Bound star clusters observed in a lensed galaxy 460 Myr after the Big Bang.

The Cosmic Gems arc is among the brightest and highly magnified galaxies observed at redshift z ∼ 10.21. However, it is an intrinsically UV faint galaxy, in the range of those now thought to drive the reionization of the universe2-4. Hitherto the smallest features resolved in a galaxy at a comparable redshift are between a few hundreds and a few tens of parsecs5,6. Here we report JWST observations of the Cosmic Gems. The light of the galaxy is resolved into five star clusters located in a region smaller than 70 parsec. They exhibit minimal dust attenuation and low metallicity, ages younger than 50 Myr and intrinsic masses of ∼ 106 M⊙. Their lensing-corrected sizes are approximately 1 pc, resulting in stellar surface densities near 105 M⊙ /pc2, three orders of magnitude higher than typical young star clusters in the local universe7. Despite the uncertainties inherent to the lensing model, they are consistent with being gravitationally bound stellar systems, i.e., proto-globular clusters (proto-GCs). We conclude that star cluster formation and feedback likely contributed to 3 shape the properties of galaxies during the epoch of reionization.

Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease.

AIM: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonist (GLP-1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP-1RA first. METHODS: We included 438 patients with CKD (GLP-1RA-first group, n = 223; SGLT2 inhibitor-first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)-matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. RESULTS: Using the PS-matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP-1RA-first group, 10%; SGLT2 inhibitor-first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). CONCLUSION: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

Demographic Traits, Clinical Status, and Comorbidities of Patients With Thromboangiitis Obliterans in Japan.

BACKGROUND: The latest demographics, clinical and living conditions, and comorbidities of patients with thromboangiitis obliterans (TAO) in Japan are unknown.Methods and Results: We conducted a retrospective cross-sectional survey using the annual database of the Japanese Ministry of Health, Labour and Welfare medical support system for patients with TAO between April 2013 and March 2014. This study included 3,220 patients (87.6% male), with current age ≥60 years in 2,155 patients (66.9%), including 306 (9.5%) patients aged ≥80 years. Overall, 546 (17.0%) had undergone extremity amputation. The median interval from onset to amputation was 3 years. Compared with never smokers (n=400), 2,715 patients with a smoking history had a higher amputation rate (17.7% vs. 13.0%, P=0.02, odds ratio [OR]=1.437, 95% confidence interval [CI]=1.058-1.953). A lower proportion of workers and students was seen among patients after amputation than among amputation-free patients (37.9% vs. 53.0%, P<0.0001, OR=0.542, 95% CI=0.449-0.654). Comorbidities, including arteriosclerosis-related diseases, were found even in patients in their 20-30 s. CONCLUSIONS: This large survey confirmed that TAO is not a life-threatening but an extremity-threatening disease that threatens patients' professional lives. Smoking history worsens patients' condition and extremity prognosis. Long-term total health support is required, including care of extremities and arteriosclerosis-related diseases, social life support, and smoking cessation.

The onset of star formation 250 million years after the Big Bang.

A fundamental quest of modern astronomy is to locate the earliest galaxies and study how they influenced the intergalactic medium a few hundred million years after the Big Bang1-3. The abundance of star-forming galaxies is known to decline4,5 from redshifts of about 6 to 10, but a key question is the extent of star formation at even earlier times, corresponding to the period when the first galaxies might have emerged. Here we report spectroscopic observations of MACS1149-JD1 6 , a gravitationally lensed galaxy observed when the Universe was less than four per cent of its present age. We detect an emission line of doubly ionized oxygen at a redshift of 9.1096 ± 0.0006, with an uncertainty of one standard deviation. This precisely determined redshift indicates that the red rest-frame optical colour arises from a dominant stellar component that formed about 250 million years after the Big Bang, corresponding to a redshift of about 15. Our results indicate that it may be possible to detect such early episodes of star formation in similar galaxies with future telescopes.

Body mass index and characteristics of coronary plaque in younger patients with type 2 diabetes.

