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Abstract Introduction Mutated human epidermal growth factor receptor 2 (HER2) is an oncogene with critical pathogenic roles in breast cancer. HER2-low-positive breast cancer is a recently described subtype. We aimed to explore the clinical and molecular characteristics of gastric cancer with low HER2 expression, drawing on recent developments in breast cancer subtypes. Materials and methods This retrospective study involved 129 patients with HER2-non-amplified gastric cancer treated in Iwate prefectural Iwai Hospital from 2013 to 2019. Tumors were classified as HER2-null or low-positive based on immunohistochemistry score 0 or 1 + or 2 + with HER2 negativity in situ hybridization, respectively. Statistical analyses, including Kaplan–Meier analyses and Cox proportional hazards model were conducted. Results Low HER2 expression was present in 26% (33/129) of the patients. Clinicopathological characteristics were not significantly different between the HER2-low and null groups. Kaplan–Meier analysis of overall survival was significantly longer in the HER2-low group than in the HER2-null group (P = 0.01). In multivariate Cox regression analysis, HER2-null status was associated with worse survival (hazard ratio 3.01; 95% confidence interval 1.18–7.65; and P = 0.02). Conclusion This study highlights the prognostic importance of low HER2 expression in gastric cancer, similar to that observed in HER2-low-positive breast cancer, and suggests reclassification of gastric cancer to improve personalized treatment. Future studies should elucidate the molecular underpinnings of low HER2 expression in gastric cancer to guide novel therapeutic strategies and improve outcomes.

Abstract The current study aimed to identify the indications for manual reduction in incarcerated obturator hernias (OH). Further, whether time to symptom onset and manual reduction outcomes can be predictors of bowel viability and the need for bowel resection in incarcerated OH were examined. This retrospective study included 26 patients with incarcerated OH who underwent surgery. All patients underwent manual reduction, and computed tomography scan after manual reduction confirmed hernia release. Multivariate analyses were performed to determine the predictors of bowel resection. The bowel resection group had a significantly longer average time to symptom onset than the nonbowel resection group (88 vs 36 h). Further, the bowel resection group was more likely to have failed manual reduction than the nonbowel resection group. A time to symptom onset of ≥ 72 h and failed manual reduction were significant predictors of bowel viability. Age, sex, hernia localization, American Society of Anesthesiologists physical status score, and laboratory findings did not differ significantly between the bowel resection and nonbowel resection groups. Time to symptom onset and manual reduction outcomes are significant predictors of bowel viability in incarcerated OH. Patients with a time to symptom onset of ≥ 72 h and failed manual reduction require surgical evaluation due to a high risk of bowel nonviability. Therefore, a cautious approach is required in the management of OH, and further research on optimized treatment protocols should be conducted.

Abstract INTRODUCTION The use of anti‐epileptic drugs (AEDs) in degenerative dementia (DD) remains uncertain. We aimed to evaluate the association of early AED administration with subsequent DD occurrence. METHODS Using a large nationwide database, we enrolled patients newly diagnosed with epilepsy from 2014 to 2019 (n = 104,225), and using propensity score matching, we divided them into treatment (those prescribed AEDs in 2014) and control groups. The primary outcome was subsequent DD occurrence in 2019. RESULTS Overall, 4489 pairs of patients (2156 women) were matched. The odds ratio (treatment/control) for DD occurrence was 0.533 (95% confidence interval: 0.459–0.617). The DD proportions significantly differed between the treatment (340/4489 = 0.076) and control (577/4489 = 0.129) groups. DISCUSSION Among patients newly diagnosed with epilepsy, compared to non‐use, early AED use was associated with a lower occurrence of subsequent DD. Further investigations into and optimization of early intervention for epilepsy in DD are warranted. Highlights Anti‐epileptic drug (AED) use before epilepsy diagnosis was linked with a lower subsequent degenerative dementia (DD) occurrence. Identifying the epileptic phenotype was crucial for justifying early AED use in DD. AED use with an epilepsy diagnosis did not pose an additional risk of DD. The potential contribution of combination drug therapy to the strategy was noted.

Abstract Emergent surgery is a common approach for incarcerated obturator hernias, with high morbidity and mortality rates. Moreover, there have been reports of elective surgery cases after noninvasive manual reduction. For a decade, the initial approach in our institution is also manual reduction unless bowel viability is poor. This study aimed to clarify the efficacy and safety of manual reduction followed by elective surgery. We retrospectively reviewed 50 cases of incarcerated obturator hernia from 2010 to 2022 at Iwate Prefectural Iwai Hospital. Manual reduction was attempted in 31 (62%) patients. The reduction was successful in 21 (42%) patients, and most of them received mesh repair using the extraperitoneal approach as elective surgery. However, two patients underwent emergent surgery in the waiting period because of late-onset constriction and a small bowel perforation. Patients with irreducible hernia underwent emergent surgery, except for two patients who received the best supportive care. Postoperative complications were observed in 5% and 22% of reducible and irreducible cases, respectively. Postoperative mortality was zero in both groups. Manual reduction is useful in some cases, but careful observation is needed because late-onset constriction and perforation could occur.

