Syntheses of Aryl Thioethers via Aromatic Substitution of Aryl Halides at 0 to 25 °C.

In this study, we developed mild conditions for the synthesis of an aryl thioether via aromatic substitution using aryl halides, which is a process that has rarely been studied. Aromatic substrates such as aryl fluorides activated with a halogen substituent are difficult to use for substitution reactions, but by using 18-crown-6-ether as an additive, these were successfully converted to their corresponding thioether products. Under the conditions we established, in addition to a wide variety of thiols, less-toxic and odorless disulfides could be used directly as nucleophiles at 0 to 25 °C.

Diffuse neutrino background from past core collapse supernovae.

Core collapse supernovae are among the most powerful explosions in the Universe, which emit thermal neutrinos that carry away most of the gravitational binding energy released. These neutrinos produce a diffuse supernova neutrino background (DSNB), which is one of the largest energy budgets among all radiation backgrounds. Detecting the DSNB is an important goal of modern high-energy astrophysics and particle physics, which provides valuable insights into core collapse modeling, neutrino physics, and cosmic supernova rate history. In this review, the key ingredients of DSNB calculation and what can be learned from future detections, including black hole formation and non-standard neutrino interactions are discussed. Moreover, an overview of the latest updates in neutrino experiments, which could lead to the detection of the DSNB in the next decade, is provided. With the promise of this breakthrough discovery on the horizon, the study of DSNB has great potential to further our understanding of the Universe.

Etherification via Aromatic Substitution on 1,3-Disubstituted Benzene Derivatives.

In this study, we developed a method for etherification via aromatic substitution at the ipso-position of an electron-withdrawing group (EWG) that exists at the meta-position of another EWG. To heighten the reactivity of the substitution reaction, we added a t-BuOK solution in tetrahydrofuran (THF) to a mixture of an aromatic substrate, an alcoholic nucleophile, and 18-crown-6-ether in dimethylformamide (DMF), which proved to be a particularly effective sequence. Under the conditions we established, aromatic substrates that are difficult to use for substitution reactions such as aryl fluorides activated with either a bromide or a chloride substituent were aptly converted to corresponding ether products at 25 °C. This reaction would potentially be useful to link an alcohol to an additional functional group through further chemical transformations via the use of a residual bromide or chloride substituent.

Relationship between Restless legs syndrome associated symptoms and presence of depression during pregnancy.

Restless legs syndrome (RLS) is associated with depression in the general population. Although depression can lead to adverse events during the perinatal period, the association between RLS and depression remains under debate. Thus, we examined the association between depression and RLS, including RLS-associated symptoms, in pregnant women. We evaluated the presence of RLS and RLS-associated symptoms in 135 pregnant women using questionnaires on RLS symptoms based on Allen's symptoms and the International Restless Legs Syndrome Rating Scale (IRLS), respectively. We defined RLS as 4/4 on Allen's symptoms. Depressive status was evaluated using the Edinburgh Postnatal Depression Scale. The mean±SD of age was 31.8 ± 4.3 years, and none of the participants had a family history of RLS. Ten percent of women had depression during their pregnancy and demonstrated higher IRLS scores than those without depression (6.1 ± 10.5 vs. 0.7 ± 3.8 points, P = 0.001). A significant association between IRLS score, including its subscales, and depression was observed, even after adjusting for confounders. It was concluded that RLS-associated symptoms may be indicators of depression during pregnancy. Comprehensive sleep evaluations and examinations of RLS-associated symptoms are needed to improve psychiatric health during pregnancy.

Successful Total Management of Multi-Causative Sleep-Disordered Breathing Complicated with Patient with Adult Congenital Heart Disease.

Sleep-disordered breathing is one of the complications commonly seen in patients with adult congenital heart disease (ACHD) due to multiple causes including complex underlying cardiac defects, cardiomegaly, previous thoracotomies, obesity, scoliosis, and paralysis of the diaphragm. It is often hard to determine its main cause and predict the efficacy of each treatment in its management. We herein report a 30-year-old woman after biventricular repair of pulmonary atresia with intact ventricular septum diagnosed as sleep-related hypoventilation disorder. Simultaneous treatment targeting obesity, paralysis of the diaphragm, and cardiomegaly followed by respiratory muscle reinforcement through non-invasive ventilation resolved her sleep-related hypoventilation disorder. Such management for each factor responsible for the hypoventilation is expected to provide synergetic therapeutic efficacy and increase daily activity in a patient with ACHD.