BACKGROUND AND AIMS: The association between the body mass index (BMI) and the characteristics of coronary plaque in younger type 2 diabetes (T2D) patients with coronary artery disease (CAD) remains to be elucidated. METHODS AND RESULTS: A total of 138 consecutive younger (<65 years) T2D patients with CAD, who underwent optical coherence tomography imaging of the culprit lesion were included. The patients were classified into either the higher BMI group (n = 68) or the lower BMI group (n = 70) according to the median of BMI (25.9 kg/m2). The prevalence of thin-cap fibroatheroma (TCFA) (35.3 vs. 17.1 %, p = 0.015) was significantly higher in the higher BMI group than in the lower BMI group. The prevalence of TCFA was significantly higher in patients with higher BMI than in those with lower BMI among patients with hemoglobin A1c (HbA1c) ≥7.0 % (odds ratio [OR] 5.40, 95 % confidence interval [CI] 1.72-17.0, p = 0.003) although the significant difference was not observed among patients with HbA1c <7.0 % (OR 0.89, 95 % CI 0.25-3.13, p = 0.851). CONCLUSION: Higher BMI was associated with a higher prevalence of TCFA in younger T2D patients with CAD, particularly in patients with HbA1c ≥ 7.0 %.

The real-world clinical decisions of physicians in the management of Takayasu arteritis and giant cell arteritis in Japan: A cross-sectional web-questionnaire survey.

OBJECTIVES: To access the real-world clinical management of physicians who treat Takayasu arteritis (TAK) and giant cell arteritis (GCA) after the publication of the Japanese Circulation Society (JCS) 2017 Guidelines for the Management of Vasculitis Syndrome. METHODS: This descriptive, cross-sectional study utilized self-administered electronic questionnaires, which were answered in February 2022 by physicians treating TAK or GCA and registered with Macromill Inc. RESULTS: The 329 survey respondents comprised 110 cardiologists, 110 rheumatologists, 34 cardiovascular surgeons, 24 surgeons, 35 internal medicine physicians, 13 nephrologists, and 7 pediatricians. The 2017 JCS Guidelines were the most commonly referenced information source for resolving clinical questions, accessed by 70% of respondents. Ophthalmoscopy was performed in only 50% of patients with TAK, and in 70% for GCA. The median percentages of patients who underwent 18F-fluorodeoxyglucose-positron emission tomography/computed tomography for TAK and GCA patients were 23% and 20% at diagnosis, respectively, and 10% each at follow-up within 12 months. Tocilizumab was the most frequently used medication in combination with glucocorticoids for both TAK and GCA, especially in remission induction therapy for relapsed patients. CONCLUSIONS: The majority of physician treating TAK and GCA referred to the 2017 JCS guidelines. This report clarified the current clinical practice for large vessel vasculitis in Japan, providing information for the next revision of the guidelines.

In Vitro Module Editing Of NRPS Enables Production Of Highly Potent Gq -Signaling Inhibitor FR900359 Derived From Unculturable Plant Symbiont.

Heterotrimeric G proteins are key mediators in the signaling of G protein-coupled receptors (GPCR) that are involved in a plethora of important physiological processes and thus major targets of pharmaceutical drugs. The cyclic depsipeptides YM-254890 and FR900359 are strong and selective inhibitors of the Gq subfamily of G proteins. FR900359 was first reported to be produced by unculturable plant symbiont, however, a culturable FR900359 producer was discovered recently by the standard strategy, screening of the producing strain from the environment. As another strategy, we introduce herein the different way to supply natural compounds of unculturable microorganism origin. We therefore embarked on constructing an artificial biosynthetic gene cluster (BGC) for FR900359 with YM-254890 BGC as a template using "in vitro module editing" technology, first developed for the modification of type-I PKS BGCs, to edit YM-254890 BGC. The resulting artificial BGCs coding FR900359 were heterologously expressed in the Pseudomonas putida KT2440 host strain.

Objective Definition and Optimized Strategy for "Biologically Borderline Resectable" Colorectal Liver Metastases.

