited understanding of the InsP7 biology owing to limited data on InsP7 levels in blood or other tissues. Given the significant role of InsP7 in maintaining biological homeostasis, further advancement in InsP7 measurement is essential. In this study, we report a highly sensitive liquid chromatography with tandem mass spectrometry method for determining InsP7 levels in whole blood, which is an easily accessible tissue and for which knowledge on InsP7 levels is limited. We applied a perchloric acid-based method to increase the extraction efficiency of InsP7 from the cells. Subsequently, we combined a YMC-Triart C18 metal-free column, ion-pair reagents, EDTA, methylenediphosphonic acid, and N,N,N',N'-Ethylenediaminetetrakis(methylenephosphonic acid) to minimize InsP7 adsorption to the detection system. We prepared blood quality control samples that were highly exposed to IP6K inhibitor, showing minimum InsP7 levels, to decrease the lower quantification limit of InsP7. Furthermore, we applied rat plasma, which was found to show no InsP7 levels, as a surrogate matrix. This setting resulted in the highly sensitive detection of InsP7 levels in blood obtained from rats, with a quantification sensitivity of 1 ng of InsP7 per mL of blood. The current method demonstrated acceptable accuracy (100 ± 15%) and precision (coefficient of variation ≤ 15%) in rat blood. Using this method, we revealed endogenous basal levels of InsP7 (37.4 ng/mL) in blood obtained from normal rats, and decreased levels of InsP7 (4.1-21.7 ng/mL) in blood obtained from IP6K inhibitor-administered rats. In summary, we established a highly sensitive method for measuring InsP7 and revealed its levels in rat blood. The current findings may help in understanding InsP7 biology.

Successful Treatment of Whole Coronary Artery Spasm after Off-Pump Coronary Artery Bypass Grafting.

Coronary artery spasm after coronary artery bypass grafting is a rare but life-threatening condition. Herein, we report the case of a 77-year-old man who received off-pump coronary artery bypass grafting. An hour after surgery, there was a sudden hemodynamic compromise due to coronary artery spasm, prompting emergent coronary angiography with extracorporeal membrane oxygenation support. Because the angiography results showed diffuse severe spasm of the entire native coronary artery, the patient was treated with an intracoronary injection of vasodilators. The patient recovered in 7 days with mechanical support, catecholamines, and vasodilators, and he was discharged on postoperative day 30. Although coronary artery spasm after off-pump coronary artery bypass surgery is a rare condition, it must be suspected when sudden circulatory collapse occurs.

Impact of COVID-19 Pandemic on Spatial Separation of New and Existing Residents: Case Study of Tsukuba City in Greater Tokyo Area.

For balancing the improvement of social capital through mutual interaction among residents and measures against infectious diseases, municipalities must understand where their residents interact with each other during epidemics. By distinguishing between new and existing residents based on the average age of the houses in their residential areas, we measured the degree of separation between them at various locations and facilities in the Tsukuba City in the Greater Tokyo Area during the daytime based on smartphone location information. We also investigated separation by visitors' residential savings and income class and their age and gender in each location. Separation was observed in almost all the public places in Tsukuba City, even before the COVID-19 outbreak. During the outbreak, many public places and facilities were visited by fewer people, and yet their separation increased. On the other hand, separation lessened in parks, increasing opportunities for residents to interact. Even after the outbreak began, lower separation environments remained in places where food courts and department stores were located compared to other places. In the post-outbreak period, separation returned to its normal level.

Two-stage hybrid repair with over-the-scope clip for atrioesophageal fistula after catheter-based ablation.

In this report, we present a case in which we successfully performed two-stage hybrid repair of heart surgery and endoscopic treatment with over-the-scope-clip system for atrio-esophageal fistula after catheter based ablation.

Surgical and multitreatment approach in a case of primary cardiac angiosarcoma: A case report.

INTRODUCTION AND IMPORTANCE: Primary cardiac angiosarcoma is extremely rare, and its prognosis remains poor, with a mean life expectancy of only a few months. Here, we report a case of primary cardiac angiosarcoma. CASE PRESENTATION: A 49-year-old Japanese woman with a month-long history of dyspnea was admitted to our hospital for pericardial effusion. Chest computed tomography and cardiac magnetic resonance imaging showed a mass in the right atrium. The patient underwent surgical resection of the tumor, and the pathological diagnosis was angiosarcoma. The patient received radiotherapy after surgery. Six months following surgery, she underwent chemotherapy following the diagnosis of lung metastasis. The patient died 18 months after the initial diagnosis. CLINICAL DISCUSSION: Cardiac angiosarcoma is rare and difficult to diagnose early because it is associated with few symptoms. Moreover, there are currently no established guidelines for the treatment of this disease because of its rarity and sparse descriptive literature Therefore, multidisciplinary therapies should be considered, including surgery, radiotherapy, and chemotherapy. CONCLUSION: There is no standard treatment for cardiac angiosarcoma, but surgical resection, chemotherapy, radiation therapy, or a combination of these therapies may be useful.