Changes in lung to finger circulation time measured via cardiopulmonary polygraphy in patients with varying types of heart disease.

Cardiopulmonary polygraphy (PG) demonstrates not only parameters for sleep disordered breathing (SDB) but also hemodynamics. We previously developed a software that detects lung to fingertip circulation time (LFCT) derived from PG dataset and reported that those LFCT reflected the cardiac output. The purpose of this study is to investigate how the LFCT changes during clinical course and whether reflects the impact of in-hospital treatment on cardiac function. Consecutive patients (N = 89) who admitted to the cardiovascular division, underwent PG at the early and late phase of admission. Parameters for SDB and LFCT were compared between an acute decompensated heart failure (ADHF) group (n = 51) and non-ADHF group (n = 38). ADHF group was further divided into subgroups: preserved ejection fraction (pEF) (EF > 40%) and reduced EF (rEF) (EF ≤ 40%). Using our original algorithm, we obtained LFCT values from all of the patients, though 29.4% of ADHF and 44.7% of non-ADHF had no or mild SDB. LFCT significantly shortened in the ADHF-rEF group, in contrast to ADHF-pEF group or non-ADHF group (ADHF-rEF group: 26.9 ± 7.6 to 24.2 ± 6.1 s, p = 0.01; ADHF-pEF group: 25.3 ± 7.3 to 25.3 ± 6.9 s, p = 0.98; non-ADHF group: 21.5 ± 5.5 to 21.9 ± 5.0 s, p = 0.65). The respiratory disorder index in the ADHF group improved after treatment, irrespective of EF (pEF: 26.9 ± 16.1 to 15.8 ± 11.9/h, p < 0.01; rEF: 27.0 ± 16.5 to 20.7 ± 13.6/h, p = 0.03). Automatic detection of LFCT was feasible in almost all cardiac patients. LFCT value changed according to the heart failure treatment in ADHF-rEF patients and reflected cardiac function. LFCT might be a useful indicator of effective cardiac disease treatment.

Aryl Ether Syntheses via Aromatic Substitution Proceeding under Mild Conditions.

In this study, mild conditions for aromatic substitutions during the syntheses of aryl ethers were developed. In the reaction conditions, the choices of solvent, base, and the sequence for the addition of the reagents proved important. A wide variety of alcohols were used directly as nucleophiles and smoothly reacted with aryl chlorides that possessed either a nitro or a cyano group at either the ortho- or para-position. Controlled experiments we performed suggested that the reaction underwent a charge-transfer process mediated by a combination of DMF and tert-BuOK.

Accumulated nocturnal hypoxemia predict arterial endothelial function in patients with sleep-disordered breathing with or without chronic heart failure.

ABTSRACT: Sleep-disordered breathing (SDB) is often accompanied with the chronic heart failure (CHF). Hypoxemia due to pulmonary congestion from CHF and concurrent SDB might synergistically impair endothelial function and worsen the prognosis. However, the main factors affecting deterioration of endothelial function are unknown and whether the influence of hypoxemia differs in SDB patients with and without CHF remains unclear. Fifty-three patients (CHF group, n = 23; non-CHF group, n = 30) underwent polysomnography to evaluate their SDB and flow-mediated vasodilation (FMD) measurements to assess arterial endothelial function. We examined the relationships between FMD and SDB-related parameters, including our original index of accumulated hypoxemia by SDB throughout one-night sleep: the time desaturation summation index (TDS), calculated as follows: (100% - averaged arterial oxygen saturation during sleep) × total sleep time. The mean age in the CHF and non-CHF groups was 59.0 ± 13.5 and 57.7 ± 11.4 years, respectively. Although the FMD in the 2 groups were not significantly different, well-known adverse factors for FMD such as serum lipid profiles, blood pressure levels, and conventional indices of SDB were worse in the non-CHF group. Only the TDS was not significantly different between 2 groups and associated with FMD as shown by the univariate analysis (CHF: p < 0.05, non-CHF: p < 0.01) and multivariate analysis (CHF: p < 0.05, non-CHF: p < 0.01). Accumulated hypoxemia (TDS) rather than the frequency of hypoxemia might more influence on the endothelial function irrespective of the cardiac state. Removal of accumulation of nocturnal hypoxemia might be a target for treatment equally in the patients with and without CHF.

