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Purpose: This study investigated the association between one-year surgical outcomes following trabeculectomy and age, accounting for confounding factors., Study Design: Retrospective observational study., Method: Analyzing data from 305 patients undergoing initial trabeculectomy from 2019 onward, we employed three approaches to adjust variables: stratified analysis, regression analysis, and propensity score matching. Surgical success at 1-year post-surgery was defined by two criteria: achieving intraocular pressure of between 5 and 15 mmHg with a ≥ 20% reduction compared to pre-surgery levels and no additional glaucoma surgery (Criterion A); achieving intraocular pressure of between 5 and 12 mmHg with a ≥ 30% reduction compared to pre-surgery levels and no additional glaucoma surgery (Criterion B)., Results: Stratified analysis by age unveiled a significant increase in exfoliation glaucoma (XFG) and a trend towards shorter axial lengths with advancing age (both p < 0.0001). Older age groups were more likely to experience surgical failure in both Criterion A and B (p = 0.21, < 0.01). Univariate analysis showed age as a significant factor in surgical failure for Criterion A (p < 0.05) and a nearly significant factor for Criterion B (p = 0.12). However, this trend was not evident in multivariate analysis (p = 0.23/0.88), where XFG became a significant factor for surgical failure (both p < 0.001) in Criteria A and B. Propensity score matching revealed no significant differences in surgical success rates for Criteria A and B between younger and older patients (p = 1.00 and 0.88)., Conclusion: Age is not a primary determinant of failure in trabeculectomy; however, the increasing incidence of XFG with aging suggests a potential for poorer outcomes., (© 2024. The Author(s).)

Introduction: Osteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells., Methods: Canine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC 5 , IC 10 , IC 20 , and IC 50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC 5 , IC 10 , IC 20 , and IC 50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo., Results and Discussion: Zoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Iwaki, Lindley, Bergman, Smith and Pondugula.)

Mechanistic model-based simulations can be deployed to project the persistence of humoral immune response following vaccination. We used this approach to project the antibody persistence through 24 months from the data pooled across five clinical trials in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-seronegative participants following vaccination with Ad26.COV2.S (5 × 10 10 viral particles), given either as a single-dose or a homologous booster regimen at an interval of 2, 3, or 6 months. Antibody persistence was quantified as the percentage of participants with detectable anti-spike binding and wild-type virus neutralizing antibodies. The projected overall 24-month persistence after single-dose Ad26.COV2.S was 70.5% for binding antibodies and 55.2% for neutralizing antibodies, and increased after any homologous booster regimen to greater than or equal to 89.9% for binding and greater than or equal to 80.0% for neutralizing antibodies. The estimated model parameters quantifying the rates of antibody production attributed to short-lived and long-lived plasma cells decreased with increasing age, whereas the rate of antibody production mediated by long-lived plasma cells was higher in women relative to men. Accordingly, a more pronounced waning of antibody responses was predicted in men aged greater than or equal to 60 years and was markedly attenuated following any homologous boosting regimen. The findings suggest that homologous boosting might be a viable strategy for maintaining protective effects of Ad26.COV2.S for up to 24 months following prime vaccination. The estimation of mechanistic modeling parameters identified the long-lived plasma cell pathway as a key contributor mediating antibody persistence following single-dose and homologous booster vaccination with Ad26.COV2.S in different subgroups of recipients stratified by age and sex., (© 2023 Janssen. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody., Objective: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study., Methods: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection., Results: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from C max in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after T max and a 97% reduction from C max in teclistamab concentration at a median time of 69 days (32-163 days) after T max . Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles., Conclusion: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM., Clinical Trial Registration: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020)., (© 2023. The Author(s).)

An 87-year-old woman who had undergone coil embolization 25 years ago for pulmonary arteriovenous fistula, which was diagnosed following repeated cerebral infarction, presented with massive hemoptysis. The coils migrated and were excreted in stool following hemoptysis during long-term follow-up. Although the technical success rate of coil embolization for pulmonary arteriovenous malformations is extremely high, and coil embolization-related complications are rare, little is known about the long-term complications. We herein report the clinical course of our case, review previous reports related to coil migration as a long-term complication, and discuss the associated mechanism.

The population pharmacokinetic (PK) and exposure-response (E-R) analyses for the safety of ibrutinib for the treatment of chronic graft-versus-host disease (cGVHD) is presented. This work aims to develop a population PK model for ibrutinib based on data from clinical studies in subjects with cGVHD, to evaluate the impact of intrinsic and extrinsic factors on PK parameters as well as systemic exposure levels, and to assess an E-R relationship for selected safety end points. Pooled data from 162 subjects with cGVHD enrolled in 4 clinical studies were included in the population PK analysis. In the studies, an ibrutinib dose of 420 mg once daily was administered orally. With the exception of 1 study, the study protocols instructed for a reduction of the ibrutinib dose to 140 or 280 mg once daily, depending on concomitant CYP3A inhibitor use. Concomitant CYP3A inhibitor use was found to be a primary covariate for relative bioavailability (F1): the F1 value increased 2.22-fold with concomitant moderate CYP3A inhibitors and 3.09-fold with concomitant strong CYP3A inhibitors, compared with the F1 value in the absence of CYP3A inhibitors. In addition, Japanese ethnicity led to an F1 value that was 1.70-fold higher than that in the non-Japanese population. Simulations using the final PK model suggest that ibrutinib exposure was appropriately controlled within the therapeutic range in the entire cGVHD population by applying dose reductions depending on the use of CYP3A inhibitors, and that additional dose modification for the Japanese population would not be required. The subsequent E-R analysis suggests no apparent association between the systemic exposure to ibrutinib and the selected safety end points., (© 2023, The American College of Clinical Pharmacology.)

