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Background: Precise acetabular cup placement is essential for successful total hip arthroplasty (THA). In obese patients, its accuracy is often difficult to achieve because of the thickness of the soft tissues. This study aimed to determine the relationship between the accuracy of acetabular cup angle and body mass index (BMI) in posterolateral THA using the computed tomography-based navigation (CT-navi) system.Methods: We retrospectively reviewed 145 consecutive primary THAs using the CT-navi system between January 2015 and January 2018. All surgeries were performed using cementless cups employing the posterolateral approach with the patient in the decubitus position. We compared the radiographic inclination and anteversion obtained from the angle displayed on the CT-navi screen with those measured by the postoperative CT using the three-dimensional templating software. We evaluated the relationship between the extent of errors and correlation with BMI. Statistical analyses were performed using the Student’s t-test and Spearman’s rank coefficient test.Results: In non-overweight patients (BMI < 25, 88 hips), the mean navigation errors for inclination were 2.8 ± 2.2° and for anteversion were 2.6 ± 2.3°. Meanwhile, in overweight patients (BMI ≥ 25, 57 hips), the mean navigation errors were 2.6 ± 2.4° for inclination and 2.4 ± 2.4° for anteversion. We found no significant difference between overweight and non-overweight patients in both inclination and anteversion. The Spearman’s rank correlation coefficients were -0.04 for inclination and -0.11 for anteversion, showing no correlation between the extent of errors and BMI.Conclusions: In posterolateral THA, CT-navi can aid the precise placement of the acetabular cup irrespective of a patient’s BMI.Trial registration: This trial was retrospectively registered and approved by the institutional ethics committee of Teikyo University. The registration number is 17-190, and the date of approval was March 1, 2018. URL of trial registry is: https://www.teikyo-u.ac.jp/application/files/7015/8432/1341/2016_all_syounin_1.pdf

Shigeru Nakamura,1 Kazuya Tanabe,1 Taiju Hyuga,1,2 Taro Kubo,1 Satoru Inoguchi,1 Shina Kawai,1 Hideo Nakai1 1Department of Pediatric Urology, Jichi Medical University, Children’s Medical Center Tochigi, Shimotsuke, Japan; 2Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University (WMU), Wakayama, JapanCorrespondence: Shigeru NakamuraDepartment of Pediatric Urology, Jichi Medical University, Children’s Medical Center, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498, JapanTel +81-285-44-2111Fax +81-285-44-8452Email naka251148@gmail.comPurpose: To evaluate the treatment outcomes and postoperative complications associated with the systematic multi-site hydrodistention implantation technique (SMHIT) for primary vesicoureteral reflux (VUR) and to determine its mid-term efficacy and safety.Patients and Methods: We retrospectively reviewed the data for 17 ureters from 12 consecutive children, aged ≥ 1 year, with grade II–IV reflux and a history of febrile urinary tract infections (FUTI), who underwent a single-session of SMHIT. The primary outcome was the absence of postoperative FUTI (clinical success). The secondary outcome was improvement in reflux to grade 0–I on postoperative voiding cystourethrography (radiographic success).Results: Five and 7 children had bilateral and unilateral reflux, respectively. Reflux was categorized as grade II, III, and IV reflux in 2, 12, and 3 ureters, respectively. Seven of 10 (70%) toilet-trained children had bladder-bowel dysfunction (BBD) preoperatively. The SMHIT was performed for all patients, after which BBD improved. The mean postoperative follow-up period was 6 years and 9 months. The clinical success rate was 100%. Radiographic success was achieved in 16/17 ureters (94%) at 3– 4 months, 17/17 (100%) ureters at 1 year, and 17/17 (100%) ureters at 3 years postoperatively. Major complications did not develop postoperatively.Conclusion: When prioritizing treatment of concomitant BBD in children with primary VUR and avoiding dextranomer/hyaluronic acid injection therapy in contraindicated children according to the Food and Drug Administration recommendations, a single-session of SMHIT may be as effective and safe in the mid-term as performing open anti-reflux surgery.Keywords: dextranomer hyaluronic acid, Dx/HA, endoscopic treatment, vesicoureteral reflux

Visualization of the surgically operated tissues is vital to improve surgical model animals including mouse. Urological surgeries for urethra include series of fine manipulations to treat the increasing number of birth defects such as hypospadias. Hence visualization of the urethral status is vital. Inappropriate urethral surgical procedure often leads to the incomplete wound healing and subsequent formation of urethro-cutaneous fistula or urethral stricture. Application of indocyanine green mediated visualization of the urethra was first performed in the current study. Indocyanine green revealed the bladder but not the urethral status in mouse. Antegrade injection of contrast agent into the bladder enabled to detect the urethral status in vivo. The visualization of the leakage of contrast agent from the operated region was shown as the state of urethral fistula in the current hypospadias mouse model and urethral stricture was also revealed. A second trial for contrast agent was performed after the initial operation and a tendency of accelerated urethral stricture was observed. Thus, assessment of post-surgical conditions of urogenital tissues can be improved by the current analyses on the urethral status.