Factors limiting habitual exercise in patients with chronic heart failure: a multicenter prospective cohort study.

Physical activity (PA) in the daily life is strongly related to prognosis in patients with or at high risk of heart failure (HF). However, factors limiting habitual exercise and their prognostic impacts remain unknown in HF patients. We sent questionnaires asking factors limiting habitual exercise in the daily life to 8370 patients with Stage A/B/C/D HF in our nationwide registry and received valid responses from 4935 patients (mean age 71.8 years, 71.0% male). Among the 5 components consisting of "busyness", "weak will", "dislike, "socioeconomic reasons" and "diseases" in the questionnaires, "busyness" (34.5%) and "diseases" (34.7%) were the most frequently reported factors limiting habitual exercise, while "socioeconomic reasons" were the least (15.3%). Multiple Cox proportional hazard models indicated that "busyness"and "diseases" were associated with better (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.39-0.72, P < 0.001) and worse prognosis (HR 1.57, 95% CI 1.21-1.98, P < 0.001), respectively, while other components were not. Furthermore, it was noted that, while prognostic relevance of "busyness" limiting exercise did not differ by age or sex, negative impact of "diseases" was particularly evident in patients with age < 75 years (P for interaction < 0.01). Factors limiting habitual exercise were associated with "busyness" and "diseases", but not with "weak will", "dislike, or "socioeconomic reasons". While "busyness" was associated with better prognosis regardless of age and sex, "diseases" was associated with worse prognosis in younger populations. Thus, physicians may pay more attentions to the reasons that limit exercise in the daily lives of HF patients rather than the low amount of exercise itself.

Influences of Phenyl Rings on NHC Ligands with Bicyclic Architectures.

In addition to phosphanes, olefins, amines, and amides, over the past two decades N-heterocyclic carbene (NHC) has emerged as a useful alternative ligand. Based on a number of derivatization studies on NHC ligands, imidazol-2-ylidene and imidazolin-2-ylidene became the standard heterocyclic form, and bulky substituents have commonly been introduced on the nitrogen(s) adjacent to carbenic carbons. Our group previously developed NHCs equipped with noncarbenic carbons with a bicyclic architecture that gives them unique steric properties that make them bulky but accessible. In this study, we synthesized a novel type of NHC ligand that possesses a bicyclo[2.2.1]heptane architecture, and we compared five derivatives using copper-catalyzed allylic arylations with aryl Grignard reagents. The regioselectivity of the substitution obviously indicates that a phenyl ring over an active site has a characteristic effect on the resultant copper catalysts when γ-substitution is the major pathway.

Crossover comparison between CPAP and mandibular advancement device with adherence monitor about the effects on endothelial function, blood pressure and symptoms in patients with obstructive sleep apnea.

Mandibular advancement device (MAD) is an alternative therapeutic option for CPAP to treat obstructive sleep apnea (OSA). While MAD showed the better adherence, patients with over moderate OSA have been treated more frequently with CPAP despite increasing positive evidence on the cardiovascular outcome with MAD, even in severe patients. Thus, more information is needed regarding the cardiovascular and symptomatic outcome of MAD treatment objectively compared to CPAP. Forty-five supine-dependent OSA patients (apnea-hypopnea index 20-40/h) were randomized to either CPAP or MAD and treated for 8 weeks and switched to another for 8 weeks. The primary endpoint was improvement in the endothelial function, indexed by the flow-mediated dilatation (FMD), and the secondary endpoint was the sleep-time blood pressure (BP). The duration of MAD use was evaluated objectively by an implanted adherence monitor. Treatment efficacy was also evaluated by home sleep monitor and a questionnaire about the symptoms. The adherence was not significantly different (CPAP vs. MAD: 274.5 ± 108.9 min/night vs. 314.8 ± 127.0 min/night, p = 0.095). FMD and sleep-time mean BP were not markedly changed from the baseline with either approach (CPAP vs. MAD: FMD, + 0.47% ± 3.1% vs. + 0.85% ± 2.6%, p = 0.64; BP, - 1.5 ± 5.7 mmHg vs. - 1.2 ± 7.5 mmHg, p = 0.48), although sleepiness, nocturia, and sleep-related parameters were similarly improved and more patients preferred MAD. As MAD and CPAP showed similar effects on cardiovascular outcome and symptomatic relief even with a comparable length of usage, we might expect MAD as an alternative treatment option for CPAP in this range of OSA group.

