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Introduction: Weekend admissions showed increased mortality in several medical conditions. This study aimed to examine the weekend effect on acute lower gastrointestinal bleeding (ALGIB) and its mortality and other outcomes., Methods: This retrospective cohort study (CODE BLUE-J Study) was conducted at 49 Japanese hospitals between January 2010 and December 2019. In total, 8,120 outpatients with acute hematochezia were enrolled and divided into weekend admissions and weekday admissions groups. Multiple imputation (MI) was used to handle missing values, followed by propensity score matching (PSM) to compare outcomes. The primary outcome was mortality; the secondary outcomes were rebleeding, length of stay (LOS), blood transfusion, thromboembolism, endoscopic treatment, the need for interventional radiology, and the need for surgery. Colonoscopy and computed tomography (CT) management were also evaluated., Results: Before PSM, there was no significant difference in mortality (1.3% vs. 0.9%, p = 0.133) between weekend and weekday admissions. After PSM with MI, 1,976 cases were matched for each admission. Mortality was not significantly different for weekend admissions compared with weekday admissions (odds ratio [OR] 1.437, 95% confidence interval [CI] 0.785-2.630; p = 0.340). No significant difference was found with other secondary outcomes in weekend admissions except for blood transfusion (OR 1.239, 95% CI 1.084-1.417; p = 0.006). Weekend admission had a negative effect on early colonoscopy (OR 0.536, 95% CI 0.471-0.609; p < 0.001). Meanwhile, urgent CT remained significantly higher in weekend admissions (OR 1.466, 95% CI 1.295-1.660; p < 0.001)., Conclusion: Weekend admissions decrease early colonoscopy and increase urgent CT but do not affect mortality or other outcomes except transfusion., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background and Aims: We aimed to determine the optimal timing of colonoscopy and factors that benefit patients who undergo early colonoscopy for acute lower GI bleeding., Methods: We identified 10,342 patients with acute hematochezia (CODE BLUE-J study) admitted to 49 hospitals in Japan. Of these, 6270 patients who underwent a colonoscopy within 120 hours were included in this study. The inverse probability of treatment weighting method was used to adjust for baseline characteristics among early (≤24 hours, n = 4133), elective (24-48 hours, n = 1137), and late (48-120 hours, n = 1000) colonoscopy. The average treatment effect was evaluated for outcomes. The primary outcome was 30-day rebleeding rate., Results: The early group had a significantly higher rate of stigmata of recent hemorrhage (SRH) identification and a shorter length of stay than the elective and late groups. However, the 30-day rebleeding rate was significantly higher in the early group than in the elective and late groups. Interventional radiology (IVR) or surgery requirement and 30-day mortality did not significantly differ among groups. The interaction with heterogeneity of effects was observed between early and late colonoscopy and shock index (shock index <1, odds ratio [OR], 2.097; shock index ≥1, OR, 1.095; P for interaction = .038) and performance status (0-2, OR, 2.481; ≥3, OR, .458; P for interaction = .022) for 30-day rebleeding. Early colonoscopy had a significantly lower IVR or surgery requirement in the shock index ≥1 cohort (OR, .267; 95% confidence interval, .099-.721) compared with late colonoscopy., Conclusions: Early colonoscopy increased the rate of SRH identification and shortened the length of stay but involved an increased risk of rebleeding and did not improve mortality and IVR or surgery requirement. Early colonoscopy particularly benefited patients with a shock index ≥1 or performance status ≥3 at presentation., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Introduction: Length of stay (LOS) in hospital affects cost, patient quality of life, and hospital management; however, existing gastrointestinal bleeding models applicable at hospital admission have not focused on LOS. We aimed to construct a predictive model for LOS in acute lower gastrointestinal bleeding (ALGIB)., Methods: We retrospectively analyzed the records of 8,547 patients emergently hospitalized for ALGIB at 49 hospitals (the CODE BLUE-J Study). A predictive model for prolonged hospital stay was developed using the baseline characteristics of 7,107 patients and externally validated