A decrease in the elasticity of the ocular lens during aging is associated with loss of the accommodative ability of the eye, leading to presbyopia. Although near vision impairment is a social issue affecting the length of healthy life expectancy and productivity of elderly people, an effective treatment to improve near vision has not yet become available. Here we examined the effect of Enterococcus faecium WB2000, Lactobacillus pentosus TJ515, and resveratrol on lens elasticity in rats, where the stiffness of the ocular lens increases exponentially during the aging process. A combination of WB2000 and resveratrol improved lens elasticity not only in the long term but also with just short-term treatment. In addition, TJ515 decreased stiffness in the eye lens with long-term treatment. Therefore, the oral administration of WB2000 and resveratrol or TJ515 may be a potential approach for managing the progression of near vision impairment.

Objectives To evaluate the efficacy and safety of additional drug-coated balloon (DCB) angioplasty after directional coronary atherectomy (DCA) for coronary bifurcation lesions. Background The optimal therapy for bifurcation lesions has not been established, even in the drug-eluting stent era. DCA possibly prevents plaque and carina shift in bifurcation lesions by plaque debulking; however, the efficacy of combined DCA and DCB (DCA/DCB) for bifurcation lesions remains unclear. Methods This multicenter registry retrospectively recruited patients with bifurcation lesions who underwent DCA/DCB and follow-up angiogram at 6-15 months. The primary endpoint was the 12-month target vessel failure (TVF) rate. The secondary endpoints were procedure-related major complications, major cardiovascular events at 12 months, restenosis at 12 months, target lesion revascularization (TLR) at 12 months, and target vessel revascularization (TVR) at 12 months. Results We enrolled 129 patients from 16 Japanese centers. One hundred and four lesions (80.6%) were located around the left main trunk bifurcations. No side branch compromise was found intraoperatively. Restenosis was observed in three patients (2.3%) at 12 months. TLR occurred in four patients (3.1%): 3 (2.3%) in the main vessel and 1 (0.8%) in the ostium of the side branch at 12 months. TVF incidence at 12 months was slightly higher in 14 patients (10.9%), and only two patients (1.6%) had symptomatic TVR. One patient (0.8%) had non-target vessel-related myocardial infarction. Conclusions Our data suggested that DCA/DCB provided good clinical outcomes and minimal side branch damage and could be an optimal non-stent percutaneous coronary intervention strategy for bifurcation lesions.

Hemodialysis (HD) is associated with a high in-stent restenosis (ISR) rate even in the second-generation era. Drug-coated balloons (DCB) generally provide excellent clinical outcomes in patients with ISR lesions. Nonetheless, safety and efficacy of DCB for ISR lesions in HD patients are largely unknown. A total of 17 centers across Japan participated in this study. Patients were eligible for the study if ISR lesions were treated with DCB. Enrolled patients were divided into 2 groups (HD and non-HD groups). Angiographic, OCT, and clinical outcomes were compared between the HD and the non-HD groups. A total of 210 patients were enrolled (36 patients in the HD group, and 174 patients in the non-HD group). At 8 months, the binary restenosis rate was significantly higher (26.3% versus 11.3%, p = 0.02) and in-segment late loss was significantly higher (0.49 ± 0.61 mm versus 0.23 ± 0.33 mm, p = 0.02) in the HD group than the non-HD group. In the OCT analyses, change of minimum stent area between post- and pre-procedure was significantly smaller in the HD group compared to the non-HD group (0.08 ± 0.95 mm

To evaluate the role of transient receptor potential melastatin 8 (TRPM8) activity in menthol-induced cold sensitivity and its qualitative perception in patients with dry eye (DE).This prospective, cross-sectional, comparative study included 52 eyes of 52 subjects (mean age: 66.8 ± 9.2 years; range: 44-86) with a tear break-up time (TBUT) of ≤5 s. The participants were classified into three groups: 17 patients with DE symptoms and keratoconjunctival (KC) staining scores of ≥3 points (positive KC-DE group), 18 patients with DE symptoms and KC staining scores of3 points (negative KC-DE group), and 17 individuals with KC staining scores of3 points and no symptoms (non-DE control group). The menthol-induced cool sensation (M-cool) and TBUT were measured after administration of 2 μl of 1.0 mM menthol eye drops. Furthermore, participants answered a questionnaire regarding their stimulus perception (pleasant, unpleasant, or neither).M-cool values were similar in the three groups. TBUT significantly increased in the negative KC-DE and control groups (P 0.05) and remained unchanged in the positive KC-DE group (P 0.05) after menthol administration. DE patients reported the sensation as pleasant or unpleasant, whereas most control participants were indifferent (P 0.05).While M-cold sensitivity was similar in DE and control groups, its qualitative perception differed between these groups. Thus, TRPM8 activation at the peripheral level alone may not be sufficient to account for the manifestation of discomfort symptoms associated with DE.