Multicenter, Prospective Study on Respiratory Stability During Recovery From Deterioration of Chronic Heart Failure.

BACKGROUND: The respiratory instability frequently observed in advanced heart failure (HF) is likely to mirror the clinical status of worsening HF. The present multicenter study was conducted to examine whether the noble respiratory stability index (RSI), a quantitative measure of respiratory instability, reflects the recovery process from HF decompensation. Methods and Results: Thirty-six of 44 patients hospitalized for worsening HF completed all-night measurements of RSI both at deterioration and recovery phases. Based on the signs, symptoms, and laboratory data during hospitalization, the Central Adjudication Committee identified 22 convalescent patients and 14 patients with less extent of recovery in a blinded manner without any information on RSI or other respiratory variables. The all-night RSI in the convalescent patients was increased from 27.8±18.4 to 34.6±15.8 (P<0.05). There was no significant improvement of RSI, however, in the remaining patients with little clinical improvement. Of the clinical and laboratory variables, on stepwise linear regression modeling, body weight, peripheral edema, and lung congestion were closely related to the RSI of recovered patients and accounted for 56% of the changes in RSI (coefficient of determination, R2=0.56). CONCLUSIONS: All-night RSI, a quantitative measure of respiratory instability, could faithfully reflect congestive signs and clinical status of HF during the recovery process from acute decompensation.

Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan　- Insights From GARFIELD-AF.

BACKGROUND: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. CONCLUSIONS: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Three nights leg thermal therapy could improve sleep quality in patients with chronic heart failure.

Sleep quality is often impaired in patients with chronic heart failure (HF), which may worsen their quality of life and even prognosis. Leg thermal therapy (LTT), topical leg warming, has been shown to improve endothelial function, oxidative stress, and cardiac function in patients with HF. However, its short-term influence to sleep quality has not been evaluated in HF patients. Eighteen of 23 patients with stable HF received LTT (15 min of warming at 45 °C and 30 min of insulation) at bedtime for 3 consecutive nights and 5 patients served as control. Subjective sleep quality was evaluated by St. Mary's Hospital Sleep Questionnaire, Oguri-Shirakawa-Azumi Sleep Inventory, and Epworth sleepiness scale, and also objectively evaluated by polysomnography. LTT significantly improved subjective sleep quality indicated by depth of sleep (p < 0.01), sleep duration (p < 0.05), number of awaking (p < 0.01), nap duration (p < 0.01), sleep quality (p < 0.05), and sleep satisfaction (p < 0.05). It was also objectively affirmed by a slight but significant decrease of sleep stage N1 (p < 0.01), and increase in sleep stage N2 (p < 0.05). No significant changes occurred in the controls. Hence, the short-term LTT could improve subjective and objective sleep quality in patients with HF. LTT can be a complimentary therapy to improve sleep quality in these patients.

An N-Heterocyclic Carbene-Nickel Half-Sandwich Complex as a Precatalyst for Suzuki-Miyaura Coupling of Aryl/Heteroaryl Halides with Aryl/Heteroarylboronic Acids.

A nickel half-sandwich complex supported by our original NHC ligand was developed as a robust precatalyst for Suzuki-Miyaura cross-coupling. The addition of PPh3 was a crucial element in the suppression of side reactions and in accelerating the cross-coupling reaction. By employing the optimal conditions, aryl-aryl, heteroaryl-aryl, and heteroaryl-heteroaryl couplings were achieved.

A dramatic synergistic effect of a flexible achiral linker on a rigid chiral cis-1,2-diamine bifunctional organocatalyst.