in 1,440 patients. Furthermore, a multivariate analysis assessed the impact of additional variables during hospitalization on LOS., Results: Focusing on baseline characteristics, a predictive model for prolonged hospital stay was developed, the LONG-HOSP score, which consisted of low body mass index, laboratory data, old age, nondrinker status, nonsteroidal anti-inflammatory drug use, facility with ≥800 beds, heart rate, oral antithrombotic agent use, symptoms, systolic blood pressure, performance status, and past medical history. The score showed relatively high performance in predicting prolonged hospital stay and high hospitalization costs (area under the curve: 0.70 and 0.73 for derivation, respectively, and 0.66 and 0.71 for external validation, respectively). Next, we focused on in-hospital management. Diagnosis of colitis or colorectal cancer, rebleeding, and the need for blood transfusion, interventional radiology, and surgery prolonged LOS, regardless of the LONG-HOSP score. By contrast, early colonoscopy and endoscopic treatment shortened LOS., Conclusions: At hospital admission for ALGIB, our novel predictive model stratified patients by their risk of prolonged hospital stay. During hospitalization, early colonoscopy and endoscopic treatment shortened LOS., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Many invasive procedures performed in the emergency room (ER) have potential risks and complications. Because of their limitations, in particular size, portable X-ray devices are generally not used during such procedures. However, miniaturized units enable physicians to obtain X-ray images without assistance., Methods: We developed a safe, compact, and lightweight X-ray unit that was used during five invasive procedures in the ER. In all procedures, a chest X-ray image was obtained, to confirm the utility of the unit., Results: Case 1 (central venous catheter placement): After needle and guidewire insertion and catheter placement, the location of the catheter could be confirmed. Case 2 (chest tube insertion): During insertion of a chest tube into the pleural space, the tip of the thoracic tube was confirmed to be at the correct location. Case 3 (percutaneous tracheostomy or cricothyroidotomy): After needle and guidewire insertion, the guidewire was visualized in the right main bronchus and was inserted into the trachea. Case 4 (resuscitative endovascular aortic balloon of the aorta): The captured image revealed that the catheter was located in zone I before balloon inflation. Case 5 (Sengstaken-Blakemore tube): The image revealed that the balloon was located in the stomach., Conclusions: The portable X-ray unit improved medical safety during invasive procedures frequently performed in the ER.

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice., Competing Interests: Declaration of competing interest All authors have no conflict of interest in this study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: In most patients presenting with hypoglycemia in emergency departments, the etiology of hypoglycemia is identified. However, it cannot be determined in approximately 10% of cases., Objective: We aimed to identify the causes of unknown hypoglycemia, especially adrenal insufficiency., Methods: In this cross-sectional study, we evaluated the etiology of hypoglycemia among patients in our emergency department with hypoglycemia (plasma glucose level < 70 mg/dL (3.9 mmol/L)] between April 1, 2016 and March 31, 2021 using a rapid adrenocorticotropic hormone (ACTH) test., Results: There were 528 cases with hypoglycemia included [52.1% male; median age 62 years (range 19-92)]. The majority [389 (73.7%)] of patients were using antidiabetes drugs. Additionally, 33 (6.3%) consumed alcohol; 17 (3.2%) had malnutrition; 13 (2.5%), liver dysfunction; 12 (2.3%), severe infectious disease; 11 (2.1%), malignancy; 9 (1.7%), heart failure; 4 (0.8%), insulin autoimmune syndrome; 3 (0.6%), insulinoma; 2 (0.4%) were using hypoglycemia-relevant drugs; and 1 (0.2%) suffered from non-islet cell tumor. Rapid ACTH tests revealed adrenal insufficiency in 32 (6.1%). In those patients, serum sodium levels were lower (132 vs 139 mEq/L, P  < 0.01), eosinophil counts were higher (14 vs 8%, P  < 0.01), and systolic blood pressure was lower (120 vs 128 mmHg, P  < 0.05) at baseline than in patients with the other etiologies., Conclusion: The frequency of adrenal insufficiency as a cause of hypoglycemia was much higher than what we anticipated. When protracted hypoglycemia of unknown etiology is recognized, we recommend that the patient is checked for adrenal function using a rapid ACTH test., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

