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Aims This study aimed to elucidate the long‐term effect of cibenzoline therapy on cardiovascular complications and prognosis in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods and results Eighty‐eight patients with HOCM were treated with cibenzoline (Group A), and 41 patients did not receive cibenzoline (Group B). The changes in left ventricular (LV) remodelling, incidences of cardiovascular complications and deaths, were examined. The mean follow‐up period was 15.8 ± 5.6 years in Group A and 17.8 ± 7.2 years in Group B. In Group A, the LV pressure gradient (LVPG) decreased immediately after treatment, and the reduction was maintained throughout the study. In Group B, the LVPG decreased gradually according to the deterioration of LV function. LV reverse remodelling was confirmed in Group A, and LV remodelling advanced in Group B. In Group A, the incidence of each cardiovascular complication was

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

To defend energy homeostasis in the cold requires energy expenditure (to support thermogenesis) and energy intake increase, enabling core temperature to be maintained with no change to body fat stores. When acutely housed at a mild cold (14°C) , mice increase both food intake and heat production rapidly (∼minutes) , and these responses occur in parallel. We hypothesized a role for Agouti-related peptide (AgRP) neurons in this response and find their activity is regulated by thermal sensory input, and they increase activity, measured by Fos induction and fiber photometry, upon cold sensation, and reduce activity as sensed temperatures rise. By inhibiting AgRP neurons during acute cold exposure, we also find this increase in AgRP neuron activity is required for the hyperphagic response to cold. Recent evidence found high-fat diet (HFD) feeding reduced AgRP neuron responsiveness to gastric hormones and standard chow diet presentation, and we hypothesized that their response to thermal input might also be blunted. We find that although 12-week HFD-fed mice exhibit intact thermogenic responses to cold and defend a normal core body temperature, they fail to increase energy intake and consequently experience weight loss not observed in chow-fed controls. This uncoupling of energy intake from energy expenditure is present even after a shorter, 2-week exposure to HFD-feeding, implying a role for diet separate from obesity in the phenotype. Using Agrp-Cre/GFP marker mice, we find acute cold exposure rapidly induces Fos in chow-fed mice, but this response is lacking in HFD-fed mice. This effect correlates with a failure to increase hypothalamic Agrp mRNA even after five days of mild cold exposure. Using photometry to measure AgRP neuron calcium activity, we find activity changes associated with thermal input, both cold and warm, are blunted with HFD feeding. Further testing will determine exactly how the food intake response to cold has become uncoupled from other thermoregulatory responses across the development of obesity. Disclosure J.D.Deem: None. T.P.Doan: None. B.N.Phan: None. K.Ogimoto: None. S.J.W.Hu: None. B.Wu: None. M.W.Schwartz: None. G.J.Morton: Research Support; Novo Nordisk A/S. Funding American Diabetes Association (1-19-PDF-103) ; NIDDK (K01 DK126793) , NIDDK (DK089056) , NIDDK (DK124238) , NIDDK (DK035816) , NIDA (P30 DA048736) , NIDDK (DK035816) , NIDDK (DK17047)

Importance: Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated. Objective: To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial. Design, Setting, and Participants: This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (

Aims This study aimed to evaluate the changes in left ventricular remodelling with time in patients with hypertrophic cardiomyopathy (HCM) using thallium‐201 myocardial scintigraphy. Methods and results Forty‐eight patients with HCM participated in the study. The extent score (ES) and a newly devised index termed the ‘mean count change’ (MCC) were used to evaluate the myocardial perfusion defects. Using the amount of thallium‐201 uptake (TU), MCC (%) was calculated using the following formula: (last TU − initial TU)∕initial TU × 100. To confirm the site of the lesion, the left ventricle was divided into five segments: anterior, septal, inferior, lateral, and apex. Cardiovascular complications and deaths were recorded. The mean follow‐up period was 8.6 ± 2.0 years. ES increased from 17.4 ± 13.7% to 44.0 ± 22.3% (P

