How Do Classical Subtypes Correspond to Endotypes in Atopic Dermatitis?

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European-American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed.

The single-base-pair deletion, MSH2 c.2635-3delC affecting intron 15 splicing can be a cause of Lynch syndrome.

The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.

Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan.

BACKGROUND: Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial. OBJECTIVES: To investigate the incidence and risk factors for HBV reactivation in patients with RD. METHODS: We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded. RESULTS: Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3-182 months; median, 66 months). CONCLUSIONS: The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

Catalytic Synthesis of Saturated Oxygen Heterocycles by Hydrofunctionalization of Unactivated Olefins: Unprotected and Protected Strategies.

A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex.

Depression and Outcomes in Japanese Outpatients With Cardiovascular Disease　- A Prospective Observational Study.

BACKGROUND: The aim of this study was to determine the prevalence of depression assessed by the 9-item test from the Patient Health Questionnaire (PHQ-9) and the effect of depression on adverse cardiovascular outcomes in Japanese outpatients with cardiovascular disease (CVD).Methods and Results:This prospective observational study enrolled 1,453 outpatients with CVD (mean age 67±13 years; 31.3% female; 32.6% ischemic heart disease). Depression was defined as a PHQ-9 score ≥10. The main composite outcome was the time to death from any cause or a cardiovascular event. 81 patients (5.6%) were diagnosed with depression (PHQ-9 ≥10). NYHA class III, living alone, and unemployment were independently associated with depression. During an average follow-up of 584±80 days, the main outcome occurred in 85 patients (5.8%). There was a higher incidence of the main outcome in patients with depression than in those without depression (P<0.001). Depression was an independent predictor of the primary outcome (hazard ratio 4.64, 95% confidence interval 2.24-9.09, P<0.001). CONCLUSIONS: Depression assessed by the PHQ-9 was found in 5.6% of Japanese outpatients with CVD and was an important risk factor for adverse outcomes. (UMIN-CTR No. UMIN 000023514) (Circ J 2016; 80: 2482-2488).

A Clinical Tissue Oximeter Using NIR Time-Resolved Spectroscopy.

The tNIRS-1, a new clinical tissue oximeter using NIR time-resolved spectroscopy (TRS), has been developed. The tNIRS-1 measures oxygenated, deoxygenated and total hemoglobin and oxygen saturation in living tissues. Two-channel TRS measurements are obtained using pulsed laser diodes (LD) at three wavelengths, multi-pixel photon counters (MPPC) for light detection, and time-to-digital converters (TDC) for time-of-flight photon measurements. Incorporating advanced semiconductor devices helped to make the design of this small-size, low-cost and low-power TRS instrument possible. In order to evaluate the correctness and reproducibility of measurement data obtained with the tNIRS-1, a study using blood phantoms and healthy volunteers was conducted to compare data obtained from a conventional SRS device and data from an earlier TRS system designed for research purposes. The results of the study confirmed the correctness and reproducibility of measurement data obtained with the tNIRS-1. Clinical evaluations conducted in several hospitals demonstrated a high level of usability in clinical situations and confirmed the efficacy of measurement data obtained with the tNIRS-1.

Seroprevalence of IgG1 and IgG4 class antibodies against Mycobacterium avium subsp. paratuberculosis in Japanese population.

Mycobacterium avium subsp. paratuberculosis (MAP) is the established causative agent of Johne's disease in cattle and other ruminants, and it has also been speculated to be a putative etiological agent of several human autoimmune diseases. It is acknowledged that dairy products deriving from infected animals play a role (could be vehicles) in exposing humans to MAP. MAP could stimulate the human immune system by means of their complex antigen (in the case of lipids, multivalent antigens) and may modulate it, acting as adjuvant molecules such as Freund's complete adjuvant. The immune system might be abnormally stimulated by the constant presence of MAP antigens (for example, in the dairy products), and this might be particularly relevant in genetically predisposed individuals. However, there is limited understanding about the current human exposure to MAP. The present study analyzed the antibody recognition profile of MAP lipophilic antigens in a cohort of 126 healthy Japanese. We measured the serum levels of total immunoglobulin G (IgG) and subclasses targeting MAP surface antigens through ethanol vortex indirect enzyme-linked immunosorbent assay (EVELISA) by using serum absorbed with Mycobacterium phlei. Elevated IgG (especially IgG1 and IgG4) responses were observed in 14% of the sera. To assess the specificity of EVELISA, the same samples were analyzed by means of a commercially available Johnelisa II kit. It was noteworthy that a high degree of correlation was observed when comparing the two methodologies (rs=0.7, p<0.0001). Moreover, in order to investigate the specificity of the binding, inhibition assay experiments were carried out also searching for antibodies against Bacillus Calmette-Guérin antigens, but no cross-reaction was observed. The result obtained represents the first evidence implying that the Japanese population is exposed to MAP, and additionally the existence of a foodborne chain of exposure that transmits MAP antigens to humans.