BACKGROUND : Prior studies have shown the effectiveness of both endoscopic band ligation (EBL) and clipping for colonic diverticular hemorrhage (CDH) but have been small and conducted at single centers. Therefore, we investigated which was the more effective and safe treatment in a multicenter long-term cohort study. METHODS : We reviewed data for 1679 patients with CDH who were treated with EBL (n = 638) or clipping (n = 1041) between January 2010 and December 2019 at 49 hospitals across Japan (CODE BLUE-J study). Logistic regression analysis was used to compare outcomes between the two treatments. RESULTS : In multivariate analysis, EBL was independently associated with reduced risk of early rebleeding (adjusted odds ratio [OR] 0.46; P  < 0.001) and late rebleeding (adjusted OR 0.62; P  < 0.001) compared with clipping. These significantly lower rebleeding rates with EBL were evident regardless of active bleeding or early colonoscopy. No significant differences were found between the treatments in the rates of initial hemostasis or mortality. Compared with clipping, EBL independently reduced the risk of needing interventional radiology (adjusted OR 0.37; P  = 0.006) and prolonged length of hospital stay (adjusted OR 0.35; P  < 0.001), but not need for surgery. Diverticulitis developed in one patient (0.16 %) following EBL and two patients (0.19 %) following clipping. Perforation occurred in two patients (0.31 %) following EBL and none following clipping. CONCLUSIONS : Analysis of our large endoscopy dataset suggests that EBL is an effective and safe endoscopic therapy for CDH, offering the advantages of lower early and late rebleeding rates, reduced need for interventional radiology, and shorter length of hospital stay., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Patients with blunt chest trauma have a high mortality rate. The assessment of blush in hepatic and splenic trauma is important for determining the need for emergency hemostatic interventions. However, the frequency and importance of blush in lung contusions are unknown. Therefore, this study aimed to evaluate the frequency of blush in patients with lung contusions and elucidate the relationship between blush and the clinical outcomes of patients with blunt chest trauma., Materials and Methods: In this retrospective observational study, we enrolled patients with an injury severity score of 16 or higher and a chest abbreviated injury scale (AIS) score of 3 or higher who were admitted to the emergency department of Hokkaido University Hospital from January 1, 2003, to December 31, 2016. Blush was defined as active extravasation of an intravascular contrast agent recognized on contrast-enhanced computed tomography. The date of trauma, trauma severity, treatments, and outcomes were obtained from the patients' electronic medical records., Results: During the study period, 83 patients had severe lung contusions and 13 had blush. In-hospital mortality of patients with blush was significantly higher than that of patients without blush (53 vs. 10%, P < 0.001). Patients with blush required thoracic drainage more frequently (100 vs. 71%, P < 0.001) and support through mechanical ventilation more often (100 vs. 64%, P < 0.001) and for a longer duration (median duration, 0 vs. 25 days, P = 0.001) than patients without blush., Conclusions: Our study revealed that blush in lung contusions was not rare and was associated with a high risk of mortality in patients with severe blunt chest trauma. Clinicians should not hesitate to intervene if blush is detected in a lung contusion of a patient with blunt chest trauma., 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 © 2022 Tominaga, Hayakawa and Yokobori.)

Mucin-containing bio-synthetic hybrid hydrogel is successfully formed under physiological conditions upon mixing aqueous solutions of native mucin and synthetic polymers carrying boronic acids. The mechanical properties and stability of the hydrogel in physiological solutions, e.g., cell culture media, are tunable depending on the boronic acid content of polymers. The hydrogel dissolved in the physiological solutions releases native mucin and boronic acid-containing polymer, which can control the adhesion of mammalian cells to the surface., (© 2022 Wiley-VCH GmbH.)