Modular synthesis of triazoles from 2-azidoacrylamides having a nucleophilic amino group.

Assembling methods using 2-azidoacrylamides having a nucleophilic amino group are disclosed. Divergent transformations of the amine-type trivalent platform were accomplished with a wide variety of electrophiles to obtain a broad range of 2-azidoacrylamides involving a fluorosulfonyl group-containing trivalent platform. Consecutive click conjugations including triazole formation, thiol-ene-type 1,4-addition, and SuFEx reactions realized the efficient assembly of easily available simple modules.

Hydride reduction of o-(fluorosilyl)benzodifluorides for subsequent C-F transformations.

An efficient method for sequential C-F transformations of o-hydrosilyl-substituted benzotrifluorides is disclosed. A key to the success is hydride reduction of o-fluorosilyl-substituted difluoromethylenes prepared by a single C-F transformation of o-hydrosilyl-substituted benzotrifluorides. We succeeded in further C-F transformations via hydride abstraction of the resulting o-hydrosilyl group, enabling us to synthesize a wide variety of organofluorine compounds.

Safety, Efficacy, and Cost-Effectiveness of Same-Day Discharge for Left Atrial Appendage Occlusion.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) with the Watchman device is FDA approved for stroke prevention in patients with nonvalvular atrial fibrillation who have an appropriate indication. During the COVID-19 pandemic, a same-day discharge protocol (SDDP) was employed to improve resource utilization, relieve hospital occupation, and reduce the possible risk of in-hospital virus transmission. OBJECTIVES: We sought to analyze the safety, feasibility, and cost effectiveness for SDDP in patients receiving LAAO. METHODS: A prospective analysis of 142 consecutive patients, 119 treated prior to SDDP and 23 who underwent SDDP following LAAO with cardiac computed tomography angiography (CTA)-guided pre-procedural planning and intracardiac echocardiogram (ICE). Procedures were performed in a single, large academic hospital in the United States. In-hospital and 45-day procedural success, adverse events, length of procedure, and length-of-stay were evaluated. RESULTS: Baseline patient characteristics including mean CHA2DS2VASc scores and mean HAS-BLED scores were similar in both groups. All procedures were successful. There was no significant difference in rates of procedural complications or in-hospital adverse events. The mean procedure time in the SDDP group was 11 minutes longer than in the conventional group (62.1 ± 5.9 vs 51.1 ± 21; P=.01). Outcomes at 45-day follow-up were similar. SDDP was associated with a reduced length of stay compared with conventional strategy and a 15% reduction in total costs. CONCLUSIONS: Same-day discharge strategy for LAAO appears safe, feasible and could become the new standard approach for LAAO. A protocol including CTA pre-procedural planning, ICE-guided deployment and conscious sedation reduces hospital occupation and lowers costs.

Surgical Strategy for Huge Right Coronary Artery Aneurysm Combined with Left Ventricular Fistula.

Coronary artery aneurysms combined with left ventricular fistulas are rare; coronary revascularization strategy after coronary artery aneurysm resection is complex in such cases. We report the surgical repair of a giant right coronary artery aneurysm with a fistula in the left ventricle in a 79-year-old woman diagnosed with an aneurysm 50 mm in diameter. Surgical repair included resection of the coronary artery aneurysm, coronary artery bypass grafting to the posterior descending artery, and isolation of reconstructed right coronary circulation from the fistula. The postoperative course was uneventful; postoperative coronary angiography revealed a patent bypass graft unconnected to the left ventricle.

Left Atrial Appendage Occlusion Using Cardiac CT Angiography and Intracardiac Echocardiography: A Prospective, Single-Center Study.