Sialic acid (Sia) is a group of acidic sugars with a 9-carbon backbone, and classified into 3 species based on the substituent group at C5 position: N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and deaminoneuraminic acid (Kdn). In Escherichia coli, the sialate aldolase or N-acetylneuraminate aldolase (NanA) is known to catabolize these Sia species into pyruvate and the corresponding 6-carbon mannose derivatives. However, in bacteria, very little is known about the catabolism of Kdn, compared with Neu5Ac. In this study, we found a novel Kdn-specific aldolase (Kdn-aldolase), which can exclusively degrade Kdn, but not Neu5Ac or Neu5Gc, from Sphingobacterium sp., which was previously isolated from a Kdn-assimilating bacterium. Kdn-aldolase had the optimal pH and temperature at 7.0-8.0 and 50 °C, respectively. It also had the synthetic activity of Kdn from pyruvate and mannose. Site-specific mutagenesis revealed that N50 residue was important for the Kdn-specific reaction. Existence of the Kdn-aldolase suggests that Kdn-specific metabolism may play a specialized role in some bacteria., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Situs inversus totalis is a rare congenital anomaly. Most surgeons have seldom performed laparoscopy-assisted distal gastrectomy for situs inversus totalis. Inadequate knowledge regarding the anatomy of situs inversus totalis can result in increased intraoperative bleeding and prolonged operative time. A 74-year-old man was diagnosed with early gastric cancer with situs inversus totalis. We performed laparoscopy-assisted distal gastrectomy with D1+ lymphadenectomy and Billroth-I reconstruction by reversing the standard laparoscopy-assisted distal gastrectomy setup. Mirror images of the operative video of the standardized laparoscopy-assisted distal gastrectomy were created using video editing software. Lymphadenectomy was performed by indocyanine green fluorescence imaging of the lymphatic flow with operative time of 220 minutes and 100 mL intraoperative bleeding. The patient was discharged on postoperative day 10, without postoperative complications. Laparoscopy-assisted distal gastrectomy with indocyanine green navigation is safe and effective in patients with situs inversus totalis and is comparable with standard laparoscopy-assisted distal gastrectomy., (© 2022 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Sleep in Drosophila was defined in the year 2000 by using Drosophila Activity Monitor (DAM) system. But DAM is very small tube space and one fly per tube is very limited to analyze for fly social behavior. To overcome such demerits of DAM system, we developed a novel automated sleep and rhythm analysis system (AutoCircaS) which monitors and records any behaviors like social mating, sleep, and circadian rhythm in flies (Drosophila) and small fishes medaka (Oryzias latipes) in free space using the time-lapse (one frame per 10 sec) imaging. AutoCircaS can detect the caffeine-induced insomnia in flies in light-dark (LD) and constant dark (DD) conditions. Thus, using the AutoCircaS, we discovered that Japanese traditional herbal medicines, KyushinKannouGan-ki (KKG), NouKassei (NK) as well as, and Sansoninto, significantly improved caffeine-induced insomnia in flies. The data suggest that AutoCircaS is useful for sleep analysis of small animals and screening of new sedative-hypnotics from many origins., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

An 80-year-old woman presented to our emergency department with vomiting which had begun half a day prior to presentation. She had undergone open mesh plug repair for a right obturator hernia 1 year prior to presentation. Computed tomography detected recurrence of the right obturator hernia. Since intestinal viability was maintained, manual reduction of the incarcerated intestine was performed. The patient was admitted to our department to monitor delayed intestinal perforation. Laparoscopic transabdominal preperitoneal repair for obturator hernia was performed 5 days after admission. A self-fixating mesh was placed over the obturator hernia defect and femoral ring without tacking. The patient was discharged on postoperative day 6 without postoperative complications. At the 4-month follow-up, no signs of hernia recurrence or neuropathy were observed. Laparoscopic transabdominal preperitoneal repair for recurrent obturator hernia status post-open mesh plug repair by using self-fixating mesh is a safe and suitable procedure., (© 2022 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Purpose: The sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of glucose-lowering drugs for individuals with diabetes. Large-scale clinical trials indicated that SGLT2 inhibitors have both a cardiovascular-protective and renal-protective effects. A reduction in glomerular hyperfiltration and a decrease in albuminuria are suspected as the main causes of SGLT2 inhibitors' renoprotective effect. The effects of SGLT2 inhibitors on tubular damage in non-albuminuric diabetic patients are unclear., Methods: The SGLT2 inhibitor tofogliflozin (20 mg, 1 × /day) was orally administered to 14 non-albuminuric diabetic patients. Serum and urine samples were collected at baseline (before) and after the start of tofogliflozin treatment. Hemoglobin A1c, hemoglobin, estimated glomerular filtration rate (eGFR), body weight, and blood pressure (BP) were analyzed as clinical parameters at baseline and 1, 3, and 6 months later. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-β-D-glucosaminidase were measured as tubular damage markers and the urinary 8-hidroxydeoxyguanosine (8-OHdG) values were measured as an oxidative stress marker at baseline and at 1 and 3 months., Results: Compared to baseline, the patients' HbA1c values and body weights were significantly decreased post-tofogliflozin administration, and their eGFR values were decreased at 3 months but recovered at 6 months; the hemoglobin concentrations were significantly increased at 3 and 6 months and the urinary NGAL level tended to be decreased at 3 months. No significant changes in blood urea nitrogen, BP, NAG, urine sodium concentration, or urinary 8-OHdG values occurred. The effect of this SGLT2 inhibitor was not influenced by the use of an angiotensin receptor blocker or dipeptidyl-peptidase 4 inhibitor., Conclusion: For individuals with non-albuminuric diabetes, tofogliflozin has a good glucose-lowering effect and might have a tubular-protective effect., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Nonregenerative anemia is occasionally seen in dogs and can be caused by many factors, among which nonregenerative immune-mediated anemia (NRIMA) and pure red cell anemia are relatively common causes. These are thought to be caused by immune-mediated destruction of the erythroid lineage and are treated with immunosuppressive drugs, but some of them are refractory or recurrent, so new treatments are needed., Objectives: To examine the efficacy of allogeneic adipose-derived stem cells (ADSCs) for the treatment of nonregerative anemia in dogs., Methods: ADSCs were administered to total five nonregenerative anemia cases; two NRIMA cases and two suspected NRIMA cases that were refractory to immunosuppressive agents, and one NRIMA case that has not been treated with immunosuppressive agents., Results: In all cases, anemia was improved, and blood transfusion was no longer necessary., Conclusions: This study suggests that allogeneic ADSCs may be one of the rescue therapies for the refractory immune-mediated anemia in dogs., Competing Interests: T.M. received research funding from FUJIFILM Corporation. KK was associated with Anicom Specialty Medical Institute Inc., Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 The Author(s). Published by Elsevier Ltd.)