Background and Aims: Treatment strategies for colonic diverticular bleeding (CDB) based on stigmata of recent hemorrhage (SRH) remain unstandardized, and no large studies have evaluated their effectiveness. We sought to identify the best strategy among combinations of SRH identification and endoscopic treatment strategies., Methods: We retrospectively analyzed 5823 CDB patients who underwent colonoscopy at 49 hospitals throughout Japan (CODE-BLUE J-Study). Three strategies were compared: find SRH (definitive CDB) and treat endoscopically, find SRH (definitive CDB) and treat conservatively, and without finding SRH (presumptive CDB) treat conservatively. In conducting pairwise comparisons of outcomes in these groups, we used propensity score-matching analysis to balance baseline characteristics between the groups being compared., Results: Both early and late recurrent bleeding rates were significantly lower in patients with definitive CDB treated endoscopically than in those with presumptive CDB treated conservatively (<30 days, 19.6% vs 26.0% [P < .001]; <365 days, 33.7% vs 41.6% [P < .001], respectively). In patients with definitive CDB, the early recurrent bleeding rate was significantly lower in those treated endoscopically than in those treated conservatively (17.4% vs 26.7% [P = .038] for a single test of hypothesis; however, correction for multiple testing of data removed this significance). The late recurrent bleeding rate was also lower, but not significantly, in those treated endoscopically (32.0% vs 36.1%, P = .426). Definitive CDB treated endoscopically showed significantly lower early and late recurrent bleeding rates than when treated conservatively in cases of SRH with active bleeding, nonactive bleeding, and in the right-sided colon but not left-sided colon., Conclusions: Treating definitive CDB endoscopically was most effective in reducing recurrent bleeding over the short and long term, compared with not treating definitive CDB or presumptive CDB. Physicians should endeavor to find and treat SRH for suspected CDB., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to analyze the role of homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 (Herpud1) gene in the development of cardiomyocyte hypertrophy., Method: In order to examine the effect of suppressing Herpud1 expression, Herpud1 small interfering RNA (siRNA) was introduced into H9C2 cells, which are cell lines derived from rat myocardium, and the degree of Herpud1 protein expression and cell hypertrophy in the Herpud1 siRNA-transfected group and the control group was compared by immunostaining 48 h after Herrpud1 siRNA introduction. To examine whether hypertrophy induced by angiotensin II (Ang II) can be suppressed by the overexpression of Herpud1, the green fluorescent protein (GFP)-Herpud1 plasmid was introduced into H9C2 cells, and the degree of cell hypertrophy was examined in the GFP-Herpud1-and control groups for 48 h. Nuclear translocation of nuclear factor of activated T-cells, cytoplasmic 4 (NFATc4), a transcription factor for hypertrophic genes, was also examined., Results: [1] Herpud1 siRNA-transfected cells showed decreased Herpud1 protein expression and hypertrophy formation compared to control cells [2]; Overexpression of Herpud1 suppresses Ang II-induced cell hypertrophy; and [3] Overexpression of Herpud1 inhibits nuclear translocation of NFATc4., Discussion: It was suggested that Herpud1 might be an anti-hypertrophic gene in Ang II induced cardiomyocytes hypertrophy., Competing Interests: All authors have no conflict of interest in this study., (© 2022 The Authors.)

Urban dust has been contaminated with toxic heavy metals from various diffused sources. On August 28, 2019, the compact fluorescence lamp (CFL) factory that generates light for Rang Dong Light Source and Vacuum Flask in Hanoi City in Vietnam was accidentally fired. The assessment for Hg contamination and its human health impact 2 months after the incident was conducted in autumn 2019. The heavy Hg pollution is still found near CFL. Additionally, localized Hg pollution by air and wind direction was identified at sites in the northeast direction from CFL. Namely, in the area located downstream of the southwest monsoon wind, Hg had a trend higher than other directions. The hazard quotient (HQ) and the hazard index (HI) were evaluated by four routes of Hg exposure pathways. The HI values for children and adults in the most polluted site (Site 15) were 0.968 and 0.468, respectively. This meant that children who lived around this site and commuted to schools were the most at risk regarding the potential adverse health effects of Hg in street dust around the polluted areas. This study also showed that Hg levels were affected by wind direction and that the higher Hg levels in the most polluted sites resulted from the wind flow to the sites. This study revealed that street dust may be a useful tool for the assessment of human and environmental health., (© 2021 John Wiley & Sons, Ltd.)