Background We previously reported that PD-L1 polymorphisms are associated with the efficacy and immune-related adverse events of PD-1 blockade with nivolumab. However, the association between PD-L1 polymorphisms and survival outcomes under PD-1/PD-L1 blockade is still uncertain. Here, we aimed to investigate whether PD-L1 polymorphisms are associated with survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab. Methods PD-1/PD-L1 polymorphisms and survival outcomes were retrospectively analysed in two independent cohorts (133 patients treated with nivolumab and 96 patients with no treatment history of an immune checkpoint inhibitor (ICI) (the non-ICI cohort)) with advanced NSCLC. Results Among the 7 studied single-nucleotide polymorphisms, PD-L1 rs822339 and rs1411262 were associated with overall survival (OS) in patients treated with nivolumab. Patients with the A/A genotype of rs822339 had a significantly longer OS than those with A/G or G/G genotypes (not reached versus 12.0 months; hazard ratio (HR), 0.35; 95% confidence interval (CI), 0.18–0.64; p = 0.0008). A similar survival benefit with the A/A genotype was observed regardless of driver mutation status. In multivariate analysis, performance status (PS) and PD-L1 rs822339 genotype were independent prognostic factors for OS. In the non-ICI cohort, the PD-L1 rs822339 genotype did not correlate with OS (HR, 0.77; 95% CI, 0.31–1.70; p = 0.55). The T/T genotype of rs1411262 also showed a significant prolongation of OS compared to that with the C/T or C/C genotypes in patients treated with nivolumab. Conclusions PD-L1 polymorphisms are associated with favourable OS in nivolumab-treated NSCLC patients and may be useful predictive biomarkers, regardless of driver mutation status.

Immune checkpoint therapy (ICT) with nivolumab has been widely used to treat malignant pleural mesothelioma (MPM) since clinical trials confirmed its efficacy. However, only a few clinical trials have been conducted for the treatment of sarcomatoid MPM, which is a rare histological type of MPM. Additionally, clinical reports of sarcomatoid MPM are scarce. Therefore, the benefits and risks of nivolumab treatment for sarcomatoid MPM remain unclear. The present report describes the treatment of 3 cases of sarcomatoid MPM (all 3 were men) with nivolumab monotherapy. In all three cases, nivolumab was effective despite variations in the duration of treatment, although side effects were observed in 2 patients. Programmed death ligand 1 (PD-L1) expression was positive in all 3 cases. In particular, the patient with the highest PD-L1 expression had the most rapid response of the 3 patients, and the effect lasted as long as those of the other 2, despite receiving the smallest number of doses of nivolumab. It has been reported that sarcomatoid MPM tends to respond poorly to chemotherapy and express higher levels of PD-L1 than epithelial MPM; thus, ICT may be necessary in these cases. This case series suggests that ICT with nivolumab is a promising treatment option for sarcomatoid MPM.

It is unclear whether afterload mismatch occurs during the initial stage of essential hypertension (EHT). Additionally, critical left ventricular hypertrophy (LVH) between preserved and reduced systolic functions in hypertension is also unclear. Thus, we aimed to clarify these points.Forty-five normal control subjects (NCS) and 140 EHT patients participated. EHT patients were subdivided into three groups: group I, without LVH (n = 37); group II, with LVH (n = 80); and group III, with LVH and LV heart failure (LVHF) (n = 23). Routine electrocardiographic and echocardiographic parameters, V5R/V6R ratio, relative wall thickness (RWT), LV mass (LVM) index, and peak systolic wall stress (PSWS) were measured.In group I, LV systolic functions were preserved despite the increase of PSWS. In group II, LVH advanced, but LV systolic functions remained normal. A negative T-wave was observed in 69% of group II and 100% of group III. A significant correlation between RWT and LVM index was seen in NCS and groups I and II (rAfterload mismatch did not occur in group I, but it was observed in group III due to the exhaustion of preload reserve.

Japan has been experiencing a rapid deployment of photovoltaics (PVs) since the Feed-In Tariff (FIT) Scheme for Renewable Energy was launched in July 2012 . The increasing penetration levels of variable renewable generation, especially PVs and wind, have been affecting power system operations in each of Japan's 10 balancing areas. To accommodate this rapid growth in variable generation, the government established the Working Group on Grid Connection of Renewable Energy in 2014 to continually discuss and make timely decisions about these operational issues, including capacity connections, operation enhancement and asset improvement in each balancing area, and inevitable curtailment procedures for renewable generation.