BACKGROUND: The prognostic benefit of preoperative chemotherapy leading to conversion surgery for unresectable colorectal liver metastases (CRLM) is well recognized, while that of neoadjuvant chemotherapy (NAC) compared with upfront surgery (UFS) for resectable CRLM is negligible. This study aims to assess the prognostic benefit and search for optimal indication of NAC for resectable advanced CRLM by establishing an objective definition of biologically borderline resectable (bBR) CRLM. METHODS: A bicentric retrospective analysis of patients with CRLM undergoing curative-intent initial liver resection between 2007 and 2021 was performed. An original classification matrix was established, which reassessed technical resectability using virtual hepatectomy and oncological favorability using Beppu's nomogram. Patients with technically resectable but biologically unfavorable CRLM were classified into the bBR group. The propensity score matching analysis using preoperatively available factors was performed to assess long-term outcomes of the bBR-UFS and bBR-NAC groups. RESULTS: Of 831 patients reviewed, 240 were categorized into the bBR group: bBR -UFS (n = 139) and bBR-NAC (n = 101). Ten (10%) in the bBR-NAC group (n = 101) experienced biological status change from unfavorable to favorable after NAC (Biological Conversion) and showed significantly longer overall survival (hazard ratio 5.63, 95% confidence interval 1.37-23.1; P = 0.016) than the bBR-UFS group. However, after propensity score matching, no significant difference between the UFS and NAC groups (n = 67 for each) was found in long-term outcomes. CONCLUSIONS: NAC for bBR-CRLM did not enhance the prognostic impact of the following liver resection, except for a limited number of optimal candidates experiencing the Biological Conversion.

A prospective investigation of impacts of comorbid attention deficit hyperactivity disorder (ADHD) on clinical features and long-term treatment response in adult patients with obsessive-compulsive disorder (OCD).

BACKGROUND: A close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. METHODS: We assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD- group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. RESULTS: Of the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD- group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD- group (44.6%). CONCLUSION: The lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients.

The Infrapopliteal Global Limb Anatomic Staging System Predicts Wound Healing and Pain Relief after Partial Revascularization.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) is frequently associated with crural artery occlusion. Complete revascularization beyond the diseased crural artery is preferable; however, complete revascularization is challenging in many cases for various reasons. On the other hand, partial reconstruction for inflow disease sometimes leads to complete relief of symptoms. It is not elucidated which patients may recover from CLTI with partial revascularization (PR). Therefore, we aimed to evaluate the factors affecting outcomes after PR. METHODS: We retrospectively reviewed the medical records of patients who underwent first-attempt PR, for CLTI, for limb salvage, in our institution, between April 2012 and December 2020. We divided these 103 cases into 2 groups: the salvage group (who achieved wound healing or relief from rest pain with PR; n = 81) and the nonsalvage group (who ended with major amputation or additional distal revascularization; n = 22). We evaluated the factors affecting the outcome of PR in terms of patient risk, limb severity (Society for Vascular Surgery Lower Extremity Threatened Limb Classification System; wound, ischemia, and foot infection [WIfI] classification), and anatomical pattern (Global Limb Anatomic Staging System; GLASS classification). RESULTS: Although patient risk between the 2 groups was not statistically significant, hypoalbuminemia (< 3.0 mg/dL) was more prevalent in the nonsalvage group without significance (P = 0.068). Regarding limb severity status, there was no significant difference in WIfI grades. Wound grade showed the strongest correlation (P = 0.11) and reduced wound grade suggested future wound healing. In terms of GLASS, infrapopliteal grade was statistically significant (P = 0.033). Upon a multivariate analysis, among infrapopliteal grade, hypoalbuminemia, and wound grade, infrapopliteal grade (P = 0.0096) and hypoalbuminemia (P = 0.2512) revealed significant differences. Wound grade also showed correlation (P = 0.085). CONCLUSIONS: The usefulness of the WIfI classification and GLASS classification to predict wound healing after PR for CLTI was validated.

An N-Fluorinated Imide for Practical Catalytic Imidations.

Catalytic imidation using NFSI as the nitrogen source has become an emerging tool for oxidative carbon-nitrogen bond formation. However, the less than ideal benzenesulfonimide moiety is incorporated into products, severely detracting its synthetic value. As a solution to this challenge, we report herein the development of a novel N-fluorinated imide, N-fluoro-N-(fluorosulfonyl)carbamate (NFC), by which the attached imide moiety acts as a modular synthetic handle for one-step derivatization to amines, sulfonamides, and sulfamides. Furthermore, this study revealed the superior reactivity of NFC as showcased in a copper-catalyzed imidation of benzene derivatives and imidocyanation of aliphatic alkenes, overcoming the limitation of NFSI-mediated reactions.