Cyclophosphamide is a commonly used chemotherapy in the treatment of lymphoma. It can cause sterile hemorrhagic cystitis (SHC), and furosemide is used to decrease the incidence of SHC. The aim of this study is to evaluate the incidence of SHC in dogs treated with a bolus maximum tolerated dose of oral cyclophosphamide and oral furosemide at a dose of 1 mg/kg. Medical records were reviewed to determine the incidence of SHC, dose and number of oral cyclophosphamide treatments, and the dose of furosemide. Other side effects from cyclophosphamide were also recorded. Eighty-one client-owned dogs that received a single oral maximum tolerated dose of cyclophosphamide concurrent with oral furosemide as part of a chemotherapy protocol for lymphoma were included in the study. A total of 252 doses of cyclophosphamide were administered to 81 dogs. The median dose of cyclophosphamide was 239.3 mg/m2. The median dose of furosemide was 1.08 mg/kg. SHC was suspected in 2 dogs (2.46%). Concurrent use of furosemide at a dose of 1 mg/kg with cyclophosphamide yields a similar incidence of SHC than using a higher dose of furosemide as previously reported., (© 2022 by American Animal Hospital Association.)

Guselkumab is a human IgG1λ monoclonal antibody that has been approved for treatment of multiple immunologic diseases including palmoplantar pustulosis in Japan. The efficacy of guselkumab in reducing disease severity as compared with placebo has been demonstrated in phase 2 and 3 clinical studies. In some patients assigned to the placebo treatment, worsening of Palmoplantar Pustulosis Area and Severity Index (PPPASI) score was noted. Most of these patients were smokers, raising a possibility of an association of smoking with the disease progression. To understand the clinical implications of guselkumab dose, baseline disease severity, and smoking on the treatment effect and describe the longitudinal relationship between guselkumab exposure and the PPPASI score, a pharmacokinetic/pharmacodynamic modeling analysis was conducted using the pooled data from 1 phase 2 and 1 phase 3 study. Data from 207 Japanese patients (77% women and 60% smokers) with a median PPPASI score of 24.6 were included in the analysis. The observed treatment efficacy (the PPPASI score reduction) appeared to be similar at the current approved dose (100 mg) and the higher dose (200 mg). A greater PPPASI score reduction (in absolute points) is expected in patients with higher baseline PPPASI score (severe disease). However, the higher baseline did not translate to larger magnitude of the change from baseline (in percentage) in the PPPASI score. Incorporating a linear disease progression effect in the model significantly decreased the Nonlinear Mixed Effects Modeling objective function value (P < .001). Smoking status appeared to be related to disease worsening in some patients, but the covariate did not reach statistical significance in the model., (© 2021, The American College of Clinical Pharmacology.)

Introduction: We investigated the effectiveness of a self-gripping mesh, which has microgrips attached to fibrous tissue, in laparoscopic transabdominal preperitoneal (TAPP) obturator hernia (OH) repair to minimize the risk of postoperative pain and obturator nerve injury., Presentation of Case: The patient was an 80-year-old woman who was transferred to our emergency department with abdominal pain in the right lower quadrant and low back pain that began half a day prior to presentation. Computed tomography (CT) detected right OH. Based on the results of the laboratory examination and dynamic CT, intestinal viability was maintained. Ultrasonography-assisted manual reduction of the incarcerated intestine was performed, followed by admission to our department to check for delayed perforation of the intestine. Laparoscopic TAPP OH repair was performed on day seven as an elective surgery. A self-gripping mesh was placed over the OH defect and the femoral ring without tacking. The patient was discharged on postoperative day four, without any complications., Discussion: Tacking of the mesh at the lateral and dorsal sides of the obturator canal is dangerous due to the presence of the obturator nerve and vessels. Self-gripping mesh use in laparoscopic TAPP OH repair is a rational decision in terms of avoiding tacking or suturing around the obturator canal while maintaining stable fixation of the mesh to prevent recurrence., Conclusion: Laparoscopic TAPP OH repair with self-gripping mesh is a rational treatment option that reduces the risk of obturator nerve injury while maintaining the secure fixation of a mesh to prevent recurrence., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aim: Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy of DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity., Methods: Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed., Results: Co-treatment of DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS., Conclusion: Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice., Competing Interests: Conflicts of interest The authors report no conflict of interest