Background: Direct and indirect clipping treatments are used worldwide to treat colonic diverticular bleeding (CDB), but their effectiveness has not been examined in multicenter studies with more than 100 cases., Objective: We sought to determine the short- and long-term effectiveness of direct versus indirect clipping for CDB in a nationwide cohort., Methods: We studied 1041 patients with CDB who underwent direct clipping (n = 360) or indirect clipping (n = 681) at 49 hospitals across Japan (CODE BLUE-J Study)., Results: Multivariate analysis adjusted for age, sex, and important confounding factors revealed that, compared with indirect clipping, direct clipping was independently associated with reduced risk of early rebleeding (<30 days; adjusted odds ratio [AOR] 0.592, p = 0.002), late rebleeding (<1 year; AOR 0.707, p = 0.018), and blood transfusion requirement (AOR 0.741, p = 0.047). No significant difference in initial hemostasis rates was observed between the two groups. Propensity-score matching to balance baseline characteristics also showed significant reductions in the early and late rebleeding rates with direct clipping. In subgroup analysis, direct clipping was associated with significantly lower rates of early and late rebleeding and blood transfusion need in cases of stigmata of recent hemorrhage with non-active bleeding on colonoscopy, right-sided diverticula, and early colonoscopy, but not with active bleeding on colonoscopy, left-sided diverticula, or elective colonoscopy., Conclusions: Our large nationwide study highlights the use of direct clipping for CDB treatment whenever possible. Differences in bleeding pattern and colonic location can also be considered when deciding which clipping options to use., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background and Aim: Elobixibat is a novel ileal bile acid transporter inhibitor. This study aimed to compare the efficacy, tolerability, and safety of the combination of elobixibat and 1 L of polyethylene glycol formulation containing ascorbic acid (PEG-Asc) solution versus the combination of sodium picosulfate and 1-L PEG-Asc solution as bowel preparation for colonoscopy., Methods: This multi-center, randomized, observer-blinded, non-inferiority study recruited 210 outpatients who were assigned to either the elobixibat plus 1-L PEG-Asc group (group A) or the sodium picosulfate plus 1-L PEG-Asc group (group B). The quality of the bowel cleansing level was assessed by the Boston Bowel Preparation Scale (BBPS) and compared the bowel cleansing level between the groups. Data regarding bowel preparation time, patients' tolerability, and adverse events were also analyzed., Results: Data for 196 patients (99 in group A and 97 in group B) were analyzed finally. BBPS was comparable between group A and B (8.3 ± 0.9 vs. 8.3 ± 0.7; P = 0.88). Consequently, the adequate bowel preparation rate in groups A and B was 95.0% and 99.0%, respectively (-4.0%, 95% CI -9.3 to 1.5). Bowel preparation time in group A was similar to that in group B (348.2 ± 79.8 min vs. 330.8 ± 82.5 min; P = 0.13), whereas, sleep disturbance was significantly less frequent in group A than in group B (10.2% vs. 22.7%; P = 0.02)., Conclusions: The combination of elobixibat and 1-L PEG-Asc can be considered an alternative bowel preparation for colonoscopy considering the equivalent bowel cleansing effect and less frequent sleep disturbance. The Japan Registry of Clinical Trials (jRCTs41180026)., (© 2021 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

A 34-year-old man with no medical history presented with fever 4 days after receiving the first dose of mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. He had no prior clinical evidence of severe acute respiratory syndrome coronavirus 2 infection and was negative for serial polymerase chain reaction testing. Ten days after vaccination, he was referred to our hospital because of no response to antibiotics and the emergence of neutropenia, thrombocytopenia, and liver dysfunction. Blood tests also showed elevated serum ferritin and plasma soluble interleukin-2 receptors. Serological and PCR testing excluded active infections of cytomegalovirus, Epstein-Barr virus, and hepatitis viruses. Blood culture yielded no growth. Computed tomography revealed mild hepatosplenomegaly and porta hepatis lymphadenopathy but no focus on infection. Bone marrow aspiration demonstrated hemophagocytosis but no infiltrating lymphoma cells. Immediately, 2-mg/kg intravenous methylprednisolone was commenced based on the presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH), leading to the rapid and durable improvement of his symptoms and laboratory data. Later, without other causes triggering hemophagocytosis, and with the close link between vaccination and disease onset, the final diagnosis of vaccination-induced secondary HLH was made. HLH after COVID-19 vaccination, though extremely rare, can occur regardless of the vaccine type. Therefore, clinicians should recognize and deal with this occasionally fatal adverse event.

Dysferlinopathies are muscular dystrophies caused by recessive loss-of-function mutations in dysferlin ( DYSF ), a membrane protein involved in skeletal muscle membrane repair. We describe a cell-based assay in which human DYSF proteins bearing missense mutations are quantitatively assayed for membrane localization by flow cytometry and identified 64 localization-defective DYSF mutations. Using this platform, we show that the clinically approved drug 4-phenylbutryric acid (4-PBA) partially restores membrane localization to 25 mutations, as well as membrane repair to cultured myotubes expressing 2 different mutations. Two-day oral administration of 4-PBA to mice homozygous for one of these mutations restored myofiber membrane repair. 4-PBA may hold therapeutic potential for treating a subset of humans with muscular dystrophy due to dysferlin deficiency., Competing Interests: L.P.G. is a founder of Elysium Health and Galilei Biosciences., (© 2021 The Author(s).)