Phase I/II study of streptozocin monotherapy in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000-1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). RESULTS: Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%.Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32-40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. CONCLUSIONS: STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Organoiodine-Catalyzed Enantioselective Intermolecular Oxyamination of Alkenes.

Metal-free, catalytic enantioselective intermolecular oxyamination of alkenes is realized by use of organoiodine(I/III) chemistry. The protocol is applicable toward aryl- and alkyl-substituted alkenes with high enantioselectivity and electronically controlled regioselectivity. The oxyaminated products can be easily deprotected in one step to reveal free amino alcohols in high yields without loss of enantioselectivity. A key to our success is the discovery of a virtually unexplored chemical entity, N-(fluorosulfonyl)carbamate, as a bifunctional N,O-nucleophile.

Short interposition with a small-diameter prosthetic graft for flow reduction of a high-flow arteriovenous fistula.

OBJECTIVE: The objective of this study was to evaluate the outcome of a short interposition using a small-diameter prosthetic graft as a flow-limiting procedure to manage symptomatic high-flow arteriovenous fistula (AVF). METHODS: A retrospective review of medical records on a case series was conducted. From June 2004 to April 2017, there were 25 patients with clinical symptoms of high output cardiac failure and progressive dilation of aneurysmal fistula vein due to high-flow AVF (≥1.5 L/min) who underwent short interposition with a 5-mm prosthetic graft at Saitama Medical Center. The primary outcome was the relief of clinical symptoms; other outcome measures included technical success, surgical complications, patency of vascular access, and postoperative changes in local and systemic hemodynamics as assessed by Doppler ultrasound. RESULTS: Twenty-five patients underwent short interposition for cardiac indications (n = 16) and aneurysmal dilation (n = 9). The technical success rate was 100%. The clinical symptoms were relieved in 24 patients (96.0%). Mean reduction in access blood flow was 52.4%. Cumulative primary unassisted patency rates (± standard error) at 1 year, 2 years, and 3 years were 76.2% ± 9.3%, 70.4% ± 10.3%, and 58.1% ± 11.6%, respectively. Secondary patency rates (± standard error) at 1 year, 2 years, and 3 years were 81.8% ± 8.2%, 71.5% ± 9.9%, and 71.5% ± 9.9%, respectively. Complications included access occlusion due to late thrombosis (n = 5 [21.7%]) and graft infection (n = 1 [4.3%]) in the median follow-up period of 3.9 years. CONCLUSIONS: Short interposition with a prosthetic graft is a simple, effective, and durable treatment option for end-stage renal disease patients with cardiac symptoms and progressive dilation of the fistula vein due to high-flow AVF, offering clinical symptom resolution while preserving the autologous behavior of the initial access.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized 13 C fumarate metabolism to hyperpolarized 13 C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

Hyperpolarized [1-13 C]fumarate is a promising magnetic resonance imaging (MRI) biomarker for cellular necrosis, which plays an important role in various disease and cancerous pathological processes. To demonstrate the feasibility of MRI of [1-13 C]fumarate metabolism using parahydrogen-induced polarization (PHIP), a low-cost alternative to dissolution dynamic nuclear polarization (dDNP), a cost-effective and high-yield synthetic pathway of hydrogenation precursor [1-13 C]acetylenedicarboxylate (ADC) was developed. The trans-selectivity of the hydrogenation reaction of ADC using a ruthenium-based catalyst was elucidated employing density functional theory (DFT) simulations. A simple PHIP set-up was used to generate hyperpolarized [1-13 C]fumarate at sufficient 13 C polarization for ex vivo detection of hyperpolarized 13 C malate metabolized from fumarate in murine liver tissue homogenates, and in vivo 13 C MR spectroscopy and imaging in a murine model of acetaminophen-induced hepatitis.

Macropinocytosis-Inducible Extracellular Vesicles Modified with Antimicrobial Protein CAP18-Derived Cell-Penetrating Peptides for Efficient Intracellular Delivery.