Different effects of an extended photoperiod treatment on growth, gonadal function, and condition of hair coats in Thoroughbred yearlings reared under different climate conditions.

One- to two-year-old Thoroughbred colts and fillies being reared in Miyazaki (warm climate) and Hidaka (cold climate), Japan, were administered extended photoperiod (EP) treatment between December 20 and the following April 10, and its effect on growth, endocrine changes, gonadal activation, and hair coat condition was investigated. In colts reared in Miyazaki, no effect of EP treatment was noted on the growth indices, including body weight (BW), height at withers (HW), girth, and cannon circumference (CC), whereas the BWs and CCs of fillies were significantly higher in the EP treatment group than the control. In Hidaka, the BWs and HWs of colts and HWs of fillies were significantly higher in the EP treatment group. Gonadal activation characterized by an increase in circulating hormone concentrations was earlier in the EP treatment group for fillies reared in Miyazaki [luteinizing hormone (LH), follicle-stimulating hormone (FSH), progesterone (P4), and estradiol-17ß (E2)] and in colts (LH, testosterone, and E2) and fillies (LH, FSH, P4, and E2) reared in Hidaka. Regardless of sex and climate, prolactin was significantly higher in the EP treatment group, whereas insulin-like growth factor (IGF-I) was not. Initial ovulation occurred before April in more of the EP treatment group than the control regardless of the climate. Molting of the hair coat, examined in March, was advanced in the EP treatment group regardless of sex and climate. These results suggest that EP treatment may promote growth and gonadal activation in fillies reared in Miyazaki and in colts and fillies reared in Hidaka and that the effect may be mediated by prolactin.

Comparison of growth and endocrine changes in Thoroughbred colts and fillies reared under different climate conditions.

Development and endocrine changes in Thoroughbreds colts and fillies were compared between those reared at two facilities of the Japan Racing Association, the Hidaka Training and Research Center (Hidaka) and Miyazaki Yearling Training Farm (Miyazaki). Thoroughbred colts and fillies born in Japan between 2003 and 2010 were used. Each colt group and filly group was divided into 2 groups, respectively, and raised in Hidaka or Miyazaki for 7 months from September at 1 year old to April at 2 years old. For the growth parameters, the body weight, height at withers, and girth and cannon circumferences were measured once a month. For parameters of endocrine function, circulating prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin-like growth factor-1 (IGF-1), testosterone, progesterone, and estradiol-17ß levels were measured. Regarding growth, the rate of increase over the 7-month period was significantly higher in both colts and fillies raised in Miyazaki than in Hidaka in all 4 parameters: body weight, height at withers, and girth and cannon circumferences. The endocrine changes of the colts and fillies born in 2007 were as follows. In colts, although circulating prolactin tended to be higher in colts reared in Hidaka from October to April, circulating LH, FSH, testosterone, estradiol-17ß and IGF-1 tended to be higher in colts reared in Miyazaki than in Hidaka, suggesting that the gonadotropin-releasing hormone-LH/FSH system and the growth hormone-IGF-1 system were more active in colts reared in Miyazaki as compared with those reared in Hidaka. In fillies, circulating prolactin tended to be higher in fillies reared in Hidaka in February and March, but no significant difference was noted in the serum LH, FSH, IGF-1, or progesterone level between the 2 groups. Circulating estradiol-17ß tended to be higher in fillies reared in Miyazaki than in Hidaka in October and November. Regarding ovarian function, the initial ovulation occurred by the end of March in 2 (16.7%) of 12 fillies reared in Hidaka and 7 (38.9%) of 18 fillies reared in Miyazaki, suggesting that the ovarian function was more active in fillies reared in Miyazaki as compared with those reared in Hidaka. Based on these findings, it was clarified that development of the body and gonads was faster in Miyazaki compared with Hidaka in both colts and fillies.