Calcified lesion is a risk factor for adverse events, even in the drug-eluting stent (DES) era. Recently, drug-coated balloon (DCB) has been shown to have favourable results for in-stent restenosis and small vessels, but its results for calcified lesions are unknown. This study aimed to clarify the rotational atherectomy (RA) and DCB results for calcified lesions of nonsmall vessels. A total of 194 consecutive de novo lesions from 165 cases underwent RA for calcified lesions of nonsmall vessels between January 2016 and August 2018 in a single centre. Overall, 8 cases/10 lesions were excluded because of RA followed plain old balloon angioplasty (POBA). Remaining lesions were grouped into the DES (88 cases/104 lesions) and DCB (69 cases/80 lesions) groups and then compared retrospectively. The primary endpoint was post-discharge major adverse cardiovascular events (MACE) at 1 year, and it was defined as cardiac death, noncardiac death, target-vessel-related myocardial infarction, target lesion revascularization (TLR), and major bleeding (BARC ≥ type 3). There was no difference in the clinical follow-up rate between RA + DES (96/104 lesions) and RA + DCB (78/80 lesions). The post-discharge MACE values after 1 year of RA + DES and RA + DCB were 8% and 11% (P = 0.30), respectively, in terms of cardiac death (0% vs. 0%, respectively), noncardiac death (4% vs. 3%, respectively, P = 0.36), target-vessel-related myocardial infarction (0% vs. 0%, respectively), TLR (4% vs. 8%, respectively, P = 0.30), and major bleeding (1% vs. 0%, respectively). For calcified lesions of nonsmall vessels, RA + DCB showed good results as well as RA + DES. RA + DCB is a potential new strategy for these lesions.

We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter–defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p

To solve the inter-node bandwidth bottleneck in parallel computing systems, we propose a wavelength-routing inter-node interconnect "Optical Hub". The physical topology of Optical Hub is star network, which leads to advantages in term of its throughput, size, energy consumption and life-time cost. The logical topology is full-mesh network, which leads to advantages in term of its latency and reliability. We introduced multi-path routings, which expand the effective bandwidth with the full-mesh topology such as Optical Hub, by replacing conventional MPI functions with our wrapper functions. We simulated execution time of parallel benchmarks on the parallel computing system with Optical Hub using parallel computing simulator SimGrid. As a result, we have confirmed that the parallel computing system with Optical Hub can achieve higher performance and lower energy consumption than conventional ones. We also examined the scalability of Optical Hub and showed that recursive hierarchical configurations of Optical Hub can save cable count drastically in case of large number of nodes against Dragonfly networks.

Aims Harmonized Assessment by Randomized Multicentre Study of OrbusNEich’s Combo StEnt (HARMONEE) (NCT02073565) was a randomized pivotal registration trial of the Combo stent, which combined sirolimus and an abluminal bioabsorbable polymer with a novel endoluminal anti-CD34+ antibody coating designed to capture endothelial progenitor cells (EPC) and promote percutaneous coronary intervention (PCI) site healing. Methods and results Clinically stabilized PCI subjects were randomized 1:1 to receive Combo or everolimus-eluting stents (EES). Between February 2014 and June 2016, 572 subjects with 675 coronary lesions underwent 1-year angiography and fractional flow reserve, with optical coherence tomography (OCT) in the first 140 patients. The primary clinical endpoint was non-inferior 1-year target vessel failure (TVF). The primary mechanistic endpoint of EPC capture activity was superior strut coverage by OCT. Target vessel failure occurred in 7.0% Combo (20/287) vs. 4.2% EES (12/285), a 2.8% [95% confidence interval (95% CI) −1.0%, 6.5%] difference, meeting the non-inferiority hypothesis (P = 0.02). There were no cardiac deaths, with one stent thrombosis observed in the EES group. Quantitative coronary angiography late loss with Combo was equivalent to EES. Optical coherence tomography strut coverage at 1 year was superior with Combo vs. EES [91.3% (95% CI 88.7%, 93.8%) vs. 74.8% (95% CI 70.0%, 79.6%), P

The outcomes of stent implantation in managing May-Thurner syndrome (MTS) are not well understood. To clarify the acute and long-term outcomes of stent implantation in patients with MTS having acute deep venous thrombosis (DVT), we retrospectively investigated consecutive 59 patients from 10 hospitals in Japan who were treated with stents for left iliac vein stenosis with acute DVT. Stents were considered successful if the stent was patent at discharge, which in turn was defined as patient success. The primary endpoint for the study was stent patency, and the secondary endpoint was recurrence of DVT and development of post-thrombotic syndrome (PTS) during follow-up. The patient success was achieved in 56 patients (95%). Clinical follow-up was conducted for 50 patients (89%) for a median duration of 40 months (range 8-165 months). Among them, 44 patients (79%) were followed up using imaging modalities. During this period, stent occlusion was revealed in four patients (9%), and one patient was successfully treated using balloon angioplasty. Primary and secondary patency rates were 84% at 19 months and 93% at 20 months, respectively. Recurrence of DVT was documented in 3 (8%) patients. PTS was evaluated from 36 patients. Three patients (8%) had PTS; however, none of the patients had severe PTS. This multicenter retrospective study of the use of stents for treating patients with MTS having acute DVT demonstrated good acute and long-term outcomes and long-term stent patency.

BACKGROUND: Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS: This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION: Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.FUNDING: Bayer AG.

Giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that contains numerous osteoclasts formed from marrow-derived precursors through receptor activator of nuclear factor κ-B ligand (RANKL), an osteoclast differentiation factor expressed in neoplastic cells of GCTB. Denosumab, a fully human monoclonal antibody targeting RANKL, has recently been used for the treatment of GCTB, and superior treatment effects have been reported. The aim of this work was to elucidate the mechanism of action of denosumab, and the differences between denosumab and zoledronic acid at the level of GCTB cells. We isolated GCTB cells from 3 patients and separated them into osteoclasts, osteoclast precursors and proliferating spindle-shaped stromal cells (the true neoplastic component), and examined the action of denosumab on differentiation, survival and bone resorption activity of osteoclasts. Denosumab and zoledronic acid inhibited osteoclast differentiation from mononuclear cells containing osteoclast precursors. Zoledronic acid inhibited osteoclast survival, whereas an inhibitory effect of denosumab on osteoclast survival was not observed. The inhibitory effect on bone resorption by both agents was confirmed in culture on dentin slices. Furthermore, zoledronic acid showed dose-dependent inhibition of cell growth of neoplastic cells whereas denosumab had no inhibitory effect on these cells. Denosumab has an inhibitory effect on osteoclast differentiation, but no inhibitory effects on survival of osteoclasts or growth of neoplastic cells in GCTBs.

Aneurysmal bone cysts of the lumbar spine are usually treated by curettage followed by bone or bioactive ceramics grafting. Here, we present the first case of an aneurysmal bone cyst of the lumbar spine treated by percutaneous endoscopic lumbar discectomy (PELD). We describe the clinical characteristics of the patient including the radiological and pathological findings of the tumor and the surgical technique used. A 15-year-old boy presented with low back pain, and he was diagnosed with an aneurysmal bone cyst of the L3 vertebra based on radiological findings, including plain radiograph, computed tomography, and magnetic resonance imaging. The technique and equipment of PELD were used to perform curettage of the tumor cavity and fill it with hydroxyapatite granules. The skin incision was only 8 mm. The patient was discharged 1 day postoperatively and could walk without assistance. The postoperative course was uneventful and the symptoms improved following surgery. Endoscopic surgery via PELD can be a treatment option for ABCs of the lumbar spine.

Hydrogen gas (H2) reacts with strong oxidants, and the effectiveness of H2 inhalation or ingestion of H2 water has been demonstrated for many diseases. H2 produced by the intestinal microbiome from indigestible components is the major source of exogenous H2. In this study, we screened a wide variety of indigestible components that induce H2 production by the intestinal microbiome, which exhibits large diversity, and developed a beverage composed of cows’ milk with galactooligosaccharide, maltitol, and glucomannan (H2-producing milk). In clinical trials, the breath H2 concentration of most volunteers was increased by consumption of H2-producing milk 1 (each material: 1%) and H2-producing milk 2 (galactooligosaccharide: 1.5%, maltitol: 1%, and glucomannan: 0.1%). The total range of H2 production (area under the curve) increased and a higher peak concentration was observed compared with consumption of H2 water or pure cows’ milk. Thus, this material may be a desirable functional milk.

Azoospermia affects up to 1% of adult men. Non-obstructive azoospermia is a multifactorial disorder whose molecular basis remains largely unknown. To date, mutations in several genes and multiple submicroscopic copy-number variations (CNVs) have been identified in patients with non-obstructive azoospermia. The aim of this study was to clarify the contribution of nucleotide substitutions in known causative genes and submicroscopic CNVs in the genome to the development of non-obstructive azoospermia. To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization. We studied 40 Japanese patients with idiopathic non-obstructive azoospermia. Functional significance of molecular alterations was assessed by in silico analyses. As a result, we identified four putative pathogenic mutations, four rare polymorphisms possibly associated with disease risk, and four probable neutral variants in 10 patients. These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia. Copy-number analysis detected five X chromosomal or autosomal CNVs of unknown clinical significance, in addition to one known pathogenic Y chromosomal microduplication. Five patients carried multiple molecular alterations. The results indicate that monogenic and oligogenic mutations, including those in SOHLH1 and TEX11, account for more than 10% of cases of idiopathic non-obstructive azoospermia. Furthermore, this study suggests possible contributions of substitutions in various genes as well as submicroscopic CNVs on the X chromosome and autosomes to non-obstructive azoospermia, which require further validation.

We investigated the efficacy and safety of using paclitaxel-coated balloon (PCB) to treat small vessel disease. In this multicenter, prospective, randomized controlled trial, one-hundred and thirty-five patients with native coronary lesions in small vessels were randomized into a PCB group and plain balloon angioplasty (POBA) group at a ratio of 2:1. There were no differences in target vessel failure (TVF) that was defined as cardiac death or target vessel-related myocardial infarction or target lesion revascularization (TLR), between the two groups (3.4 vs. 10.3%; P = 0.20), and TLR was slightly lower in the PCB group (2.3%) than that in the POBA group (10.3%) during 24 weeks follow-up. The late lumen loss (LLL) was significantly lower in the PCB group (0.01 ± 0.31 vs. 0.32 ± 0.34 mm; P

Objectives The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. Background The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. Methods The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. Results NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of −2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). Conclusions Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227)