Background: Vaccination is one of the effective ways to develop immunity against potential life-threatening diseases in children in early age. This study is focused on analysing the age-appropriate vaccination coverage at national and subnational levels and identify the factors associated with age-appropriate coverage in Nepal., Methods: 460 children aged 12-36 months were included in the study. The data was obtained from Nepal Demographic and Health Survey (NDHS) 2016-17. Age-appropriate coverage of Bacillus Calmette-Guerin vaccine (BCG), oral polio vaccine (OPV) doses 1-3, pentavalent vaccine (PE) doses 1-3, and first dose of measles, mumps, and rubella vaccine (MMR) were estimated using Kaplan Meier method. Multilevel logistic regression with random intercept was used to identify the factors associated with age-appropriate vaccination., Results: The crude coverage of the vaccines included in the study ranged from 91.5% (95% CI, 88.5-93.7) for PE3 to 97.8% (95.8-98.7) for BCG. Although the crude coverage of all the vaccines was above 90%, the age-appropriate coverage was significantly low, ranging from 41.5% (36.5-46.6) for PE3 to 73.9% (69.2-78.1) for PE1. Furthermore, high disparity in timely vaccination coverage was observed at regional level. Compared to the age-appropriate vaccination coverage in other provinces, Province 2 had the lowest coverage of all, followed by that in Province 6. The timeliness of vaccination was significantly associated with subnational regions i.e., provinces and the season of childbirth., Conclusion: Although the immunization program in Nepal has achieved the target of 90% crude coverage of all the childhood vaccines, the age-appropriate coverage is significantly low which undermines the effectiveness of the vaccines administered. Thus, along with crude coverage, timeliness of the vaccines administered should be taken into consideration and thoroughly monitored at national and subnational levels. Provincial government should formulate tailored strategies to ensure the timely administration of the childhood vaccines., (© 2021. The Author(s).)

Introduction: Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) is complicated by bile leakage or liver failure, especially in patients with hepatocellular carcinoma (HCC). Precise surgical performance supported by high quality intraoperative surgical visualization is essential to prevent mortality. Therefore, we aimed to investigate, for the first time, the effects of introducing a surgical microscope (ORBEYE™) intraoperatively during a stage I ALPPS., Presentation of Case: The patient was a 77-year-old male patient with a 9-cm right hepatic lobe HCC. 4K-3D surgical microscope-assisted ALPPS was performed to manage the insufficient future liver remnant following right lobectomy. Hilar dissection was performed first; thereafter, the right portal vein was ligated, and the right hepatic artery and right hepatic vein were encircled by surgical tape. The parenchyma was split along the ischemic demarcation line with indocyanine green (ICG) fluorescence navigation using the microscope. The remnant liver volume and function increased without postoperative complications., Discussion: Laparoscopic approach for ALPPS benefits from enhanced intraoperative visualization in a deep, narrow operative field. However, a laparoscopic procedure requires an experienced learning curve and a longer operation time, whereas using the 4 K 3D digital microscope requires no technical demand. Secondly, it provided an excellent operative view during ALPPS., Conclusions: To our knowledge, this is the first report on the intraoperative application of the ORBEYE™ surgical microscope in hepatic surgery with 4K3D imaging and ICG-fluorescence navigation, which minimized the invasiveness of ALPPS and ensured high safety and precision., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tuberculosis (TB) has still remained a serious global health threat in low- and middle-income countries in recent years. As of 2021, Nepal is one of the high TB burden countries, with an increasing prevalence of cases. This study evaluates factors associated with TB awareness in Nepal. This study uses data from the Nepal Demographic and Health Survey, a cross-sectional survey carried out from June 2016 to January 2017. Multilevel logistic regression is performed to examine the association of demographic and socioeconomic factors with TB awareness. Our findings show a high level of TB awareness in all seven provinces of Nepal. Province 5 has the highest level of awareness (98.1%) among all provinces, followed by provinces 3 and 4, while province 6 has the lowest awareness level (93.2%) compared to others. Socioeconomic factors such as wealth, education and owning a mobile phone are significantly associated with TB awareness. Socioeconomic determinants are influential factors associated with TB awareness in Nepal. The wide variation in the proportion of awareness at a regional level emphasizes the importance of formulating tailored strategies to increase TB awareness. For instance, the use of mobile phones could be an effective strategy to promote TB awareness at a regional level. This study provides valuable evidence to support further research on the contribution of information and communication technology (ICT) usage to improving TB awareness in Nepal.