Many viruses often use a protein degradation system (e.g., the ubiquitin-proteasome pathway or lysosome pathway) to modulate viral propagation and viral pathogenesis. We reported that hepatitis C virus (HCV) infection promotes the lysosomal degradation of hepatocyte nuclear factor-1α (HNF-1α) via chaperone-mediated autophagy (CMA) through an NS5A-mediated association of HNF-1α with cellular chaperone heat shock cognate 70 kDa (HSC70) protein. HSC70 binds to the pentapeptide KFERQ motif (also known as a CMA-targeting motif) on HNF-1α protein and promotes the lysosomal degradation of HNF-1α. The KFERQ motif plays a crucial role in the two lysosomal degradation pathways, CMA and endosomal microautophagy (eMI). Herein, we searched for a novel substrate of HCV-induced lysosomal degradation by examining the NS5A-interacting proteins that carry the KFERQ motif. We identified diacylglycerol O-acyltransferase 1 (DGAT1), which is a key factor for HCV particle formation, as a candidate substrate for HCV-induced lysosomal degradation pathway. The region spanning from amino acids 149–153 of DGAT1 protein matches the rule for the KFERQ motif. DGAT1 protein was co-immunoprecipitated with HSC70, whereas DGAT1 Q149A mutant was not co-immunoprecipitated with HSC70, suggesting that the KFERQ motif is responsible for the interaction between DGAT1 and HSC70. Knockdown of LAMP-2A protein in HCV J6/JFH1-infected cells did not recover DGAT1 protein, whereas knockdown of VPS4B recovered the level of DGAT1 protein, suggesting that DGAT1 is degraded via eMI. These findings lead us to propose that HCV NS5A protein facilitates the recruitment of HSC70 to DGAT1, thereby promoting the lysosomal degradation of DGAT1 via eMI. Abbreviations 3-MA: 3-methyladenine; aa: amino acids; AH: amphipathic helix; BSA: bovine serum albumin; CMA: chaperone-mediated autophagy; DAAs: direct-acting antiviral; DGAT1: diacylglycerol O-acyltransferase 1; DMSO: dimethyl sulfoxide; EL: extracellular lumen; eMI: endosomal microautophagy; ESCRT: endosomal sorting complex required for transport; HA: hemagglutinin; HCV: hepatitis C virus; HNF-1α: hepatocyte nuclear factor-1α; HRP: horseradish peroxidase; HSC70: heat shock cognate 70 kDa protein; IB: immunoblotting; IL: intracellular lumen; IP: immunoprecipitation; LAMP-2A: lysosome-associated membrane protein type 2A; LCS: low-complexity sequences; mAb: monoclonal antibody; MOI: multiplicity of infection; MVB: multivesicular bodies; NS: nonstructural protein; pAb: polyclonal antibody; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PLA: proximity ligation assay; PS: phosphatidylserine; RT: room temperature; TM: transmembrane; TSG: tumor susceptibility gene; VPS4A: vacuolar protein sorting-associated protein 4A; VPS4B: vacuolar protein sorting-associated protein 4B

Abstract Upright computed tomography (CT) provides physiologically relevant images of daily life postures (sitting and standing). The volume of the human airway in sitting or standing positions remains unclear, and no clinical study to date has compared the inspiratory and expiratory airway volumes and luminal areas among standing, sitting, and supine positions. In this prospective study, 100 asymptomatic volunteers underwent both upright (sitting and standing positions) and conventional (supine position) CT during inspiration and expiration breath-holds and the pulmonary function test (PFT) within 2 h of CT. We compared the inspiratory/expiratory airway volumes and luminal areas on CT among the three positions and evaluated the correlation between airway volumes in each position on CT and PFT measurements. The inspiratory and expiratory airway volumes were significantly higher in the sitting and standing positions than in the supine position (inspiratory, 4.6% and 2.5% increase, respectively; expiratory, 14.9% and 13.4% increase, respectively; all P

Abstract Background Phlebitis is an important complication occurring in patients with peripheral intravascular catheters (PIVCs). The risk factors for phlebitis in the intensive care unit (ICU) was examined. Methods A secondary analysis of a prospective multicenter cohort study was conducted, involving 23 ICUs in Japan—the AMOR–VENUS study. Consecutive patients aged ≥ 18 years admitted to the ICU with newly inserted PIVCs after ICU admission were enrolled. Characteristics of the ICU, patients, PIVCs, and the drugs administered via PIVCs were recorded. A marginal Cox regression model was used to identify the risk factors associated with phlebitis. Results A total of 2741 consecutive patients from 23 ICUs were reviewed for eligibility, resulting in 1359 patients and 3429 PIVCs being included in the analysis population. The median dwell time was 46.2 h (95% confidence interval [CI], 21.3–82.9). Phlebitis occurred in 9.1% (95% CI, 8.2–10.1%) of catheters (3.5 cases/100 catheter days). The multivariate analysis revealed that the only factors that increased the risk of developing phlebitis were drugs administered intravenously. This study included 26 drugs, and 4 were associated with increased phlebitis: nicardipine (HR, 1.85; 95% CI, 1.29–2.66), noradrenaline (HR, 2.42; 95% CI, 1.40–4.20), amiodarone (HR, 3.67; 95% CI, 1.75–7.71) and levetiracetam (HR, 5.65; 95% CI, 2.80–11.4). Alternatively, factors significantly associated with a reduced risk of phlebitis were: standardized drug administration measures in the ICU (HR, 0.35; 95% CI, 0.17–0.76), 30≤ BMI (HR, 0.43; 95% CI, 0.20–0.95), catheter inserted by a doctor as nurse reference (HR, 0.55; 95% CI, 0.32–0.94), and upper arm insertion site as forearm reference (HR, 0.52; 95% CI, 0.32–0.85). The nitroglycerin was associated with a reduced phlebitis risk (HR, 0.22; 95% CI, 0.05–0.92). Conclusion Various factors are involved in the development of phlebitis caused by PIVCs in critically ill patients, including institutional, patient, catheter, and drug-induced factors, indicating the need for appropriate device selection or models of care in the ICU. Trial registration: UMIN-CTR, the Japanese clinical trial registry (registration number: UMIN000028019, July 1, 2017).

Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The release of infectious HCV particles from infected hepatocytes is a crucial step in viral dissemination and disease progression. While the exact mechanisms of HCV particle release remain poorly understood, emerging evidence suggests that HCV utilizes intracellular membrane trafficking and secretory pathways. These pathways include the Golgi secretory pathway and the endosomal trafficking pathways, such as the recycling endosome pathway and the endosomal sorting complex required for transport (ESCRT)-dependent multivesicular bodies (MVBs) pathway. This review provides an overview of recent advances in understanding the release of infectious HCV particles, with a particular focus on the involvement of the host cell factors that participate in HCV particle release. By summarizing the current knowledge in this area, this review aims to contribute to a better understanding of endosomal pathways involved in the extracellular release of HCV particles and the development of novel antiviral strategies.

The vomeronasal system regulates sensing of various environmental cues. Here, the authors show that exposure to hemoglobin results in the activation of Vmn2r88+ vomeronasal sensory neurons in both male and female mice. However, exposure to hemoglobin enhances digging and rearing behaviour in lactating female mice only.

BackgroundPessimistic thinking about the future is one of the cardinal symptoms of major depression. Few studies have assessed changes in pessimistic thinking after undergoing cognitive behavioral therapy (CBT). A randomized clinical trial (RCT) was conducted with patients diagnosed with major depressive disorder (MDD) to determine whether receiving a course of CBT affects pessimistic future thinking using a future thinking task.MethodsThirty-one patients with MDD were randomly assigned to either CBT (n = 16) or a talking control (TC) (n = 15) for a 16-week intervention. The main outcomes were the change in response time (RT) and the ratio of the responses for positive valence, measured by the future thinking task. Secondary outcomes included the GRID-Hamilton Depression Rating Scale, the Beck Depression Inventory-Second Edition (BDI-II), the Dysfunctional Attitude Scale (DAS), and the word fluency test (WFT).ResultsRegarding the main outcomes, the CBT group showed reduced RT for the positive valence (within-group Cohen’s d = 0.7, p = 0.012) and negative valence (within-group Cohen’s d = 0.6, p = 0.03) in the distant future condition. The ratio of positive valence responses in both groups for all temporal conditions except for the distant past condition increased within group (distant future: CBT: Cohen’s d = 0.5, p = 0.04; TC: Cohen’s d = 0.8, p = 0.008; near future: CBT: Cohen’s d = 1.0, p < 0.001; TC: Cohen’s d = 1.1, p = 0.001; near past: CBT: Cohen’s d = 0.8, p = 0.005; TC: Cohen’s d = 1.0, p = 0.002). As for secondary outcomes, the CBT group showed greater improvement than the TC group regarding the need for social approval as measured by the DAS (p = 0.012).ConclusionPatients with MDD who received CBT showed a reduced RT for the positive and negative valence in the distant future condition. RT in the future thinking task for depressed patients may be a potential objective measure for the CBT treatment process. Because the present RCT is positioned as a pilot RCT, a confirmatory trial with a larger number of patients is warranted to elucidate the CBT treatment process that influences future thinking.Clinical trial registrationhttps://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000021028, identifier UMIN000018155.

Applications of Cu catalysts at high-temperature is a long-sought goal but limited by their serious deactivation due to low copper’s Tammann temperature. Here, the authors introduce an encapsulation layer to improve thermal stability at 800 °C by reconstructing electronic structure of Cu atoms.

Introduction: Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI. Setting: NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models. Methods: The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 106 cells will be transplanted into the injured spinal cord parenchyma 14–28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000035074; Japan Registry of Clinical Trials [jRCT] number, jRCTa031190228). Discussion/conclusion: We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.

Abstract Aims Heart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non‐SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction. Methods We evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non‐cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate ‘proportion’ of SCD among death events) would affect its performance. Results The mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2‐year follow‐up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non‐cardiac death). Absolute risk of PFD (P

IntroductionPeripheral intravascular catheters (PIVCs) are inserted in most patients admitted to the intensive care unit (ICU). Previous research has discussed various risk factors for phlebitis, which is one of the complications of PIVCs. However, previous studies have not investigated the risk factors based on the patient’s severity of illness, such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Different treatments can be used based on the relationship of risk factors to the illness severity to avoid phlebitis. Therefore, in this study, we investigate whether the risk factors for phlebitis vary depending on the APACHE II score.Materials and methodsThis study was a post hoc analysis of the AMOR-VENUS study involving 23 ICUs in Japan. We included patients with age ≥ 18 years and consecutive admissions to the ICU with PIVCs inserted during ICU admission. The primary outcome was phlebitis, and the objective was the identification of the risk factors evaluated by hazard ratio (HR) and 95% confidence interval (CI). The cut-off value of the APACHE II score was set as ≤15 (group 1), 16–25 (group 2), and ≥26 (group 3). Multivariable marginal Cox regression analysis was performed for each group using the presumed risk factors.ResultsA total of 1,251 patients and 3,267 PIVCs were analyzed. Multivariable marginal Cox regression analysis reveals that there were statistically significant differences among the following variables evaluated HR (95%CI): (i) in group 1, standardized drug administration measures (HR, 0.4 [0.17–0.9]; p = 0.03) and nicardipine administration (HR, 2.25 [1.35–3.75]; p < 0.01); (ii) in group 2, insertion in the upper arm using the forearm as a reference (HR, 0.41 [0.2–0.83]; p = 0.01), specified polyurethane catheter using polyurethane as a reference (HR, 0.56 [0.34–0.92]; p = 0.02), nicardipine (HR, 1.9 [1.16–3.12]; p = 0.01), and noradrenaline administration (HR, 3.0 [1.52–5.88]; p < 0.01); (iii) in group 3, noradrenaline administration (HR, 3.39 [1.14–10.1]; p = 0.03).ConclusionWe found that phlebitis risk factors varied according to illness severity. By considering these different risk factors, different treatments may be provided to avoid phlebitis based on the patient’s severity of illness.