The combination of a "rigid" chiral bicyclic cis-1,2-diamine skeleton with steric bulkiness and a "flexible" achiral linker was newly designed as a bifunctional organocatalyst framework and it showed excellent catalytic activity of up to 0.05 mol%, accompanied by the reversal of enantioselection depending on the position of the linker, in an amine-thiourea organocatalyzed asymmetric Michael reaction.

Seasonal ambient changes influence inpatient falls.

Background: falls by inpatients often result in serious injuries and deterioration in a patient's physical abilities and quality of life, especially among older individuals. Although various factors have been found to be associated with falls, the combined effects of behavioural and ambient factors are not fully evaluated. Objective: we investigated the influence of both behavioural and ambient factors on inpatient falls, focusing on seasonal and diurnal variations. Design: retrospective study. Methods: we surveyed the incident reports related to falls from April 2010 to March 2014 and examined the relationship between the incidents and seasonal and diurnal variations in behavioural and ambient factors, including the sunrise time, the night-time length and temperature. Results: we identified 464 fallers from 3,037 incident reports. The average fall-rate of the study population was 1.4 ± 0.5/1,000 occupied bed-days. The seasonal and diurnal variations in falls were compared. The number of falls around dawn in October-February was higher than that in April-September. Toileting was the behaviour most frequently related to the falls (56.9%, n = 264), and 57.1% of the falls occurred at night. A multivariate analysis showed that the night-time length was significantly related to an increase in night-time falls (P = 0.047). Conclusion: these results suggested that the inpatient falls increased in the early morning from November to March and tended to be related to toileting activities. Considering these results, additional attention and support during the higher risk hours and seasons, especially in relation to toileting activities, might help to reduce the incidence of falls. Clinical trial name, URL and registration number: N/A (Because of retrospective nature).

A Study of the Strength of a Template Molecule-A Functional Monomer Interaction That Affects the Performance of Molecularly Imprinted Polymers and Its Application to Chiral Amplification.

A novel type of molecularly imprinted polymer (MIP), N-benzoyl-(S)-valine anilide-imprinted polymer (IP-2), was prepared using hydrogen-bonding interactions as a main force in the pre-polymerization step. The performance of the IP-2 was evaluated via batch procedure and compared with a (S)-valine anilide-imprinted polymer (IP-1) that was prepared using an ionic interaction that is stronger than hydrogen bonding. Although both polymers showed a preferential adsorbability for (S)-amino acid derivatives, different performances were observed in terms of adsorbability and enantioselectivity. In addition, the IP-2 was able to recognize the enantiomer of a valine-derived chiral catalyst. This phenomenon was applied to a chiral amplification reaction, and a highly selective asymmetric Mannich-type amination was achieved using the combination of a racemic catalyst and a MIP.

A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures.

A major hurdle in stem cell therapy is the tumorigenic risk of residual undifferentiated stem cells. This report describes the design and evaluation of synthetic hybrid molecules that efficiently reduce the number of human induced pluripotent stem cells (hiPSCs) in cell mixtures. The design takes advantage of Kyoto probe 1 (KP-1), a fluorescent chemical probe for hiPSCs, and clinically used anticancer drugs. Among the KP-1-drug conjugates we synthesized, we found an exceptionally selective, chemically tractable molecule that induced the death of hiPSCs. Mechanistic analysis suggested that the high selectivity originates from the synergistic combination of transporter-mediated efflux and the cytotoxicity mode of action. The present study offers a chemical and mechanistic rationale for designing selective, safe, and simple reagents for the preparation of non-tumorigenic clinical samples.

Improved Accuracy of Automated Estimation of Cardiac Output Using Circulation Time in Patients with Heart Failure.

BACKGROUND: Lung-to-finger circulation time of oxygenated blood during nocturnal periodic breathing in heart failure patients measured using polysomnography correlates negatively with cardiac function but possesses limited accuracy for cardiac output (CO) estimation. METHODS AND RESULTS: CO was recalculated from lung-to-finger circulation time using a multivariable linear model with information on age and average overnight heart rate in 25 patients who underwent evaluation of heart failure. The multivariable model decreased the percentage error to 22.3% relative to invasive CO measured during cardiac catheterization. CONCLUSIONS: This improved automated noninvasive CO estimation using multiple variables meets a recently proposed performance criterion for clinical acceptability of noninvasive CO estimation, and compares very favorably with other available methods.