We investigated the susceptibility of type I and type II skeletal myofibres to atrophy in hens with hepatic fibrosis induced by bile duct ligation (BDL). Seven hens, approximately 2 years old, were randomly assigned to BDL (n = 4) and sham surgery (SHAM) (n = 3) groups. Mean body weight and mean liver weight as a percentage of mean body weight were significantly lower in the BDL group than in the SHAM group at 4 weeks post surgery (P = 0.002, P = 0.005, respectively). Mean plasma aspartate aminotransferase activity was slightly higher, while total cholesterol (P <0.001), total bilirubin (P = 0.022) and NH 3 (P = 0.048) concentrations were significantly higher in the BDL group than in the SHAM group. Liver lesions were induced in all hens in the BDL group. The weights of the pectoralis (PCT) (P = 0.049) and flexor perforans et perforatus digiti III (FPPD III) muscles (P = 0.006) as a percentage of body weight were significantly decreased in the BDL group. A significantly reduced mean myofibre cross-sectional area in the PCT of BDL hens (P = 0.005) was indicative of atrophy. No significant differences were observed in the fibre type composition of the PCT, supracoracoideus or FPPD III muscles between the SHAM and BDL groups. However, there was an approximate 43% increase in the number of type I fibres in the femorotibialis lateralis of the BDL group and small angular type II fibres and large round type I fibres in this muscle were characteristic of peripheral neuropathy. The results suggest that type II fibres are more susceptible to atrophy than type I fibres in this model of hepatic fibrosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Policymaking for science, technology, and innovation (R&D) is stepping into a new era in the twenty-first century within a highly integrated production network, making it more challenging to capture the impact of R&D investment from an evidence-based approach. To unfold the paradox of the R&D spillover effect spared in the global supply chain, we use computable general equilibrium model with the GTAP database v10 to analyze the impact of Japan's public R&D investment to the world focus on key sectors of global supply chain, namely chemical and pharmaceutical, electronic equipment, machinery, and transportation equipment to examine its output, external trades, and welfare. The productivity parameters triggered by public R&D investment are calibrated from the SciREX Policymaking Intelligent Assistance System-Economic Simulator (SPIAS-e). The simulation results show significant increase in Japan's output and export for chemical and pharmaceutical, electronic equipment, and transportation equipment. The GDP growth was stimulated by 0.6% and substantial welfare improvement by USD 78,000 million, while other countries such as Malaysia and Taiwan by 0.4-0.6%. In contrast, the economic indicators of China reveal a negative impact, implying a structural change in the composition of the production network. It is notable to see a higher economic integration of Oceania within the region through its vibrant production and trades. The study provides comprehensive global analysis on production networks and insights for evaluating the R&D investment spillover effects., (© Institute for Social and Economic Change 2020.)

Background: A higher incidence of apalutamide-related skin rash has been observed in Japanese patients with prostate cancer (PC)., Methods: This integrated analysis of data of Japanese patients from 2 global Phase 3 studies, SPARTAN ( NCT01946204 ; patients with non-metastatic castration-resistant PC [nmCRPC]) and TITAN ( NCT02489318 ; patients with metastatic castration-sensitive PC [mCSPC]), and the Phase 1 study 56021927PCR1008 ( NCT02162836 ; patients with metastatic CRPC [mCRPC]), assessed clinical risk factors of apalutamide-related skin rash as well as the potential correlation with plasma exposure to apalutamide. Kaplan-Meier method was used for time-to-event analyses. Clinical risk factors for skin rash were assessed using odds ratio., Results: Data from 68 patients (SPARTAN: n = 34, TITAN: n = 28, 56021927PCR1008: n = 6) receiving apalutamide 240 mg orally once-daily were analyzed. Rash (13 [19.1%]) and maculo-papular rash (11 [16.2%]) were the most frequently reported skin rash. All Grade and Grade 3 skin rash occurred in 35 (51.5%) and 10 (14.7%) patients, respectively. Most (85.7%) skin rash occurred within 4 months of apalutamide initiation and resolved in a median time of 1 month following the use of antihistamines, topical or systemic corticosteroids, with/without apalutamide dose interruptions/reductions. Median time-to-remission of first incidence of rash and maximum grade incidence of rash were 1.0 month (IQR: 0.36-1.81) and 1.0 month (IQR: 0.30-2.43), respectively. No significant clinical risk factors for the incidence of skin rash were observed. Areas under the curve (0-24 h) (AUC 0-24, ss ) at steady-state of plasma apalutamide concentration were numerically slightly higher in patients with skin rash than those without., Conclusions: No clinical risk factors for rash could be detected. There is a potential correlation between incidence of skin rash and plasma exposure to apalutamide. In general, apalutamide-related skin rash is easily managed, with appropriate treatment with or without dose adjustment., Trial Registration: Retrospective pooled analysis of NCT01946204 , NCT02489318 , and NCT02162836 .

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that elicits a number of biological functions, including smooth muscle contraction, cell motility, proliferation, and morphological change. LPA is endogenously produced by autotaxin (ATX) from extracellular lysophosphatidylcholine (LPC) in plasma. Herein, we report our medicinal chemistry effort to identify a novel and highly potent ATX inhibitor, ONO-8430506 ( 20 ), with good oral availability. To enhance the enzymatic ATX inhibitory activity, we designed several compounds by structurally comparing our hit compound with the endogenous ligand LPC. Further optimization to improve the pharmacokinetic profile and enhance the ATX inhibitory activity in human plasma resulted in the identification of ONO-8430506 ( 20 ), which enhanced the antitumor effect of paclitaxel in a breast cancer model., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Bacterial sialidases are widely used to remove sialic acid (Sia) residues from glycans. Most of them cleave the glycosides of N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) under acidic pHs; however, currently available bacterial sialidases had no activity to the glycosides of deaminoneuraminic acid (Kdn). In this study, we found a novel sialidase from Sphingobacterium sp. strain HMA12 that could cleave any of the glycosides of Neu5Ac, Neu5Gc, and Kdn. It also had a broad linkage specificity, i.e., α2,3-, α2,6-, α2,8-, and α2,9-linkages, and the optimal pH at neutral ranges, pH 6.5-7.0. These properties are particularly important when sialidases are applied for in vivo digestion of the cell surface sialosides under physiological conditions. Interestingly, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (Neu5Ac2en), which is a transition state analog-based inhibitor, competitively inhibited the enzyme-catalyzed reaction for Kdn as well as for Neu5Ac, suggesting that the active site is common to the Neu5Ac and Kdn residues. Taken together, this sialidase is versatile and useful for the in vivo research on sialo-glycoconjugates., Competing Interests: Declaration of competing interest On behalf of all the authors for this manuscript, the corresponding author declare: None declared., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13 , which paved the path to our clinical candidate., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC., Methods: In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1., Results: All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC 0-24 . Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92-310.11) ng/mL at baseline to 11.70 (0.37-47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients., Conclusion: Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients., Trial Registration: ClinicalTrials.gov identifier: NCT02162836.