Calcified lesions still remain a technical challenge even in the treatment of infrainguinal artery disease. The aim of this retrospective, multicenter observational study was to investigate interventional outcomes of a high-speed rotational atherectomy device (Rotablator™) and to compare clinical outcomes in patients who underwent Rotablator and those who did not even after failed balloon angioplasty because of underlying calcified lesions. This study enrolled patients who underwent Rotablator (Rota group) and those who did not (Non-rota group) between January 2010 and 2014 December at 12 hospitals. A total of 67 limbs and 68 lesions in 65 patients were included (Rota group; 54 limbs and 55 lesions in 52 patients, Non-rota group; 13 limbs and 13 lesions in 13 patients). In the Rota group, a technical success rate was 94.5% with a complication rate of 1.8%, and all lesions underwent subsequent postdilatation following the adjunctive use of Rotablator, and approximately half of above-the-knee lesions underwent stent implantation. The Rota group had a significantly lower clinically driven reintervention rate at 12 months than the Non-rota group (26.5% vs. 58.3%, respectively, p = 0.046). In addition, Rota group showed a trend toward a higher amputation-free survival compared to the Non-rota group at 1 month (Rota; 98.0% vs. Non-rota; 84.6%, respectively, p = 0.10). Rotablator was used as an adjunctive device with a high technical success and a low complication rates, and Patients who underwent Rotablator yielded a significantly lower clinically driven reintervention rate at 12 months compared to those who did not even after failed balloon angioplasty.

To evaluate transient receptor potential vanilloid 1 (TRPV1)-mediated pain sensitivity in patients with short tear break-up time (TBUT) dry eye (DE) by using the capsaicin stimulus test.This prospective cross-sectional comparative study included 22 eyes of 22 patients with short TBUT DE and 11 eyes of 11 non-DE control subjects. Patients were divided into two groups based on response to standard DE treatments: 10 non-responders (intractable DE) and 12 responders (responsive DE). Mechanical touch (M-touch) and mechanical pain (M-pain) were measured using a Cochet-Bonnet esthesiometer. Capsaicin-induced pain (C-pain) and C-pain duration (C-pain DT) were measured using a capsaicin stimulus test. Psychological distress was also assessed.M-touch sensitivity was similar among all three groups. M-pain sensitivity was higher in the responsive DE group than in the intractable DE and control groups (P .001). C-pain sensitivity was lower (P .001) in the intractable DE group than in the responsive DE and control groups, and C-pain DT was shorter (P = .006) in the intractable DE group than in the responsive DE group. Psychological distress was higher in the intractable DE group than in the control group (P .001).Patients with intractable short TBUT DE were less sensitive to the effects of capsaicin than patients with responsive short TBUT DE and controls. Altered neural activation may contribute to the development of DE symptoms in the short TBUT DE subjects. The capsaicin stimulus test may be used to better understand pain sensitivity in short TBUT DE patients.

Tear fluid secreted from the exocrine lacrimal gland (LG) has an essential role in maintaining a homeostatic environment for a healthy ocular surface. Tear secretion is regulated by the sympathetic and parasympathetic components of the autonomic nervous system, although the contribution of each component is not fully understood. To investigate LG innervation, we identified sympathetic and parasympathetic postganglionic nerves, specifically innervating the mouse LG, by injecting a retrograde neuronal tracer into the LG. Interruption of neural stimuli to the LG by the denervation of these postganglionic nerves immediately and chronically decreased tear secretion, leading to LG atrophy along with destruction of the lobular structure. This investigation also found that parasympathetic, but not sympathetic, innervation was involved in these alterations.

The number of patients with dry eye disease (DED) is increasing, and DED has become an urgent public health problem. A comorbidity of mental disorders has been reported in DED patients. We hypothesized that physical and psychological stressors impair tear secretion. To examine the relationship between stress loading and decreased tear secretion, we established a stress-induced DED mouse model, which permitted us to address the underlying mechanism of pathogenesis and resilience. Enriched environment (EE) was an effective intervention to prevent and alleviate stress-induced decreased tear secretion. Because stress loading resulted in decreased brain-derived neurotrophic factor (BDNF) expression while EE resulted in increased expression, we focused on the role of BDNF in tear secretion. Using two distinct Bdnf gene knockdown mice, we evaluated whether BDNF was a deterministic factor in regulating tear secretion in healthy and stressed conditions. Bdnf knockdown mice showed decreased basal tear secretion and loss of stress tolerance by EE for tear secretion. These results suggest that BDNF expression is related to tear secretion and to the pathology of DED.

Tearing maturates rapidly after birth, and external environmental challenges play a key role in promoting lacrimal functional maturation. However, little is known about the facilitative factors underlying this developmental process or the potential of application of these factors to treat hypofunction of the lacrimal gland. In this study, eye opening and the subsequent ocular surface sensory experience, which is thought to be involved in postnatal maturation of lacrimal function, were investigated. Our results demonstrated that eye opening after birth is essential for the maturation of neonatal tearing. The maturation process of lacrimal function is dependent on the ocular surface sensory experience via transient receptor potential cation channel subfamily member 1 after birth. This study provides, for the first time, important evidence of the sensory experience of the ocular surface in relation to the maturation of functional tear secretion during the postnatal period.