Central volume shift is one of the major pathophysiological mechanisms of acute pulmonary oedema in acute heart failure (AHF). Pathological vasoconstriction results in central volume shift; however, its onset and course have been rarely detected or recorded in clinical practice. We report an exceptional case of AHF developing during haemodialysis, with marked blood pressure (BP) elevation and paradoxical repeated reduction in blood volume (BV) detected by real-time BV monitoring, accompanied by worsening dyspnoea. This inverse correlation of BV and BP during haemodialysis indicates that the theoretical central volume shift was captured in real-world AHF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Cell-cell communication is an important mechanism in biological processes. Extracellular vesicles (EVs), also referred to as exosomes, microvesicles, and prostasomes, are microvesicles secreted by a variety of cells. EVs are nanometer-scale vesicles composed of a lipid bilayer and contain biological functional molecules, such as microRNAs (miRNAs), mRNAs, and proteins. In this review, "EVs" is used as a comprehensive term for vesicles that are secreted from cells. EV research has been developing over the last four decades. Many studies have suggested that EVs play a crucial role in cell-cell communication. Importantly, EVs contribute to cancer malignancy mechanisms such as carcinogenesis, proliferation, angiogenesis, metastasis, and escape from the immune system. EVs derived from cancer cells and their microenvironments are diverse, change in nature depending on the condition. As EVs are thought to be secreted into body fluids, they have the potential to serve as diagnostic markers for liquid biopsy. In addition, cells can encapsulate functional molecules in EVs. Hence, the characteristics of EVs make them suitable for use in drug delivery systems and novel cancer treatments. In this review, the potential of EVs as anti-cancer therapeutics is discussed.

Purpose: Undesired drug sorption on laboratory material surfaces reduces the performance of analytical methods and results in the generation of unreliable data. Hence, we characterized the sorption of drugs and evaluated the sorption extent using a linear free energy relationship (LFER) model with Abraham solvation parameters of drugs. Furthermore, to prevent sorption, the effects of additives, such as organic solvents and salts, were evaluated., Methods: The sorption of fifteen model drugs (concentration: 2 μM), with various physicochemical properties, on materials in 0.2% dimethyl sulfoxide aqueous solutions was evaluated. Drug sorption extent on the materials was determined using high-performance liquid chromatography. The obtained results were analyzed using an LFER model with Abraham solvation parameters of the drugs. The effect of additives on the sorption of itraconazole, one of the most hydrophobic drugs among those tested in this study, was investigated., Results: Sorption was dependent on the physicochemical properties of drugs, rather than the type of materials used, and additives altered the rate of drug sorption. Equations were developed to evaluate the sorption extent (nmol) of drugs to glass and polypropylene using the Abraham solvation parameters of the drugs., Conclusions: LFER modeling with Abraham solvation parameters of drugs enabled us to evaluate drug sorption on materials. All the additives altered the rate of drug sorption, and some organic solvents effectively prevented sorption. The developed LFER model would be useful for assessment of the sorption properties of compounds in in vitro evaluations in drug discovery research and various other biochemical fields., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The bleeding source of hematochezia is unknown without performing colonoscopy. We sought to identify whether colonoscopy is a risk-stratifying tool to identify etiology and predict outcomes and whether presenting symptoms can differentiate the etiologies in patients with hematochezia., Methods: This multicenter retrospective cohort study conducted at 49 hospitals across Japan analyzed 10,342 patients admitted for outpatient-onset acute hematochezia., Results: Patients were mostly elderly population, and 29.5% had hemodynamic instability. Computed tomography was performed in 69.1% and colonoscopy in 87.7%. Diagnostic yield of colonoscopy reached 94.9%, most frequently diverticular bleeding. Thirty-day rebleeding rates were significantly higher with diverticulosis and small bowel bleeding than with other etiologies. In-hospital mortality was significantly higher with angioectasia, malignancy, rectal ulcer, and upper gastrointestinal bleeding. Colonoscopic treatment rates were significantly higher with diverticulosis, radiation colitis, angioectasia, rectal ulcer, and postendoscopy bleeding. More interventional radiology procedures were needed for