Introduction : Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities. Area covered : Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins. Expert opinion : Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.

Older people living alone has been reported to be socially isolated and suffering from loneliness. Although spiritual care is a core element of end-of-life care for older people, a clear-cut definition of spirituality has not been established yet. It remains unclear how spirituality is perceived by heath care professionals and how spiritual care is delivered in the end of life. Also, most of the previous studies on perspective of older people living alone targeted women, while very few researches shed light on the experience of older men. The aim of the present study was to investigate the spirituality of older men living alone near the end-of-life. We conducted group interviews targeting 30 care managers and individual in-depth interviews to 15 older men living alone. Qualitative content analysis was used. Five main themes emerged: worthlessness and hopelessness, autonomy and independence, comfort and gratitude, past experiences, and well-being indicator. Our findings provide important additional information that can help clinicians, nurses and care managers achieve better patient-centered care for older men living alone and enhance their dignity. Our investigation found that Japanese older men living alone were enjoying their autonomous status and freedom, despite wide spread negative views of them. Their spiritual health was found to be enhanced through gratitude to everyone with whom they had crossed paths in their life, yearning for the presence of a female companion, and confirming their health measurements were comparative or better than those of others in the same age group., Competing Interests: The authors have no conflict of interest to declare.

Introduction: The mortality due to uterine cervical cancer has been gradually increasing in women under 40 years of age (U40) in Japan. We investigated the effect of high-risk human papillomavirus (HR-HPV) on U40 subjects without any overt cytological abnormalities., Materials and Methods: We retrospectively examined the clinical data, including the findings of a cobas 4800 HPV test that was approved in Japan in 2013 to triage women with atypical squamous cells of undetermined significance (ASC-US) and a histological examination in 589 Japanese women., Results: The overall prevalence rate of HR-HPV was 34.5%. Biopsy-confirmed cervical intraepithelial neoplasia (CIN) 2, or worse (CIN2+) was identified in 45.1% (23/51) of HR-HPV-positive women with ASC-US, who underwent colposcopy immediately. The mean period from the HPV test to the diagnosis of CIN2+ was 3.7 months. CIN2+ was more common (69.6%) in U40 patients. The rates of single or multiple infections of HPV-16, HPV-18, and 12 other HR-HPV (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) in CIN2+ U40 patients were 31.3%, 0%, and 81.3%, respectively. The relative risk for CIN 2+ among U40 women with HPV-16 was not significantly different from that of the patients with infection of any of the 12 other HR-HPVs., Conclusion: The results of this study suggest that the 12 other HR-HPVs have a potential to generate high-grade cervical lesions among young women, and the examination rate of colposcopy should be increased., Competing Interests: There are no conflicts of interest.

Background: Myxosarcomas are known to be classified as soft tissue sarcomas. However, there is limited clinical characterization pertaining specifically to canine cutaneous myxosarcomas in the literature. The objective of this study is to evaluate the local recurrence rate, metastatic rate and prognosis of canine myxosarcoma., Results: A total of 32 dogs diagnosed with myxosarcoma via histopathology were included in this retrospective study. All dogs had surgical resection. No adjunct treatments were performed in 9 dogs, while 22 dogs also received either radiation therapy or chemotherapy, or a combination of both. One dog received only NSAID after surgery. Overall median survival time (MST) was 730 days (range 20-2345 days). The MST of dogs with a tumor mitotic count < 10/10 HPF was 1393 days (range 20-2345 days). The dogs with a tumor mitotic count of 10 or greater/10 HPF had a MST of 433 days (range 169-831 days). There was no significant difference of MST among different treatment modalities. Local recurrence was noted in 13 cases (40.6%) and the median time to recurrence was 115.5 days (range 50-1610 days). The median time to local recurrence in dogs with mitotic count of < 10/10 HPF was 339 days (range 68-1610 days) and in dogs with mitotic count of 10 or greater/10 HPF was 119 days (range 50-378). Metastasis to local lymph node or lung was noted in 8 cases (25%) with median time to metastasis of 158.5 days (range 0-643 days)., Conclusions: Based on the results of this retrospective study, myxosarcoma may have a higher local recurrence rate and risk of metastasis to the local lymph nodes compared to other soft tissue sarcomas.

The patient was a 42-year-old man who presented with dysphagia.Upper gastrointestinal endoscopy revealed a protruding lesion in the lower thoracic esophagus.Pathological analysis of the lesion showed squamous cell carcinoma.Laboratory data showed leukocytosis(21,200/mL)despite no evidence of infection, and the serum levels of granulocyte colony-stimu- lating factor(G-CSF)were elevated to 283 pg/mL.We diagnosed him with esophageal squamous cell carcinoma(Lt, type 1, cT4N4M0, cStage IV a).After administering 2 courses of docetaxel plus cisplatin plus S-1(DCS)as neoadjuvant chemotherapy, the patient underwent surgery.The pathological diagnosis was pType 2, T2, N4, M0, pStage IV a. G-CSF immunostaining was positive in tumor cells.After the surgery, the number of leukocytes and serum G-CSF levels decreased to within normal limits.Adjuvant chemotherapy was administered.