BACKGROUNDS The relative apical sparing pattern (RASP) of left ventricular (LV) longitudinal strain (LS) is frequently associated with cardiac amyloidosis (CA). However, the visual assessment of RASP is inconsistent, and the quantitative assessment of RASP is time-consuming. This study aimed to compare assessments of RASP for the identification of CA with conventional assessments and investigate their reproducibility and relevance on the assessments. METHODS Forty patients with biopsy-proven CA were compared with 80 hypertrophied patients matched for mean LV wall thickness. We compared the discriminative abilities of three assessments of RASP to identify CA (visual, quantitative, and semiquantitative). Nine patterns of semiquantitative RASP were investigated; finally, it was defined as "reduction of LS" (≥ -10%) in ≥5 (of 6) basal segments, relative to "preserved LS" (

The objective of this study is to propose and evaluate a set of modifications to enhance a machine-learning-based method for forecasting day-ahead solar irradiation. To assess the proposed modifications, they were implemented in an initial forecast method, and their effectiveness was analyzed using two years of data on a national scale in Japan. In addition, the accuracy of the modified method was compared with one of the forecast methods for solar irradiation used by the Japan Meteorological Agency (JMA), namely, the mesoscale model (MSM). Such forecasts were made publicly available only recently, which makes this study one of the first ones to compare them with machine-learning-based forecasts. The annual root-mean-square error (RMSE) of local forecasts of the JMA-MSM varied from 0.1 to 0.14 kW h m−2; the regional equivalent varied from 0.062 to 0.091 kW h m−2. In comparison with these results, the modified model achieved an average RMSE reduction of 7.5% on the local scale and 16% on the regional scale. The modified model also had a skill score that was 23% higher than that of the JMA model. Furthermore, the performance of the JMA model had strong spatial and seasonal dependencies, which were reduced in the machine-learning-based forecasts. The results show that the proposed modifications are effective in reducing large forecasts errors, but they cannot compensate for situations in which the input data used to make the forecasts are highly inaccurate.

日本人における、野菜摂取の認知症罹患に対する効果を総括するために、システマチックレビューとメタアナリシスを行った。野菜接種を曝露として認知症の罹患または有病のリスクを報告しているものは3件しかなかった。これらのリクス比の固定効果モデルによる加重平均値は0.78で統計学的にも有意に1.0よりも小さかった。研究相互の不均一性は統計学的には明らかではなく、日本人における研究でも野菜摂取が認知症のリスクを抑制するものと考えられる。ただし、使用できた研究報告はエビデンスレベルが高くなく、また曝露情報にバイアスが影響している可能性があるものもあり、より多くの追跡研究による報告に基づく見当が必要と考えられる。国内では、複数の大きなコホート研究が実施されている。これらから、野菜摂取を含む形の食品摂取習慣、あるいは食品摂取パターンによる認知症リスクの報告は見られるが、単独の食品（群）としての野菜の寄与を評価できるデータはまだ少ない。生活習慣からの予防の可能性を明らかにするために、このような視点からの解析や報告が進められることが重要であると思われる。

Wilson病における銅の摂取制限は、理論的には有効であることが推察されるが、実施方法は確立しておらず、効果に関する臨床研究も報告されていない。今回、日本食品標準成分表2015年版をもとに、含まれる銅とそのほかのミネラルの量を網羅的に比較した。これにより摂取回避や代替により銅とともに減る他のミネラルの給与量を推定した。単位重量当たりの銅含有量の高い食品は、ほたるいか、牛肝臓、干しえび、ピュアココア、しゃこ、さくらえび、湯葉、エスカルゴ、いいだこ、かき、紅茶、バジル、えごまなどであった。次に、代表的な食品146品目を選定し、１回に標準的に食される量を仮定した。その結果、銅含有量は、牛肝臓（2.65mg/50g）が極端に多く、次いで、こういか（0.56mg/125g）、豚肝臓（0.50mg/50g）、まだこ（0.45mg/150g）、牡蠣（0.45mg/50g）、干しそば（0.34mg/100g）、だいず（0.32mg/30g）、さつまいも（0.31mg/180g）、あずきあん（0.28mg/120g）、ミルクチョコレート（0.28mg/50g）であった。したがって、銅給与の目標が1.0mg/ 日以下の場合、牛肝臓は避けなければならないが、牡蠣や大豆製品は、週１回以下であれば給与可能であると考えられた。銅の給与を0.6mg/ 日（12歳以上の女性の推定平均必要量に相当）以下にするには、主食の穀類、種実類が制限され、日本人の食事摂取基準を満たす献立は困難であることが推察された。次に、特定の食品の制限により減少する他のミネラルに関する相関散布図を作成した。その結果、使用しないこと、あるいは、献立から排除することにより、銅とともにその他のミネラルの給与も大きく減る食品、および、銅制限食において除去の対象とはならない食品の中で、銅以外のミネラルを効率よく（あるいは過剰に）給与するものを視覚的に判別できた。相関散布図による表示は、銅制限食の食事設計において、栄養価計算にいたる前の食材選択の幅を広げるものと考えられる。