Background: Penetration of the thyroid gland by a fish bone is rare, and there is no literature describing a patient with hyperthyroidism at initial examination in whom the thyroid gland was penetrated by a fish bone. Case presentation: A 51-year-old woman visited our hospital with left-sided neck pain. She had sensed a foreign body in her throat when eating a fish the previous day, but no abnormality was found by endoscopy. Blood examination revealed hyperthyroidism, and ultrasonography (US) revealed enlargement of the bilateral lobe with multiple adenomatous nodules and heterogeneous hypoechoic areas. The presumptive diagnosis was subacute thyroiditis, and treatment with prednisolone was initiated. Pain was reduced and tenderness moved to the right lobe. The phenomenon was diagnosed as creeping thyroiditis. However, computed tomography (CT) on day 4 demonstrated a linear hyperdense body in the left lobe. Esophagogastroduodenoscopy was repeated and revealed a fissure at the cervical esophagus. Her condition was then diagnosed as penetration of a fish bone into the thyroid gland. She was treated conservatively with monitoring to observe the course. Inflammatory signs significantly improved, so she was discharged on day 15. Subsequent CT and US did not show the presence of the fish bone. Conclusions: Penetration of the thyroid gland by a fish bone could result in a clinical course resembling subacute thyroiditis. CT and careful endoscopic inspection should be performed for patients with hyperthyroidism if foreign body insertion is not ruled out from the medical history.

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes mild-to-severe respiratory symptoms, including acute respiratory distress. Despite remarkable efforts to investigate the virological and pathological impacts of SARS-CoV-2, many of the characteristics of SARS-CoV-2 infection still remain unknown. The interferon-inducible ubiquitin-like protein ISG15 is covalently conjugated to several viral proteins to suppress their functions. It was reported that SARS-CoV-2 utilizes its papain-like protease (PLpro) to impede ISG15 conjugation, ISGylation. However, the role of ISGylation in SARS-CoV-2 infection remains unclear. We aimed to elucidate the role of ISGylation in SARS-CoV-2 replication. We observed that the SARS-CoV-2 nucleocapsid protein is a target protein for the HERC5 E3 ligase-mediated ISGylation in cultured cells. Site-directed mutagenesis reveals that the residue K374 within the C-terminal spacer B-N3 (SB/N3) domain is required for nucleocapsid-ISGylation, alongside conserved lysine residue in MERS-CoV (K372) and SARS-CoV (K375). We also observed that the nucleocapsid-ISGylation results in the disruption of nucleocapsid oligomerization, thereby inhibiting viral replication. Knockdown of ISG15 mRNA enhanced SARS-CoV-2 replication in the SARS-CoV-2 reporter replicon cells, while exogenous expression of ISGylation components partially hampered SARS-CoV-2 replication. Taken together, these results suggest that SARS-CoV-2 PLpro inhibits ISGylation of the nucleocapsid protein to promote viral replication by evading ISGylation-mediated disruption of the nucleocapsid oligomerization. IMPORTANCE ISG15 is an interferon-inducible ubiquitin-like protein that is covalently conjugated to the viral protein via specific Lys residues and suppresses viral functions and viral propagation in many viruses. However, the role of ISGylation in SARSCoV-2 infection remains largely unclear. Here, we demonstrated that the SARS-CoV-2 nucleocapsid protein is a target protein for the HERC5 E3 ligase-mediated ISGylation. We also found that the residue K374 within the C-terminal spacer B-N3 (SB/N3) domain is required for nucleocapsid-ISGylation. We obtained evidence suggesting that nucleocapsid-ISGylation results in the disruption of nucleocapsid-oligomerization, thereby suppressing SARS-CoV-2 replication. We discovered that SARS-CoV-2 papain-like protease inhibits ISG15 conjugation of nucleocapsid protein via its de-conjugating enzyme activity. The present study may contribute to gaining new insight into the roles of ISGylation-mediated anti-viral function in SARS-CoV-2 infection and may lead to the development of more potent and selective inhibitors targeted to SARS-CoV-2 nucleocapsid protein. [ABSTRACT FROM AUTHOR]

Abstract Background The lack of precise information on the epidemiology of peripheral intravascular catheter (PIVC)-related phlebitis and complications in critically ill patients results in the absence of appropriate preventive measures. Therefore, we aimed to describe the epidemiology of the use of PIVCs and the incidence/occurrence of phlebitis and complications in the intensive care unit (ICU). Methods This prospective multicenter cohort study was conducted in 23 ICUs in Japan. All consecutive patients aged ≥ 18 years admitted to the ICU were enrolled. PIVCs inserted prior to ICU admission and those newly inserted after ICU admission were included in the analysis. Characteristics of the ICU, patients, and PIVCs were recorded. The primary and secondary outcomes were the occurrence and incidence rate of PIVC-related phlebitis and complications (catheter-related blood stream infection [CRBSI] and catheter failure) during the ICU stay. Results We included 2741 patients and 7118 PIVCs, of which 48.2% were inserted in the ICU. PIVC-related phlebitis occurred in 7.5% (95% confidence interval [CI] 6.9–8.2%) of catheters (3.3 cases / 100 catheter-days) and 12.9% (95% CI 11.7–14.2%) of patients (6.3 cases / 100 catheter-days). Most PIVCs were removed immediately after diagnosis of phlebitis (71.9%). Grade 1 was the most common phlebitis (72.6%), while grade 4 was the least common (1.5%). The incidence rate of CRBSI was 0.8% (95% CI 0.4–1.2%). In cases of catheter failure, the proportion and incidence rate per 100 intravenous catheter-days of catheter failure were 21% (95% CI 20.0-21.9%) and 9.1 (95% CI 8.7–10.0), respectively. Conclusion PIVC-related phlebitis and complications were common in critically ill patients. The results suggest the importance of preventing PIVC-related complications, even in critically ill patients. Trial registration UMIN-CTR, the Japanese clinical trial registry (registration number: UMIN000028019 , July 1, 2017).