This single-center, double-blind, placebo-controlled, sequential-group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ-39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single-ascending-dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m 2 ). In part 2, a multiple-ascending-dose study, 36 Japanese subjects were enrolled and received once-daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single-dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady-state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half-life, ranging from 68 to 101 and 82-130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men., (© 2017, The American College of Clinical Pharmacology.)

A 10-year-old greyhound dog was presented because of an incidental finding of a tonsillar mass. Excisional surgical biopsy was performed and the dog was diagnosed with an incompletely resected plasma cell tumor. Adjuvant therapy was declined. One year later there was no local recurrence or distant metastasis of the mass or clinical signs associated with the tonsillar plasmacytoma.

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.

Lissencephaly is one of the central nervous system anomalies of Miller-Dieker Syndrome (MDS). Fetuses with lissencephaly have an abnormal smooth brain with fewer folds and grooves that will be detected by ultrasounds or fetal magnetic resonance imaging (MRI) after 30 weeks of gestation. We report a fetus with lissencephaly diagnosed as Miller-Dieker Syndrome postnatally. G banded chromosome analysis revealed 45,X,psu dic(17;Y)(p13;p11.32).ish dic (17;Y)(LIS1-,RARA+, SRY+, DYZ3+) by G-banding analysis using high resolution banding technique. Fetal delayed cortical development will be the findings to perform further investigations including fluorescence in situ hybridization analysis for MDS, a 17p13.3 microdeletion syndrome, pre/postnatally. This will be the first case of MDS with unbalanced translocation between deleted short arm of chromosome 17 and Y chromosome., (© 2016 Japanese Teratology Society.)

Introduction: It is unclear whether hysterotomy closure techniques can affect niche development. Therefore, this study aimed to analyze the effect of single-layer and double-layer interrupted closures of hysterotomy incisions during primary cesarean section on the formation of uterine niches., Material and Methods: A prospective cohort study of women undergoing primary cesarean section was performed between June 2011 and July 2014. Saline contrast sonohysterography was used to measure the niche depth and residual myometrium. The ratio of the niche depth to the sum of the niche depth and residual myometrium thickness (niche ratio) was calculated., Results: Niches were identified in 14/58 (24.1%) women with single-layer sutures and 55/209 (26.3%) women with double-layer sutures (p = 0.74). Single-layer closure was associated with more than a five-fold increase in the odds of a niche ratio ≥0.4 (odds ratio 5.59; 95% CI 1.71-18.28)., Conclusion: Single-layer closure may be associated with an increased risk of larger niches (niche ratio ≥0.4), although it may not increase the overall frequency of niche formation., (© 2016 Nordic Federation of Societies of Obstetrics and Gynecology.)

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

The first patient was a man in his eighties who visited our department because of anemia. Gastrofiberscopy revealed a bleeding submucosal tumor, approximately 50mm in diameter, in the cardia ofthe stomach. Considering that he underwent coronary-artery bypass surgery and received 3 oral antithrombotic medicines, his bleeding tendency was so high that we decided to choose partial gastrectomy. A postoperative histopathological examination revealed that the tumor was a small cell endocrine carcinoma. The second patient was a woman in her seventies. She had consulted her personal physician because of gastric ulcers; periodic gastrofiberscopy revealed a type 3 gastric cancer, approximately 40mm in diameter, on the posterior wall ofthe middle section ofher stomach. It was histologically diagnosed as a poorly differentiated neuroendocrine carcinoma. On a preoperative blood examination, the levels ofhormones such as glucagon, serotonin, and gastrin were within their respective normal limits. Total gastrectomy was performed, and she received oral S-1 for adjuvant chemotherapy since her discharge from the hospital.

Background: Many patients with acute exacerbation of asthma are non-responders to inhaled β-adrenergic agonists. The goal of this study was to evaluate the safety and efficacy of intravenous bedoradrine (MN-221), a highly selective β2-adrenergic agonist, as adjunct to standard therapy in the management of patients with acute exacerbation of asthma who did not respond to standard therapy., Methods: Patients (N = 167) received standard therapy and were randomized to either bedoradrine (1200 μg) or placebo. Safety and efficacy parameters were monitored hourly for 3 h, followed by a 24-h follow-up visit and an 8-day follow-up phone call. Change in %FEV1 from baseline to Hour 3 was the primary outcome. Secondary outcome measures included change in %FEV1 at 1 and 2 h, change in dyspnea score at 1, 2, and 3 h, treatment failure rate, defined as a combination of hospitalization on the index visit or return to the emergency department within 1 week, and safety monitoring., Results: There was no significant difference in %FEV1 at 3 h between the 2 groups. The dyspnea scores were significantly improved for patients treated with bedoradrine compared to placebo (AUC0-2 hP < 0.005, AUC0-3 hP < 0.05). The safety profile for those treated with bedoradrine was consistent with the known mechanism of action of β-adrenergic agonists, and included both cardiovascular and metabolic effects., Conclusions: Intravenous bedoradrine, in addition to standard therapy, did not significantly increase %FEV1 at 3 h, but it was associated with significantly improved dyspnea scores., Trial Registration: Clinicaltrials.gov; study name: MN-221-CL-007, registration number: NCT00838591; www.clinical trials.gov., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose of Investigation: To assess the effects of the diclofenac suppository pretreatment in prevention of vasovagal reflex-associated complications for infertile women undergoing local endometrial injury (LEI)., Materials and Methods: Eighty-six infertile outpatients with repeated implantation failure following transfer of morphologically good embryos and/or blastocysts underwent single curettage LEI to improve the pregnancy outcome in the subsequent embryo/blastocyst transfer cycle. Of them, 35 patients chose diclofenac suppository administration prior to LEI, whereas 51 patients did not. The occurrence of palpitations, bradycardia, hypotension, presyncope, and requirement of bed rest was compared between the two groups., Results: There were no significant differences in the demographics between the two groups. The prevalence of presyncope and requirement of bed rest was significantly lower in the diclofenac suppository group than in the control group. The pregnancy outcome was similar between the two groups., Conclusion: The diclofenac suppository administration is a low-cost effective method to reduce the risk of the vasovagal reflex-associated complications in infertile women undergoing LEI.