It is essential to secure flexible resources in power systems to increase the proportion of variable renewable energy generation systems. One flexible resource is demand response (DR) of the batteries of electric vehicles (EVs). In this study, we propose an electric vehicle driving simulator using the Markov chain Monte Carlo (MCMC) method and an EV demand response evaluation model. The former is a highly versatile EV driving simulator that can produce a random driving pattern based on actual EV fleet data, taking into account various features. The latter is a residential DR evaluation model that minimizes a household electricity bill based on the simulated fleet data and enables realistic DR operation using three processes: forecasting, planning, and operation. The contribution of this paper is to enable evaluation of realistic EV battery value in various housing and EV utilization combinations. We found that the EV battery control provides an economic benefit of US$62 (5% of the night-charging case cost) with only charge control and US$370 (31%) with charge and discharge control, as the average expected value based on our assumption of evaluation. Because 40-kWh EV batteries have a sufficiently large capacity to store surplus power from a rooftop PV, they can be operated by determining the operation schedule based on a fixed-fee structure without forecasting or planning.

Although serum uric acid (UA) is considered as a risk factor for cardiovascular disease, few data exist regarding the relationship between hyperuricemia, coronary blood flow, and subsequent outcome in patients with acute myocardial infarction (AMI). The purpose of our study is to assess whether hyperuricemia is associated with suboptimal coronary flow and increased risk of mortality in patients with AMI after percutaneous coronary intervention (PCI).Using the Rural AMI registry data, 989 consecutive patients with AMI who underwent emergent PCI and had UA measurement at admission were analyzed. We defined hyperuricemia as serum UA ≥7.0 mg/dL in men and ≥ 6.0 mg/dL in women. The primary endpoint was suboptimal coronary flow, defined as post PCI Thrombosis In Myocardial Infarction flow grade ≤ 2. The secondary outcome was in-hospital mortality.Hyperuricemia was found in 249 (25.2%) patients. Patients with hyperuricemia were more often complicated with cardiogenic shock compared with those without (16.9% vs. 7.4%, p 0.001). In addition, the median high-sensitivity C-reactive protein was significantly higher in patients with hyperuricemia (0.18 mg/dL; IQR, 0.09-0.71 mg/dL) than in those without (0.14 mg/dL; IQR, 0.07-0.41 mg/dL, p 0.05). Under these conditions, the prevalence of suboptimal coronary flow after PCI (17.3% vs. 10.1%, p 0.05) and in-hospital mortality (10.8% vs. 3.6%, p 0.001) were significantly higher in patients with hyperuricemia compared with those without. Multivariable logistic regression analysis revealed that hyperuricemia was significantly associated with suboptimal coronary flow [odds ratio (OR), 1.60; 95% confidence interval (CI), 1.02-2.49; p 0.05] and in-hospital mortality (OR, 2.08; 95% CI, 1.05-4.12; p 0.05).Assessment of serum UA upon admission provides useful information for predicting suboptimal coronary flow and in-hospital mortality in patients with AMI undergoing PCI.

BACKGROUND Improvements in the Short Physical Performance Battery (SPPB) rather than exercise tolerance reportedly lead to favorable prognosis in elderly patients with acute decompensated heart failure (ADHF). However, about 50% of heart failure shows heart failure with preserved ejection fraction, safe and effective interventions to improve SPPB for these types remain unclear. In addition, although a standard cardiac rehabilitation (CR) program for heart failure is widely used in Japan, whether this is sufficient to improve SPPB in elderly patients with ADHF remains unclear. AIM This study was to evaluate whether the addition of multidisciplinary physical interventions to the standard CR program would prove effective for improving SPPB among elderly patients with ADHF regardless types of heart failure. DESING Randomized, prospective study. SETTING Patients admitted to our hospital due to ADHF in Japan. POPULATION Elderly patients with ADHF between March 2019 and March 2020 were randomized to two groups, an Intervention group and a Control group. METHODS The Control group performed standard CR. The Intervention group received balance training and resistance training and used a cycling ergometer in addition to the standard CR program. The primary outcome was the improvement in SPPB after CR. RESULTS Seventy-five patients with ADHF were divided into the two groups (Intervention group, n=36; Control group, n=39). At baseline, both groups showed low physical performance and a high prevalence of frailty. Intervention size effect was an improvement in SPPB score of +2.2 (+3.7±1.1 vs. +1.5±1.7; p