Summary: Objective: Our specific aim was to introduce the TachoSil binding suturing technique for renal cell carcinoma (RCC) patients when closing the parenchymal defect after tumor excision during laparoscopic partial nephrectomy (LPN), which is a novel technique for reducing the risk of developing subsequent pseudoaneurysm (PA). Methods: We identified 113 pT1aN0M0 RCC patients who underwent LPN at our institution. Eighty-one (72%) patients underwent the suturing procedure without binding TachoSil, whereas 32 (28%) patients underwent renorraphy with the renal defect closed together with TachoSil. The vascular complications were evaluated by computed tomography or magnetic resonance imaging with enhanced contrast material at the first visit after LPN. We conducted Fischer's exact test to determine risk factors for transcatheter arterial embolization (TAE). Results: The median age was 55 (36–86) years old and the median follow-up time was 65 (12–147) months. In the overall population, there were 11 (11%) patients who underwent TAE because they developed PA. All 11 patients exhibited the imaging findings of PA, and were all from the conventional suturing group. In contrast, no patients for whom the TachoSil binding method was used had any significant findings on imaging (14% vs. 0%). Based on the analysis to determine risk factors for TAE due to PA development, the TachoSil binding suturing technique was one of the significant indicators for reducing the risk of developing PA. Conclusions: Our study demonstrated that the TachoSil binding suturing technique might reduce the development of PA after LPN. Prospective randomized study and comparison to the standard 2 or 3–layer renorrhaphy is needed to prove its actual value.

Abstract Background The optimal standard reconstruction procedure after distal gastrectomy is controversial. No large‐scale persuasive clinical studies from long‐term perspectives on this topic have yet been conducted. Study design This retrospective multicenter study analyzed a database of 2510 consecutive patients with clinical stage I gastric cancer who underwent distal gastrectomy followed by Billroth‐I (B‐I) or Roux‐en‐Y (R‐Y) anastomosis from 2006 to 2012. After adjusting for 30 potential confounding factors using propensity score matching, we compared the body weight loss and other nutritional status for 5 years as primary outcomes between the two groups. We also investigated surgical outcomes, endoscopic findings, and long‐term survival rates as secondary outcomes. Results After matching the inclusion criteria, 940 patients (470 in each group) were enrolled. There was no marked difference in the body weight loss and other nutritional indicators. The incidence of grade ≥3 postoperative complications (Clavien‐Dindo classification) or the incidence of gallstone formation was not markedly different between the two groups. The postoperative hospital stay after surgery was significantly longer, and the readmission rate was significantly higher in the R‐Y group than in the B‐I group. An endoscopic examination revealed no trends regarding the incidence and severity of gastritis or residual food in the remnant stomach. The 5‐year overall survival rate was 92.6% in the B‐I group and 91.8% in the R‐Y group, with no significant difference (P = .379, log‐rank test). Conclusions Roux‐en‐Y reconstruction may be nearly equal to Billroth‐I with regard to the long‐term nutritional perspectives.

Introduction Chlorhexidine alcohol (1.0%–2.0%) is currently recommended as a skin disinfectant to be used prior to catheterisation for preventing catheter-related infections. However, chlorhexidine alcohol has various side effects and has little antibacterial effect on methicillin-resistant Staphylococcus aureus (MRSA). Therefore, MRSA remains a concern for catheter-related bloodstream infection (CRBSI) prevention. Olanedine, containing 1.5% olanexidine gluconate in aqueous solution, was developed in Japan in 2015 and is structurally similar to chlorhexidine. Olanexine has been used as a disinfectant against various gram-positive and gram-negative bacteria and MRSA. This study aims to compare the efficacy of 1.5% aqueous olanexidine gluconate and 1% chlorhexidine alcohol as skin antiseptics for the prevention of catheter-related infections.Methods and analysis This Apollo study is an open-label, multicentre, non-inferiority, two-arm, parallel-group, randomised controlled trial conducted at 21 intensive care units (ICUs) and high-care units (HCUs) in Japan. All patients scheduled to be admitted to the ICU or HCU of a facility participating in this study, who require central venous catheter insertion are eligible. Eligible patients will be assigned to either the 1.5% aqueous olanexidine gluconate or 1% chlorhexidine alcohol group by randomisation in a ratio of 1:1 with stratification by centres. The antibacterial agents are to be used as a skin disinfectant before and during catheter placement. The primary endpoint is the proportion of catheter-related infections, defined as a composite of catheter-related sepsis without bacteraemia and CRBSI. A total of 1980 patients will be included in this study.Ethics and dissemination This clinical trial was approved by the Institutional Review Board of Jichi Medical University and the ethics committees of the participating institutions. The study results will be disseminated through conferences, peer-reviewed publications and meetings with interested parties.Trial registration number University hospital Medical Information Network (registration ID: UMIN000042343). This registration includes all items in the WHO Trial Registration Data Set.Protocol version This protocol corresponds to the original protocol version 5.