The article Clinical expert consensus document on rotational atherectomy

We demonstrate compact and low-loss $8 \times 8$ silicon photonic switch modules, which are applicable to transponder aggregators (TPAs) in colorless, directionless, and contentionless reconfigurable optical add-drop multiplexers. Newly designed silicon optical switch chips incorporating spot size converters with polarization insensitive and wavelength insensitive properties over C/L bands are packaged. The developed module shows about 6-dB average excess optical loss, including optical coupling loss, on all 64 optical paths with low-polarization-dependent loss and low crosstalk. Using these compact optical switch modules, we construct a TPA prototype featuring over 100-port optical switch subsystem densely mounted on one board and confirm its feasibility.

In recent decades, silicon photonics has attracted much attention in telecom and data-com areas. Constituted of high refractive-index contrast waveguides on silicon-on-insulator (SOI), a variety of integrated photonic passive and active devices have been implemented supported by excellent optical properties of silicon in the mid-infrared spectrum. The main advantage of the silicon photonics is the ability to use complementary metal oxide semiconductor (CMOS) pro-cess-compatible fabrication technologies, resulting in high-volume production at low cost. On the other hand, explosively growing traffic in the telecom, data center and high-performance computer demands the data flow to have high speed, wide bandwidth, low cost, and high energy-efficiency, as well as the photonics and electronics to be integrated for ultra-fast data transfer in networks. In practical applications, silicon photonics started with optical interconnect transceivers in the data-com first, and has been now extended to innovative applications such as multi-port optical switches in the telecom network node and integrated optical phased arrays (OPAs) in light detection and ranging (LiDAR). This paper overviews the progresses of silicon photonics from four points reflecting the recent advances mentioned above. CMOS-based silicon photonic platform technologies, applications to optical transceiver in the data-com network, applications to multi-port optical switches in the telecom network and applications to OPA in LiDAR system.

The core mechanism of dry eye is the tear film instability. Tear film-oriented diagnosis (TFOD) is a concept to clarify the cause of tear film instability by tear film, and tear film-oriented treatment (TFOT) is a concept to treat dry eye disease by replacing the lacking components of the tear film layer based on the TFOD. In TFOD, the fluorescein breakup pattern of the tear film is important, and the subtype of dry eye can be judged to some extent from the breakup patterns. Current noninvasive devices related to the dynamic analysis of the tear film and visual acuity enabled the diagnosis of dry eye, subtype analysis, and the extent of severity. In Asian countries, secretagogues represent the main treatment in TFOT. Since meibomian gland dysfunction is a factor that greatly affects the tear breakup time, its treatment is also essential in the dry eye treatment strategy. A newly discovered dry eye subtype is the short breakup time-type (BUT) of dry eye. The only abnormal finding in this disease is the short BUT, suggesting a relationship with ocular neuropathic pain and eye strain. Recently, data from many studies have accumulated which show that dry eye is a life-style disease. In addition to the treatment of dry eyes, it is becoming possible to prevent the onset by intervening with the daily habits, diet, exercise and sleep, etc. It has been pointed out that oxidative stress is also involved in the pathology of dry eye, and intervention is being carried out by improving diet and taking supplements. Future research will be needed to link clinical findings to the molecular biological findings in the tear film.

Intracellular calcium ([Ca2+]i) signaling regulates physiological functions in most cells. In secretory organs, such as the pancreas, salivary gland, and lacrimal gland (LG), [Ca2+]i elevation in acinar cells triggers fluid secretion, which plays vital roles in the maintenance of functional health across the life-course. It is important to understand the secretory mechanism of secretory organs, but lack of analytic systems available for living animals limits the scope of research to gain deeper insights into the precise mechanism of secretion. We established an intravital imaging system for specific cell types of secretory organs to monitor the [Ca2+]i changes using mouse line expressing Yellow Cameleon 3.60, a genetically encoded Ca2+ indicator. Elevation of [Ca2+]i in specific cell types of secretory organs could be monitored after cholinergic stimulation ex vivo and intravitally. We found that a marked attenuation of LG [Ca2+]i response to cholinergic stimulation was induced under pathological conditions by postganglionic denervation. Intravital Ca2+ imaging in secretory organs will broaden our understanding of the cellular mechanisms in animal models of secretory diseases.

A voided volume (VV) of50% of the expected bladder capacity for age is considered small VV. It was recommended that a VV ≥50% of expected bladder capacity for age is required to assess uroflowmetry (UFM) curves because a small VV causes changes in UFM curve characteristics. However, no clear consensus has been reached on the criterion for evaluating UFM curve patterns.The aim of the study was to evaluate the reproducibility and characteristics of UFM curve patterns in children with daytime urinary incontinence (DUI) and with a variety of VVs.This study investigated 119 children (79 boys and 40 girls) with primary DUI who underwent UFM 3 times on the same day and were classified into two groups: small VV (50% of expected bladder capacity for age) in 0-1 of the 3 UFM measurements (group 1; normal VV) or in 2-3 of the 3 UFM measurements (group 2; small VV). The authors then evaluated the agreement of UFM curve patterns among the 3 measurements, classifying complete, partial, or no agreement according to the number of identical curve patterns. The authors also evaluated the most characteristic patterns of UFM curve patterns for each group.Group 1 comprised 45 children, and group 2 comprised 74 children. Rates of complete agreement (group 1, 24/45; group 2, 30/74), partial agreement (group 1, 19/45; group 2, 35/74), and no agreement (group 1, 2/45; group 2, 9/74) did not differ significantly between groups (p = 0.226). Bell curve patterns were significantly more common in group 1 than in group 2 (p = 0.025). Frequency of the tower pattern was significantly higher in group 2 than in group 1 (p = 0.006) (Summary table).No differences in agreement rates of UFM curve patterns were seen between two groups (small and normal VV). The authors thus suggest that UFM curve patterns can be validly assessed in children with DUI and with small VV. It was found that the bell pattern was significantly more common among children with normal VV, whereas the tower pattern was significantly more common among children with small VV. The tower pattern reflects an overactive bladder. The present results suggest that some children have DUI that is not attributable to urgency.Reproducibility of UFM curve patterns might be properly assessed even in children with DUI and with small VV. This result suggests the presence of various pathological conditions other than the conditions with urgency underlying DUI.