Impact of atrial remodeling on the outcome of radiofrequency catheter ablation of paroxysmal atrial fibrillation.

BACKGROUND: Both the left atrial volume index (LAVI) and estimated total atrial conduction time measured using tissue Doppler imaging of the atria (PA-TDI duration) are echocardiographic parameters reflecting atrial remodeling. We investigated their prognostic value for atrial tachyarrhythmia (AF/AT) recurrence after radiofrequency catheter ablation (RFCA) of paroxysmal atrial fibrillation (PAF). METHODS AND RESULTS: We analyzed the data for 100 consecutive patients with drug-refractory PAF who underwent RFCA. The correlation between the LAVI and PA-TDI was extremely weak (r=0.26, P<0.01). We categorized the patients into 4 groups based on the median LAVI and PA-TDI duration: group 1 (LAVI <29ml/m(2)/PA-TDI duration <143ms), group 2 (LAVI ≥29ml/m(2)/PA-TDI duration <143ms), group 3 (LAVI <29ml/m(2)/PA-TDI duration ≥143ms), and group 4 (LAVI ≥29ml/m(2)/PA-TDI duration ≥143ms). With a mean follow-up of 20.2±8.9 months after a single RFCA procedure, 60 patients (60%) were in sinus rhythm without any antiarrhythmic drugs. Multivariate analysis using a Cox proportional hazards model demonstrated that the group was an independent predictor of AF/AT recurrence after RFCA (P=0.0017). The patients in groups 2, 3, and 4 had a 4.0-fold (P=0.048), 6.8-fold (P=0.0034) and 10.9-fold (P=0.0001) increase, respectively, in the probability of recurrent AF/AT as compared with group 1. CONCLUSIONS: Preprocedural echocardiographic estimation of atrial remodeling was a useful predictor of AF/AT recurrence following a single RFCA of PAF.

Development of takotsubo cardiomyopathy with severe pulmonary edema before a cesarean section.

Takotsubo cardiomyopathy is an acute syndrome involving apical ballooning and consequent dysfunction of the left ventricle. Most cases of left ventricular dysfunction resolve within 1 month. We present the case of a 40-year-old woman who developed severe heart failure caused by takotsubo cardiomyopathy with severe left ventricular dysfunction during the perinatal period. Because of the presence of multiple myomas, she was scheduled to undergo a cesarean section under general anesthesia. However, after induction of general anesthesia, she had to be awakened because of the presence of a difficult airway. Because she exhibited insufficient oxygenation, she was transferred to the emergency center. Upon hospital admission, she expectorated large amounts of pink sputum, indicating severe pulmonary edema. Cesarean section was performed immediately. Echocardiography revealed severe left ventricular dysfunction. Full recovery of cardiac function required almost 1 month, after which she was discharged from the hospital without further complications. This is the first reported case of takotsubo cardiomyopathy induced by a failed intubation during a scheduled cesarean section. Takotsubo cardiomyopathy usually shows a good prognosis, but if this myopathy develops during the perinatal period, it can worsen because of excessive preload following the termination of fetoplacental circulation.

Natto (fermented soybeans)-induced anaphylaxis in a surfer with the possibility of sensitization to poly(γ-glutamic acid) from cutaneous exposure to jellyfish sting: a case report.

BACKGROUND: We report a case of anaphylaxis induced by natto (fermented soybeans) allergy that occurred following dermal sensitization from a jellyfish sting. CASE PRESENTATION: A 49-year-old male presented to the emergency room complaining of an acute onset of erythema with pruritis that appeared while he was surfing. Given that his heart rate dropped to ~ 40 bpm without a decline in blood pressure or oxygen saturation, we suspected anaphylaxis and administered 0.5 mg of adrenaline intramuscularly. Immediately after the muscular adrenaline injection, his heart rate recovered to ~ 60-70 bpm. CONCLUSIONS: The major allergen that induces natto allergy is poly(γ-glutamic acid) (PGA), which is present in its mucilage. Given that PGA is also produced by jellyfish tentacles, it can be inferred that the PGA sensitization occurred via dermal exposure to jellyfish PGA. This is an example of a food allergy induced by animal stings. As PGA is a high-molecular-weight polymer, natto allergy, despite being IgE-mediated, often presents with late-onset anaphylaxis, which typically develops half a day after digestion. PGA has a wide range of applications in pharmaceuticals, cosmetics, and foods. Patients may develop allergic symptoms and experience repeated anaphylaxis with no known cause. Therefore, it is important to obtain a detailed medical history and individually instruct patients suspected of being allergic to PGA to avoid PGA-containing products.