Purpose of Investigation: To investigate prospectively if the pregnancy outcome in infertile women undergoing assisted reproductive technology (ART) is predictable by a combination of psychological stress examinations on the day of embryo/blastocyst transfer., Materials and Methods: From April 2012 to May 2012, 114 women aged 42 years old or less underwent transfer of morphologically-good embryo/blastocyst(s) in the present in vitro fertilization (IVF) center. Immediately before the transfer, salivary secretion was obtained and frozen. α-amylase and cortisol concentrations were quantified using biochemical assays. In addition, patients were asked to answer General Health Questionnaire 28 (GHQ28) and Zung's Self Rating Depression Scale (SDS) following transfer. The results were compared between the pregnant group and non-pregnant group., Results: There were no significant differences in the age of the infertile couples between the pregnant group and non-pregnant group as well as body mass index of the infertile women. The GHQ28 and SDS scores were similar between the two groups, as were the salivary α-amylase and cortisol concentrations., Conclusion: This prospective study failed to demonstrate the predictivity of the pregnancy outcome by psychological stress examinations in infertile women in an ART program, even though these tests were used in combination.

Primary renal lymphoma (PRL) is a rare disease which is often mistaken for renal cell carcinoma. In the present study, a 56-year-old man visited a clinic complaining of an intermittent fever and right flank pain. A computerized tomography examination revealed a hypoenhancing mass in his right kidney. Radical nephrectomy was conducted, and a diagnosis of diffuse large B-cell lymphoma was confirmed. The present case was determined to be a true PRL according to the results of a positron emission tomography examination and a bone marrow biopsy to rule out any lymphoma invasions apart from the right kidney.

The authors report a case of transient azoospermia following hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitor rosuvastatin medication for hypercholesterolemia. While a primary infertile couple with oligoasthenospermia was preparing for an in vitro fertilization program, the male partner had been diagnosed with hypercholesterolemia in a medical check-up and prescribed four-week oral administration of rosuvastatin. No motile spermatozoa were found in the ejaculated semen and urine on the day of follicular aspiration. Azoospermia was confirmed by reexamination in weeks 3 and 7. Spermatozoa appeared in the ejaculated semen in two weeks of drug withdrawal. In week 16, the sperm count and motility increased to the level where intracytoplasmic sperm injection was available.

Human cycling endometrium displays a series of periodic transitions unique to this mucosal tissue, which includes rapid proliferation, secretory transformation, physiological angiogenesis, interstitial edema, and menstrual shedding. Among these properties of the endometrium are the inflammatory changes that occur dynamically across the menstrual cycle. Immunocompetent cell composition and inflammatory gene expression pattern in the human endometrium drastically fluctuate from the proliferative phase to the secretory phase, particularly at the time of ovulation. These local immune responses are fine-tuned by the direct or indirect action of two representative ovarian steroids, estradiol and progesterone, and are essential for successful blastocyst implantation. Meanwhile, studies have been accumulating the evidence that such physiological endometrial inflammatory status is altered in the presence of certain gynecologic pathologies. Given that blastocysts are semi-allografts for maternal tissue, even subtle alterations in endometrial immunity potentially have a negative impact on implantation process. In this article, we aimed to review and discuss the physiological and pathological mucosal inflammatory conditions that can affect endometrial receptivity.

Rabies is a fatal zoonotic disease for which no effective treatment measures are currently available. Rabies virus (RABV) has anti-apoptotic and anti-inflammatory properties that suppress nerve cell damage and inflammation in the CNS. These features imply that the elimination of RABV from the CNS by appropriate treatment could lead to complete recovery from rabies. Ten rabbits showing neuromuscular symptoms of rabies after subcutaneous (SC) immunization using commercially available vaccine containing inactivated whole RABV particles and subsequent fixed RABV (CVS strain) inoculation into hind limb muscles were allocated into three groups. Three rabbits received no further treatment (the SC group), three rabbits received three additional SC immunizations using the same vaccine, and four rabbits received three intrathecal (IT) immunizations, in which the vaccine was inoculated directly into the cerebrospinal fluid (the SC/IT group). An additional three naïve rabbits were inoculated intramuscularly with RABV and not vaccinated. The rabbits exhibited neuromuscular symptoms of rabies within 4-8 days post-inoculation (dpi) of RABV. All of the rabbits died within 8-12 dpi with the exception of one rabbit in the SC group and all four rabbits in SC/IT group, which recovered and started to respond to external stimuli at 11-18 dpi and survived until the end of the experimental period. RABV was eliminated from the CNS of the surviving rabbits. We report here a possible, although still incomplete, therapy for rabies using IT immunization. Our protocol may rescue the life of rabid patients and prompt the future development of novel therapies against rabies., (© 2014 The Authors. Neuropathology published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Society of Neuropathology.)