Background We previously reported that the top-down approach (TDA) for infants with febrile urinary tract infections (fUTI) could prevent recurrent fUTI (r-fUTI) but produced a high number of false-positives on acute-phase 99m Tc dimercaptosuccinic acid (DMSA) renal scintigraphy. Therefore we compared the ultrasonography-oriented approach (USOA) with TDA from the viewpoint of prevention of r-fUTI. Methods The TDA was applied between July 2010 and February 2014 and the USOA was applied between March 2014 and April 2017 in infants with first fUTI. In the USOA group, voiding cystourethrography (VCUG) was performed in the case of abnormality on acute-phase renal bladder ultrasonography (RBUS) or on chronic- phase DMSA, which were performed in all cases. The frequency of r-fUTI was compared between the TDA group and USOA group retrospectively. Results Seventy-four infants (52 male) and 79 infants (60 male) received TDA or USOA, respectively. No significant differences were found between the TDA and USOA groups in male : female ratio, age in months at initial onset of fUTI, observation period, or number of cases of r-fUTI (TDA group, n = 4; USOA group, n = 5). Seventy-four DMSA scintigraphy and 25 VCUG were carried out in the USOA group, and 111 DMSA scintigraphy and 34 VCUG in the TDA group. Conclusions Both USOA and TDA were valid for prevention of r-fUTI, but USOA was superior to TDA with regard to the reduced number of patients undergoing VCUG and DMSA.

To compare the main outcomes of radial versus femoral access at long-term follow-up.Little is known about the long-term major cardiovascular events and bleeding complications of patients undergoing percutaneous coronary intervention (PCI) with radial vs femoral approach.A total of 1107 patients from the CENTURY II trial were included. To minimize baseline differences between radial and femoral groups, we applied propensity-score matching for this comparison.In this multicenter study, the radial approach was used in 73.4% of patients. After propensity-score matching, baseline and procedural characteristics were comparable between both groups. Procedural success was high and similar in radial and femoral approaches (98.2% vs 97.5%; P=.47) while radial access was associated with a shorter hospital stay (1.69 ± 1.92 days vs 2.08 ± 1.98 days; P.01). The short-term bleeding and vascular complication rates were significantly lower in the radial group (1.7% vs 6.2% [P.001 in-hospital] and 2.7% vs 9.6% [P.001 at 1-month follow-up]). At 3-year follow-up, radial access was associated with lower rates of all-cause mortality (3.9 vs 6.9%; P=.04) and cardiovascular death (2.1 vs 4.9%; P=.02). The composite of all-cause mortality, myocardial infarction, and revascularization showed no differences between groups (18.2 vs 21.1%; P=.29).Compared to the femoral approach, the radial approach is associated with significantly lower long-term all-cause mortality rate as well as lower in-hospital and short-term bleeding rates. These results suggest additional long-term benefits of radial access for PCI, but should be interpreted within the context of the current study and further verified in future studies.

Silicon photonic switches are attractive for extensible optical switch systems required for optical networks in telecom areas and datacenters. We show our low-loss silicon photonic switch modules and their application to CDC-ROADMs using multiple modules.

A 9-year-old girl was diagnosed with primary alveolar soft part sarcoma of the bladder after imaging examinations and transurethral resection (TUR) of the bladder tumor. As a positive surgical margin of the TUR indicated residual tumor cells, we performed a cystourethrectomy to remove the tumor. A continent urinary reservoir for self-catheterization was constructed using the Mainz pouch technique, and an abdominal (umbilical) continent catheterizable stoma using the appendix was performed. For 2.5 years postoperatively, the patient remained free of local recurrence and distant metastasis. The patient’s clinical course has been favorable, with good management of clean intermittent self-catheterization.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, pINTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.FUNDING: Bayer AG.

Percutaneous coronary intervention (PCI) of severely calcified coronary artery lesions are associated with lower procedure success rates and higher rates of target lesion failure compared with non-calcified lesions even in the DES era. Scoring balloon and Rotational atherectomy are applied to modify

STX2 encodes a sulfoglycolipid transporter. Although Stx2 nullizygosity is known to cause spermatogenic failure in mice, STX2 mutations have not been identified in humans. Here, we performed STX2 mutation analysis for 131 Japanese men clinically diagnosed with nonobstructive azoospermia. As a result, we identified a homozygous frameshift mutation [c.8_12delACCGG, p.(Asp3Alafs*8)] in one patient. The mutation-positive patient exhibited loss-of-heterozygosity for 58.4 Mb genomic regions involving STX2, suggesting possible parental consanguinity. The patient showed azoospermia, relatively small testes, and a mildly elevated follicle stimulating hormone level, but no additional clinical features. Testicular histology of the patient showed universal maturation arrest and multinucleated spermatocytes, which have also been observed in mice lacking Stx2. PCR-based cDNA screening revealed wildtype STX2 expression in various tissues including the testis. Our results indicate that STX2 nullizygosity results in nonsyndromic maturation arrest with multinucleated spermatocytes, and accounts for a small fraction of cases with nonobstructive azoospermia.