OBJECTIVES: We reviewed the periprocedural events, accuracy of device selection, and outcomes of a series of patients receiving percutaneous left atrial appendage occlusion (LAAO) with cardiac computed tomography angiography (CTA)-guided preprocedural planning and intracardiac echocardiography (ICE)-guided device deployment. BACKGROUND: Percutaneous LAAO with the Watchman device (Boston Scientific) is approved by the United States Food and Drug Administration for stroke prevention in patients with non-valvular atrial fibrillation with a demonstrated contraindication to oral anticoagulation. Cardiac CTA preprocedural planning with utilization of an ICE-guided deployment may be associated with favorable outcomes. METHODS: A prospective analysis of 71 non-consecutive patients who underwent LAAO over an 18-month period with cardiac CTA-guided preprocedural planning and ICE was conducted. Procedures were performed in a single large, academic hospital in the United States. Procedural success, correlation of CTA preprocedural device sizing with final device size utilization, adverse events, length of procedure, and length of stay were evaluated. RESULTS: Preprocedural cardiac CTA-guided device sizing was consistent with the final deployed device in 69 patients (97.2%) evaluated in this case series. Procedure success rate was 100%. All implants were performed using Watchman devices, 45 (63.4%) with the original 2.5 platform and 26 (36.6%) with the Watchman FLX platform. All patients were treated with conscious sedation and the mean length of stay was 1.45 ± 0.72 days. Only 2 adverse events occurred and both resolved. CONCLUSIONS: Cardiac CTA-guided preprocedural planning resulted in accurate device sizing in this patient sample and may be used in conjunction with ICE and conscious sedation for a same-day discharge strategy in select patients.

Meta-Analysis Comparing Valve Durability Among Different Transcatheter and Surgical Aortic Valve Bioprosthesis.

Durability of transcatheter heart valve (THV) is critical as the indication of transcatheter aortic valve implantation (TAVI) expands to patients with longer life-expectancy. We aimed to compare the durability of different THV systems (balloon-expandable [BE] and self-expandable [SE]) and surgical aortic valve replacement (SAVR) prosthesis. PUBMED and EMBASE were searched through February 2021 for randomized trials investigating parameters of valve durability after TAVI and/or SAVR in severe aortic stenosis. A network meta-analysis using random-effect model was performed. Synthesis was performed with 5-year follow-up data for echocardiographic outcomes and the longest available follow-up data for clinical outcomes. Ten trials with a total of 9,388 patients (BE-THV: 2,562; SE-THV: 2,863; SAVR: 3,963) were included. Follow-up ranged from 1 to 6 years. SE-THV demonstrated significantly larger effective orifice area, lower mean aortic valve gradient (AVG), and less increase in mean AVG at 5-year compared with BE-THV and SAVR. Structural valve deterioration (SVD) was less frequent in SE-THV compared with BE-THV and SAVR (HR 0.14, 95% CI 0.07 to 0.27; HR 0.34, 95% CI 0.24 to 0.47, respectively). Total moderate-severe aortic regurgitation and reintervention was more frequent in BE-THV (HR 4.21, 95% CI 2.40 to 7.39; HR 2.22, 95% CI 1.16 to 4.26, respectively), and SE-THV (HR 7.51, 95% CI 3.89 to 14.5; HR 2.86, 95% CI 1.59 to 5.13, respectively) compared with SAVR. In conclusion, TAVI with SE-THV demonstrated favorable forward-flow hemodynamics and lowest risk of SVD compared with BE-THV and SAVR at mid-term. However, both THV systems suffer an increased risk of AR and re-intervention, and long-term data from newer generation valves is warranted.

The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals.

Circulating phosphate levels are tightly controlled within a narrow range in mammals. By using a novel small-molecule inhibitor, we show that the enzymatic activity of inositol hexakisphosphate kinases (IP6K) is essential for phosphate regulation in vivo. IP6K inhibition suppressed XPR1, a phosphate exporter, thereby decreasing cellular phosphate export, which resulted in increased intracellular ATP levels. The in vivo inhibition of IP6K decreased plasma phosphate levels without inhibiting gut intake or kidney reuptake of phosphate, demonstrating a pivotal role of IP6K-regulated cellular phosphate export on circulating phosphate levels. IP6K inhibition-induced decrease in intracellular inositol pyrophosphate, an enzymatic product of IP6K, was correlated with phosphate changes. Chronic IP6K inhibition alleviated hyperphosphataemia, increased kidney ATP, and improved kidney functions in chronic kidney disease rats. Our results demonstrate that the enzymatic activity of IP6K regulates circulating phosphate and intracellular ATP and suggest that IP6K inhibition is a potential novel treatment strategy against hyperphosphataemia.