Lysosome incorporate and degrade proteins in a process known as autophagy. There are three types of autophagy; macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Although autophagy is considered a nonselective degradation process, CMA is known as a selective degradation pathway. All proteins internalized in the lysosome via CMA contain a pentapeptide KFERQ-motif, also known as a CMA-targeting motif, which is necessary for selectivity. CMA directly delivers a substrate protein into the lysosome lumen using the cytosolic chaperone HSC70 and the lysosomal receptor LAMP-2A for degradation. Hepatitis C virus (HCV) NS5A protein interacts with hepatocyte-nuclear factor 1α (HNF-1α) together with HSC70 and promotes the lysosomal degradation of HNF-1α via CMA, resulting in HCV-induced pathogenesis. HCV NS5A promotes recruitment of HSC70 to the substrate protein HNF-1α. HCV NS5A plays a crucial role in HCV-induced CMA. Further investigations of HCV NS5A-interacting proteins containing CMA-targeting motifs may help to elucidate HCV-induced pathogenesis.

Abstract Aim The purpose of this study is to compare acceptability of two second generation antidepressants for major depressive disorder patients who have not responded to the first antidepressant for current episode. We will investigate the treatment discontinuation rate and treatment adherence as well as incidence of adverse events in order to evaluate safety. Methods This is a two‐arm, three‐phased randomized controlled trial in which independent assessors will be blinded while treating psychiatrists and patients remain unblinded to treatment allocation. Patients will be randomized to escitalopram or duloxetine in Step 1 (8 weeks), and when entering Step 2 (8 weeks), the drug will be switched to the other if the first one is not effective at the end of Step 1. The acceptability of the allocated drugs, improvements in depression from baseline, adverse events, and attrition rates will be recorded and assessed for up to 52 weeks, including the follow‐up step. Results It is going to be disseminated via our following reports or presentations. Conclusions This study will provide valuable information for clinicians who encounter patients who failed to respond to their first treatment.

Objectives This study aimed to compare the estimation error of physical activity level (PAL) estimated using a tri-axial accelerometer between an independent walking group and an assisted walking group with walking aids.Methods Subjects were 6 older adults who could walk independently and 10 older adults requiring walking assistance during gait. Total energy expenditure (TEE) was measured using the doubly labelled water (DLW) method over 2 weeks and PAL was calculated as the measured TEE divided by the basal metabolic rate measured using indirect calorimetry (PALDLW). The participants wore a tri-axial accelerometer (Active style Pro HJA-750C) on the waist simultaneously as the DLW period, and the estimated PAL was derived from it (PALACC).Results The median PAL estimation error in the assisted walking group was −0.30 kcal/day (range: −0.77 to −0.01 kcal/day) and more underestimated than that in the independent walking group (p=0.02). The estimation error of PALACC was significantly correlated with PALDLW (r=−0.80, p

Preparation of highly efficient Fe-based catalysts is a reliable and achievable goal for catalyzing CO2 hydrogenation. Herein, ethylene diamine as a benign modifier well regulates the surface properties of carbon support, achieving a good dispersion of active small-size iron carbide sites. With the further incorporation of alkaline K promoter, heavy hydrocarbon selectivity (C5+) is increased from 14.8% to 39.8%. Combining several catalyst characterization (XRD, CO2-TPD, H2-TPR, TEM, and XPS) and reaction data, discloses that good dispersion, enhanced reduction/carburization behavior, and small-size carbides formation are essential for improving CO2 performance. Simultaneous doping of nitrogen atoms and alkali metal provides a promising means for CO2 fixation and rational design of functionalized metal-supported carbon catalysts.

The Sabatier reaction, which converts CO2 and H2 into CH4 and H2O (methanation), is an attractive way to produce a hydrogen carrier for renewable energy and CO2 recycling. Also, for air revitalization in space missions, water electrolysis provides not only O2, but also H2, which can hydrogenate metabolic CO2 from human respiration using the Sabatier reaction, producing H2O for O2 regeneration with the electrolysis. In this study, we have developed a three-dimensional finite element model of a test tandem cell combining a low-temperature Sabatier reactor working at around 220 °C with a proton exchange membrane water electrolyzer at around 120 °C. The model with our developed Sabatier reaction catalyst demonstrated that appropriate heat balance between the reactor and electrolyzer establishes a CO2 conversion above 90 % and thermal self-sustainability. An appropriate thermal insulator between the reactor and electrolyzer maintains them at predetermined temperatures. The thermal analysis also shows thermal self-sustainability for a plurality of the tandem cells, simulating a cell in a stack. Exergy loss ascribed to the entropy production rate with the temperature drop between the Sabatier reactor and electrolyzer is also evaluated.