DiGeorge syndrome presenting with palmoplantar pustules: Comparative analysis of serum IL-22, NETs and IL-8 with usual palmoplantar pustulosis.

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, shows cellular immunodeficiency due to by thymic hypoplasia and hypocalcemia caused by hypoparathyroidism. It was reported that erythrodermic psoriasis occurred in a patient with 22q11 deletion syndrome. Here, we report the first case of DiGeorge syndrome presenting with a severe palmoplantar pustulosis (PPP)-like eruption with extra-palmoplantar lesions on the distal limbs. Given that PPP is a subtype of pustular psoriasis, the pustular eruption may be associated with DiGeorge syndrome. We measured serum levels of citrullinated histone H3 (CitH3), a representative marker of neutrophil extracellular traps, interleukin (IL)-8, and IL-22 and compared them with nine cases of typical PPP. In the PPP patients, the three markers were higher than in healthy subjects with significant correlations between CitH3 and IL-8/IL-22. In our patient, CitH3, IL-8, and IL-22 were also high, and IL-22 was remarkably elevated compared with the PPP patients. Our case suggests that a certain T cell abnormality associated with DiGeorge syndrome induces IL-22 overproduction, leading to the PPP-like eruption with extra- palmoplantar lesions.

From a zwitterionic phosphasilene to base stabilized silyliumylidene-phosphide and bis(silylene) complexes.

The reactivity of ylide-like phosphasilene 1 [LSi(TMS)═P(TMS), L = PhC(NtBu)2] with group 10 d(10) transition metals is reported. For the first time, a reaction of a phosphasilene with a transition metal that actually involves the silicon-phosphorus double bond was found. In the reaction of 1 with ethylene bis(triphenylphosphine) platinum(0), a complete silicon-phosphorus bond breakage occurs, yielding the unprecedented dinuclear platinum complex 3 [LSi{Pt(PPh3)}2P(TMS)2]. Spectroscopic, structural, and theoretical analysis of complex 3 revealed the cationic silylene (silyliumylidene) character of the silicon unit in complex 3. Similarly, formation of the analogous dinuclear palladium complex 4 [LSi{Pd(PPh3)}2P(TMS)2] from tetrakis(triphenylphosphine) palladium(0) was observed. On the other hand, in the case of bis(cyclooctadiene) nickel(0) as starting material, a distinctively different product, the bis(silylene) nickel complex 5 [{(LSi)2P(TMS)}Ni(COD)], was obtained. Complex 5 was fully characterized including X-ray diffraction analysis. Density functional theory calculations of the reaction mechanisms showed that the migration of the TMS group in the case of platinum and palladium was induced by the oxidative addition of the transition metal into the silicon-silicon bond. The respective platinum intermediate 2 [LSi{Pt(TMS)(PPh3)}P(TMS)] was also experimentally observed. This is contrasted by the reaction of nickel, in which the equilibrium of phosphasilene 1 and the phosphinosilylene 6 [LSiP(TMS)2] was utilized for a better coordination of the silicon(II) moiety in comparison with phosphorus to the transition metal center.

Prevalence of cerebral aneurysm in patients with acromegaly.

The prevalence of cerebral aneurysm was retrospectively investigated in 208 patients with acromegaly relative to the rate of cerebral aneurysm in a group of control subjects. Neuroradiological examinations of the cerebral vascular system were conducted in 208 acromegaly patients (101 men; mean age, 48.8 years). The prevalence of cerebral aneurysm in the acromegaly patients was compared to that in a control group consisting of 7,390 subjects who underwent "brain checkup" between 2006 and 2008 (mean age, 51.6 years). In the acromegaly group, cerebral aneurysm was detected in 4.3 % of patients. By sex, the prevalence was 6.9 % in males, a significantly proportion than that in the control group with an odds ratio of 4.40. The prevalence in females did not differ between the two groups. In the acromegaly group, the rate of hypertension was significantly higher in the patients with aneurysm compared to those without aneurysm. Multiple logistic regression identified acromegaly as a significant factor related to the prevalence of cerebral aneurysm in all male subjects; other factors, such as age, hypertension and smoking, were not found to be significant. A significantly higher prevalence of cerebral aneurysm was detected in male patients with acromegaly. This finding indicates that excess growth hormone or insulin-like growth factor 1 affects the cerebral vascular wall, resulting in aneurysm formation. In addition to known systematic complications in the cardiovascular, respiratory, metabolic, and other systems, the risk of cerebral aneurysm should be considered in the management of acromegaly.