The antimicrobial protein CAP18 (approximate molecular weight: 18 000), which was first isolated from rabbit granulocytes, comprises a C-terminal fragment that has negatively charged lipopolysaccharide binding activity. In this study, we found that CAP18 (106-121)-derived (sC18)2 peptides have macropinocytosis-inducible biological functions. In addition, we found that these peptides are highly applicable for use as extracellular vesicle (exosomes, EV)-based intracellular delivery, which is expected to be a next-generation drug delivery carrier. Here, we demonstrate that dimerized (sC18)2 peptides can be easily introduced on EV membranes when modified with a hydrophobic moiety, and that they show high potential for enhanced cellular uptake of EVs. By glycosaminoglycan-dependent induction of macropinocytosis, cellular EV uptake in targeted cells was strongly increased by the peptide modification made to EVs, and intriguingly, our herein presented technique is efficiently applicable for the cytosolic delivery of the biologically cell-killing functional toxin protein, saporin, which was artificially encapsulated in the EVs by electroporation, suggesting a useful technique for EV-based intracellular delivery of biofunctional molecules.

Is portal vein embolization safe and effective for patients with impaired liver function?

BACKGROUND AND OBJECTIVES: Portal vein embolization (PVE) is a safe and effective procedure used to increase the safety of extensive hepatectomy for selected patients. However, it is unknown whether PVE is safe for patients with impaired liver functional reserve. METHODS: Patients who underwent PVE from April 2007 to September 2016 in our hospital were retrospectively assessed. According to indocyanine green retention rate at 15 min (ICG-R15), we divided patients into Group A (≤10%), Group B (10%-20%), and Group C (>20%). We described and compared the treatment course and the outcome among the three groups. RESULTS: A total of 106 patients were assessed and divided into groups A (n = 46), B (n = 49), and C (n = 11). The morbidity and mortality after PVE showed no significant differences among the three groups (A:B:C = 37%:53%:64%, p = .16; A:B:C = 0%:0%:0%, p = 1.00, respectively). The morbidity and mortality after successive hepatectomy also showed no significant differences among the three groups (A:B:C = 55%:71%:78%, p = .19; A:B:C = 0%:2%:0%, p = 1.00, respectively). CONCLUSION: A patient with impaired liver functional reserve (ICG-R15 > 20%) can be a candidate for PVE and successive hepatectomy, as safely as a patient with normal and slightly impaired liver functional reserve (ICG-R15 ≤ 20%).

TGFß (Transforming Growth Factor-Beta)-Activated Kinase 1 Regulates Arteriovenous Fistula Maturation.

OBJECTIVE: Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires wall thickening with deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as lumen dilation. TAK1 (TGFß [transforming growth factor-beta]-activated kinase 1) is a mediator of noncanonical TGFß signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening and lumen dilation during AVF maturation. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm2) activated noncanonical TGFß signaling including TAK1 phosphorylation in mouse endothelial cells. CONCLUSIONS: TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFß signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.

Transcatheter Aortic Valve Replacement in Patients With a Small Annulus　- From the Japanese Nationwide Registry (J-TVT).

BACKGROUND: The details and consequences of a small aortic annulus among transcatheter aortic valve replacement (TAVR) patients remain uncertain. This study investigated the short-term outcomes in patients with small annular size and compared the 30-day outcome between intra- and supra-annular devices, with similar outer casing diameter in this subgroup.Methods and Results:Cases registered in the Japanese national TAVR registry between August 2013 and December 2017 were analyzed. Among a total of 5,870 registered patients, 647 (11.0%) had small annulus (area ≤314 mm2) measured by multi-detector computed tomography. Patients with a small annulus had a significantly smaller indexed effective orifice area (iEOA, 1.10 cm2/m2[0.92-1.35] vs. 1.16 cm2/m2[0.96-1.39], P<0.001) and higher mean pressure gradient (mPG, 10.0 mmHg [6.9-14.2] vs. 8.5 mmHg [6.0-11.5], P<0.001) compared with a normal-sized annulus. Among patients with a small annulus, those receiving a 20 mm intra-annular device had a smaller iEOA (0.94 cm2/m2[0.78-1.06] vs. 1.07 cm2/m2[0.8-1.24], P=0.001) and higher mPG (14.0 mmHg [10.0-18.5] vs. 11.0 [7.0-14.0], P<0.001) compared with those receiving a 23-mm supra-annular device, although the incidence of paravalvular leakage (≥moderate) was similar (14.4% vs. 16.5%, P=0.69). CONCLUSIONS: Patients with a small annulus were associated with less hemodynamic improvement. A supra-annular device is associated with better echocardiographic improvement in patients with a small annulus, without increasing paravalvular leakage.