We aimed to determine the characteristics of quantitative pupillary response parameters other than amplitude of pupillary light reflex (PLR) early after return of spontaneous circulation (ROSC) and their implications for predicting neurological outcomes early after cardiac arrest (CA). Fifty adults resuscitated after non-traumatic out-of-hospital CA from four emergency hospitals were enrolled. Pupil diameters, PLR, constriction velocity (CV), maximum CV (MCV), dilation velocity (DV), latency of constriction, and Neurological Pupil index (NPi) were quantitatively measured at 0, 6, 12, 24, 48, and 72 h post-ROSC using an automated pupillometer. Change over time of each parameter was compared between favorable (Cerebral Performance Category [CPC] 1 or 2) and unfavorable neurological outcome (CPC 3-5) groups. Prognostic values of 90-day favorable outcome by these parameters and when combined with clinical predictors (witness status, bystander cardiopulmonary resuscitation, initial shockable rhythm, implementation of target temperature management) were tested. Thirteen patients achieved favorable outcome. CV, MCV, DV (P < 0.001), and NPi (P = 0.005) were consistently greater in the favorable group than in the unfavorable outcome group. Change over time was not statistically different between the groups in all parameters. CV, MCV, DV (ρ = 0.96 to 0.97, P < 0.001, respectively), and NPi (ρ = 0.65, P < 0.001) positively correlated with PLR. The prognostic value of 0-hour CV (area under the curve, AUC [95% confidence interval]: 0.92 [0.80-1.00]), DV (0.84 [0.68-0.99]), and NPi (0.88 [0.74-1.00]) was equivalent to that of PLR (0.84 [0.69-0.98]). Prognostic values improved to AUC of 0.95-0.96 when 0-hour PLR, CV, DV, or NPi was combined with clinical predictors. The 0-hour CV, MCV, and NPi showed equivalent prognostic values to PLR alone/in combination with clinical predictors. Using PLR among several quantitative pupillary response parameters for early neurological prognostication of post-CA patients is a simple and effective strategy.

Abstract Aim To provide information about psychiatric emergency situations in Japan, we examined psychiatrists’ preference among parenteral medication since intramuscular (IM)‐olanzapine became available and clinical characteristics in patients given IM‐olanzapine compared to those given other parenteral medication. Methods We conducted a naturalistic study proceeding over a 1‐year period in 9 psychiatric emergency departments. Results Among 197 patients, the distribution of IM‐injections (n = 89) was as follows: IM‐olanzapine, 66 patients (74.2%), IM‐levomepromazine, 17 patients (19.1%), IM‐haloperidol, 5 patients (5.6%), and IM‐diazepam, 1 patient (1.1%). The distribution of intravenous (IV)‐injections (n = 108) was as follows: IV‐haloperidol, 78 patients (72.2%), and IV‐benzodiazepines (diazepam, flunitrazepam, or midazolam), 30 patients (27.8%). Advantages of IM‐olanzapine over other parenteral medications in efficacy were found as follows: less frequent needs of an additional injection despite no difference in duration until a patient became cooperative for oral administration, and less frequent needs of restraint after the injection. Furthermore, advantages of IM‐olanzapine over other injections in safety were found as follows: less frequent appearance of extrapyramidal symptoms, no occurrence of ECG abnormality and other serious adverse events except a fall, less frequent needs of an adjunctive anticholinergic drug, and less frequent needs of another kind of drug additionally injected. Conclusions Olanzapine has rapidly become the first choice of intramuscular medication in psychiatric emergency situations since it became available in Japan, probably due to the advantages in both efficacy and safety. This study reflecting psychiatric emergency practice in Japan may contribute to periodic international comparison of psychiatric emergency practice.

Abstract Background In Japan, the most commonly used hemofilters for patients with acute kidney injury (AKI) treated with continuous renal replacement therapy (CRRT) are made of polysulfone membranes. The aim of this study was to compare the efficacy of two commercially available polysulfone membranes for the removal of solutes. Methods This single-institution, prospective cross-over study was conducted between December 2010 and January 2012. Two polysulfone membranes, Hemofeel SHG (Toray) and Excelflo AEF (Asahi Kasei Medical), were compared in eight intensive care unit patients (median age, 80 years; seven men) who had severe sepsis that required CRRT and who required vasopressor treatment to maintain their mean blood pressure above 65 mmHg. The primary outcome measure was the efficacy of solute removal, evaluated for high-mobility group protein 1 (HMGB-1) and myoglobin. Results The main cause of sepsis was abdominal infection (50%); the mortality was 62.5%. Blood clearance of myoglobin in 1 h was significantly greater with SHG (p = 0.02), particularly at 24 h (p = 0.17). Blood creatinine clearance did not differ significantly between the two membranes after 1 h, but SHG demonstrated slightly greater appearance at 24 h. There were no significant differences between the two membranes in the clearance of other solutes including HMGB-1. Conclusions This preliminary study compared the use of two polysulfone membranes in patients with sepsis requiring CRRT and showed that the polysulfone membrane SHG was capable of removing myoglobin with greater efficacy.

Abstract Background To compare the efficacy of three antiseptic solutions [0.5%, and 1.0% alcohol/chlorhexidine gluconate (CHG), and 10% aqueous povidone-iodine (PVI)] for the prevention of intravascular catheter colonization, we conducted a randomized controlled trial in patients from 16 intensive care units in Japan. Methods Adult patients undergoing central venous or arterial catheter insertions were randomized to have one of three antiseptic solutions applied during catheter insertion and dressing changes. The primary endpoint was the incidence of catheter colonization, and the secondary endpoint was the incidence of catheter-related bloodstream infections (CRBSI). Results Of 1132 catheters randomized, 796 (70%) were included in the full analysis set. Catheter-tip colonization incidence was 3.7, 3.9, and 10.5 events per 1000 catheter-days in 0.5% CHG, 1% CHG, and PVI groups, respectively (p = 0.03). Pairwise comparisons of catheter colonization between groups showed a significantly higher catheter colonization risk in the PVI group (0.5% CHG vs. PVI: hazard ratio, HR 0.33 [95% confidence interval, CI 0.12–0.95], p = 0.04; 1.0% CHG vs. PVI: HR 0.35 [95% CI 0.13–0.93], p = 0.04). Sensitivity analyses including all patients by multiple imputations showed consistent quantitative conclusions (0.5% CHG vs. PVI: HR 0.34, p = 0.03; 1.0% CHG vs. PVI: HR 0.35, p = 0.04). No significant differences were observed in the incidence of CRBSI between groups. Conclusions Both 0.5% and 1.0% alcohol CHG are superior to 10% aqueous PVI for the prevention of intravascular catheter colonization. Trial registration Japanese Primary Registries Network; No.: UMIN000008725 Registered on 1 September 2012