Objectives This study was performed to determine the complications occurring during retrograde percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) based on analysis of the multicenter, prospective, nonrandomized Retrograde Summit registry. Background Retrograde PCI for CTO has improved treatment success rates, but several complications related to the retrograde approach have been reported, including collateral channel injury and donor artery injury due to their use as retrograde roots. Methods This registry included data from 1,166 patients who underwent retrograde PCI for CTO in 28 Japanese centers between January 2009 and December 2011. Results Overall procedure success and retrograde procedure success were achieved in 985 (84.5%) and 838 (71.9%) of the 1,166 patients, respectively. In-hospital major adverse cardiac and cerebrovascular events (MACCE) occurred in 18 (1.5%) of the 1,166 patients. With regard to complications related to the retrograde approach, channel injury occurred in 111 (9.5%) of the 1,166 patients, but treatment was required in only 24 (2.1%) patients and subsequent cardiac tamponade occurred in only 4 (0.3%) patients. Donor artery problems occurred in only 10 (0.9%) of the 1,166 patients. In sub-analysis regarding the types of collateral channels, the septal channel was significantly safer than epicardial channel because of the lower frequency of non-Q-wave myocardial infarction (non-QMI) and channel injury requiring treatment. Conclusions The MACCE rate during retrograde PCI for CTO determined from the Retrograde Summit registry was low and the frequency of complications related to the retrograde approach was acceptable. © 2015 Wiley Periodicals, Inc.

We evaluated the long-term outcome of the Pippi Salle procedure in patients with severe intrinsic urethral sphincter deficiency.We performed the Pippi Salle procedure in 6 males and 6 females with severe intrinsic sphincter deficiency between March 2003 and August 2013. Median patient age was 15 years (range 6 to 45). Mean followup was 75 months (range 17 to 142). Six males and 3 females had neurogenic intrinsic sphincter deficiency (spina bifida in 8 and spinal cord injury in 1). Three females had anatomical intrinsic sphincter deficiency (idiopathic bladder hypoplasia in 2 and pseudo-ureterocele in 1). Four patients had previously undergone bladder neck surgery, 3 had been treated with endoscopic injection of collagen, 2 had undergone fascial sling and 1 had been treated with tension-free vaginal tape surgery. The Pippi Salle procedure was performed alone (2 patients), or in combination with bladder augmentation (4) or catheterizable abdominal stoma (1), or both (5).Complete dryness was achieved in 7 patients (58%). Of 9 patients with neurogenic intrinsic sphincter deficiency 7 (78%) achieved complete dryness. Eight patients experienced complications, including continued urinary incontinence (5), difficulty catheterizing per urethra (3) and urinary calculi (1). These 8 patients were successfully treated with additional endoscopic interventions, including injection of collagen in 4, injection of dextranomer-hyaluronic acid in 1, transurethral incision of urethral kink in 3 and vesicolithotripsy in 1. After these simple interventions complete dryness was achieved in all 12 patients.Although we experienced some minor complications in the short term, most patients were simply and successfully treated with endoscopic surgery. The long-term results of the Pippi Salle procedure are promising.

Purpose This study aims to evaluate the endoscopic morphological features of congenital posterior urethral obstructions in boys with refractory daytime urinary incontinence and/or nocturnal enuresis. Patients and Methods A total of 54 consecutive patients underwent endoscopy and were diagnosed with a posterior urethral valve (PUV) (types 1–4). PUV type 1 was classified as severe, moderate, or mild. A transurethral incision (TUI) was mainly performed for anterior wall lesions of the PUV. Voiding cystourethrography and pressure flow studies (PFS) were performed before and 3 to 4 months after TUI. Clinical symptoms were evaluated 6 months after TUI, and outcomes were assessed according to PFS waveform pattern groups (synergic pattern [SP] and dyssynergic pattern [DP]). Results All patients had PUV type 1 and/or 3 (i.e., n = 34 type 1, 7 type 3, and 13 types 1 and 3). There were severe (n = 1), moderate (n = 21), and mild (n = 25) cases of PUV type 1. According to PFS, SP and DP were present in 43 and 11 patients, respectively. TUI was effective in the SP group and symptoms improved in 77.4 and 69.3% of patients with daytime incontinence and nocturnal enuresis, respectively. Almost no effect was observed in the DP group. A significant decrease in the detrusor pressure was observed at maximum flow rate using PFS in the SP group. Conclusions PUV type 1 encompassed lesions with a spectrum of obstructions ranging from severe to mild, with mild types whose main obstructive lesion existed at the anterior wall of urethra occurring most frequently in boys with refractory daytime urinary incontinence and/or nocturnal enuresis.