[Case of 5 year-old boy with anaphylaxis due to erythritol with negative prick test and positive intradermal test].

A 5 year-old boy experienced anaphylaxis after eating a jelly product for diet supplement containing erythritol as a major component. Prick test with the jelly product was negative, but the second oral ingestion of the jelly product at home caused another allergic reaction. Prick test with erythritol was negative even at 300 mg/ml, which was almost the solubility limit. Intradermal test was marginally positive at 0.1 mg/ml, and clearly positive at 1 mg/ml or higher concentration. We found subtle dose-response reaction utilizing basophil activation test, examined with 24 hour incubation at the concentration of 40-4000 µg/ml. At the oral challenge test in the hospital, 3 g of erythritol induced remarkable coughing, urticaria, edema, wheezing and hypoxemia. Erythritol is a natural sugar alcohol, with the molecular weight of 122.12, which is recently being widely used for diet supplements, beverages, or drug medicines due to its properties of calorie-free and good-tasting, with easy-to-use physical characteristics. We now have to recognize erythritol as a candidate for food allergen, and to be careful about negative result of prick test.

[Case of iodism complicated with severe airway stenosis due to pharyngolaryngeal edema].

A 22-year-old man was admitted to our hospital with dilute iodine tincture poisoning. He had ingested 150 mL in a suicide attempt. On arrival, he was in need of urgent airway management as he was repeatedly vomiting. Although we had difficulty with endotracheal intubation because of remarkable pharyngolaryngeal mucosal edema induced by dilute iodine tincture, we managed to secure the airway. On the 2nd day, laryngoscope showed severe mucosal erosion from the upper to middle pharynx and epiglottis. On the 4th day, we performed a tracheoctomy in anticipation of prolonged airway management. On the 16th day, laryngoscopy showed improvement in each of the 2nd day findings. On the 30th day, the patient was transferred to a psychiatric hospital. Generally, iodine poisoning induces multiple organ disorders and there have been several reports describing iatrogenic iodine poisoning. However, cases of severe airway stenosis due to ingestion of iodine are very rare. Presently, members of the public can easily purchase dilute iodine tincture in Japan, therefore emergency medical personnel should be aware of iodine poisoning as a method of suicide attempt.

Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial　- Protocol for a Multicenter Randomized Controlled Trial.

Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear. Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2 from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated. Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.

Outcome of extracorporeal membrane oxygenation use in severe accidental hypothermia with cardiac arrest and circulatory instability: A multicentre, prospective, observational study in Japan (ICE-CRASH study).

AIM: To elucidate the effectiveness of extracorporeal membrane oxygenation (ECMO) in accidental hypothermia (AH) patients with and without cardiac arrest (CA), including details of complications. METHODS: This study was a multicentre, prospective, observational study of AH in Japan. All adult (aged ≥18 years) AH patients with body temperature ≤32 °C who presented to the emergency department between December 2019 and March 2022 were included. Among the patients, those with CA or circulatory instability, defined as severe AH, were selected and divided into the ECMO and non-ECMO groups. We compared 28-day survival and favourable neurological outcomes at discharge between the ECMO and non-ECMO groups by adjusting for the patients' background characteristics using multivariable logistic regression analysis. RESULTS: Among the 499 patients in this study, 242 patients with severe AH were included in the analysis: 41 in the ECMO group and 201 in the non-ECMO group. Multivariable analysis showed that the ECMO group was significantly associated with better 28-day survival and favourable neurological outcomes at discharge in patients with CA compared to the non-ECMO group (odds ratio [OR] 0.17, 95% confidence interval [CI]: 0.05-0.58, and OR 0.22, 95%CI: 0.06-0.81). However, in patients without CA, ECMO not only did not improve 28-day survival and neurological outcomes, but also decreased the number of event-free days (ICU-, ventilator-, and catecholamine administration-free days) and increased the frequency of bleeding complications. CONCLUSIONS: ECMO improved survival and neurological outcomes in AH patients with CA, but not in AH patients without CA.