Group A rotavirus (RVA) is the most important cause of severe gastroenteritis among children worldwide, and effective RVA vaccines have been introduced in many countries. Here we performed a molecular epidemiological analysis of RVA infection among pediatric patients in East Java, Indonesia, during 2015–2018. A total of 432 stool samples were collected from hospitalized pediatric patients with acute gastroenteritis. None of the patients in this cohort had been immunized with an RVA vaccine. The overall prevalence of RVA infection was 31.7% (137/432), and RVA infection was significantly more prevalent in the 6- to 11-month age group than in the other age groups (P < 0.05). Multiplex reverse transcription-PCR (RT-PCR) revealed that the most common G-P combination was equine-like G3P[8] (70.8%), followed by equine-like G3P[6] (12.4%), human G1P[8] (8.8%), G3P[6] (1.5%), and G1P[6] (0.7%). Interestingly, the equine-like strains were exclusively detected until May 2017, but in July 2017 they were completely replaced by a typical human genotype (G1 and G3), suggesting that the dynamic changes in RVA genotypes from equine-like G3 to typical human G1/G3 in Indonesia can occur even in the country with low RVA vaccine coverage rate. The mechanism of the dynamic changes in RVA genotypes needs to be explored. Infants and children with RVA-associated gastroenteritis presented more frequently with some dehydration, vomiting, and watery diarrhea, indicating a greater severity of RVA infection compared to those with non-RVA gastroenteritis. In conclusion, a dynamic change was found in the RVA genotype from equine-like G3 to a typical human genotype. Since severe cases of RVA infection were prevalent, especially in children aged 6 to 11 months or more generally in those less than 2 years old, RVA vaccination should be included in Indonesia’s national immunization program.

Since flavors of alcoholic beverages produced in fermentation process are affected mainly by yeast metabolism, the isolation and breeding of yeasts have contributed to the alcoholic beverage industry. To produce awamori, a traditional spirit (distilled alcoholic beverage) with unique flavors made from steamed rice in Okinawa, Japan, it is necessary to optimize yeast strains for a diversity of tastes and flavors with established qualities. Two categories of flavors are characteristic of awamori; initial scented fruity flavors and sweet flavors that arise with aging. Here we isolated a novel strain of Saccharomyces cerevisiae from hibiscus flowers in Okinawa, HC02-5-2, that produces high levels of alcohol. The whole-genome information revealed that strain HC02-5-2 is contiguous to wine yeast strains in a phylogenic tree. This strain also exhibited a high productivity of 4-vinyl guaiacol (4-VG), which is a precursor of vanillin known as a key flavor of aged awamori. Although conventional awamori yeast strain 101-18, which possesses the FDC1 pseudogene does not produce 4-VG, strain HC02-5-2, which has the intact PAD1 and FDC1 genes, has an advantage for use in a novel kind of awamori. To increase the contents of initial scented fruity flavors, such as isoamyl alcohol and isoamyl acetate, we attempted to breed strain HC02-5-2 targeting the L-leucine synthetic pathway by conventional mutagenesis. In mutant strain T25 with L-leucine accumulation, we found a hetero allelic mutation in the LEU4 gene encoding the Gly516Ser variant α-isopropylmalate synthase (IPMS). IPMS activity of the Gly516Ser variant was less sensitive to feedback inhibition by L-leucine, leading to intracellular L-leucine accumulation. In a laboratory-scale test, awamori brewed with strain T25 showed higher concentrations of isoamyl alcohol and isoamyl acetate than that brewed with strain HC02-5-2. Such a combinatorial approach to yeast isolation, with whole-genome analysis and metabolism-focused breeding, has the potentials to vary the quality of alcoholic beverages.

BackgroundBudesonide foam is effective in inducing clinical remission in ulcerative colitis (UC) patients with active proctosigmoiditis. The aim of this study was to evaluate the duration of remission and predictors of relapse in UC patients who achieved clinical remission and mucosal healing by 6-week treatment with topical budesonide.MethodsThis is a retrospective, observational, multicenter study with a 2-year follow-up period. UC patients who were treated with budesonide foam in phase 2 or phase 3 clinical trials and achieved both clinical remission and mucosal healing were enrolled.ResultsAmong 84 patients who met the eligibility criteria, 60 participated in the study. Eighteen of the 60 patients (30.0%; 95% confidence interval [CI]: 18.9-43.2) experienced no relapse (i.e., maintenance of remission) during the 2-year follow-up period. The median relapse-free survival time was 0.82 years (95% CI: 0.51-1.52). Of 37 patients with a Mayo endoscopic subscore of 0 after inducing remission with budesonide foam, 25 (67.6%) relapsed within 2 years. Patients with a disease duration of 5 years, and the hazard ratio was 2.38 (95% CI: 1.04-5.45).ConclusionThis is the first study to evaluate the short- to middle-term prognosis in UC patients who achieved mucosal healing with topical preparations. After inducing remission by budesonide foam, treatment for maintaining remissions and strict follow-up may be needed for patients with shorter disease duration.

BackgroundThere is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease.MethodsWe conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model.ResultsMean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV1), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and %FEV1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups.ConclusionsMild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.