diverticulosis and small bowel bleeding. Etiologies with favorable outcomes and low procedure rates were ischemic colitis and infectious colitis. Higher rates of painless hematochezia at presentation were significantly associated with multiple diseases, such as rectal ulcer, hemorrhoids, angioectasia, radiation colitis, and diverticulosis. The same was true in cases of hematochezia with diarrhea, fever, and hemodynamic instability., Discussion: This nationwide data set of acute hematochezia highlights the importance of colonoscopy in accurately detecting bleeding etiologies that stratify patients at high or low risk of adverse outcomes and those who will likely require more procedures. Predicting different bleeding etiologies based on initial presentation would be challenging., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Outcomes of acute lower gastrointestinal bleeding have not been compared according to hospital capacity. We aimed to perform a propensity score-matched cohort study with path and mediation analyses for acute hematochezia patients. Hospitals were divided into high- versus low-volume hospitals for emergency medical services. Rebleeding and death within 30 days were compared. Computed tomography, early colonoscopy (colonoscopy performed within 24 h), and endoscopic therapies were included as mediators. A total of 2644 matched pairs were yielded. The rebleeding rate within 30 days was not significant between high- and low-volume hospitals (16% vs. 17%, P = 0.44). The mortality rate within 30 days was significantly higher in the high-volume cohort than in the low-volume cohort (1.7% vs. 0.8%, P = 0.003). Treatment at high-volume hospitals was not a significant factor for rebleeding (odds ratio [OR] = 0.91; 95% confidence interval [CI], 0.79-1.06; P = 0.23), but was significant for death within 30 days (OR = 2.03; 95% CI, 1.17-3.52; P = 0.012) on multivariate logistic regression after adjusting for patients' characteristics. Mediation effects were not observed, except for rebleeding within 30 days in high-volume hospitals through early colonoscopy. However, the direct effect of high-volume hospitals on rebleeding was not significant. High-volume hospitals did not improve the outcomes of acute hematochezia patients., (© 2021. The Author(s).)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines., Competing Interests: Financial and academic COIs as well as the role(s) of each committee member are disclosed in the additional file 1 (https://www.jsicm.org/pdf/guidelineEN/Additionalfile1.pdf). Financial COIs were disclosed in accordance with the standards used by the Japanese Association of Medical Sciences from 2017 through 2019., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

Background: Parathyroid hormone (PTH) acts on bone to indirectly increase the number and activity of osteoclasts. Thus, PTH has a stimulatory effect on bone resorption and upregulates bone turnover. However, the responsiveness of bone to PTH varies widely among patients receiving dialysis. In fact, relative to the serum PTH level, the level of serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone resorption marker derived from osteoclasts, varies as well. This study aimed to examine factors related to bone responsiveness to PTH in patients undergoing chronic hemodialysis (HD)., Methods: This study included patients receiving chronic HD in Kawasaki Municipal Tama Hospital (Kanagawa, Japan) and Yonaha Medical Clinic (Okinawa, Japan) and excluded patients who received HD for less than 6 months, those who received a combination of HD and peritoneal dialysis, and those who had cancer bone metastases or myeloma. The TRACP-5b/intact PTH (iPTH) ratio was created as an index of bone responsiveness to PTH, categorized into tertiles (low, medium, and high), and a cross-sectional study was conducted. P < 0.05 indicated statistically significant differences., Results: One hundred and six patients were analyzed. Age (P = 0.010), body mass index (BMI) (P = 0.003), use of calcium-sensing receptor (CaSR) agonists (P = 0.008), use of vitamin D receptor activators (VDRAs) (P = 0.012), plasma iPTH level (P < 0.001), serum 1,25(OH) 2 D level (P = 0.003), and serum TRACP-5b level (P < 0.001) were significantly different among the three categories. In the single linear regression analysis, age (P = 0.016), corrected serum calcium level (P = 0.007), and ln [1,25(OH) 2 D] (P = 0.044) showed a significant positive correlation with ln [TRACP-5b/iPTH], whereas BMI (P = 0.026), use of CaSR agonists (P = 0.001), use of VDRAs (P = 0.009), and serum phosphorus level (P = 0.018) showed a significant negative correlation. Upon conducting multiple linear regression analysis incorporating significant variables in the single linear regression analysis, a significant negative correlation was observed between the TRACP-5b/iPTH ratio and intravenous administration of a CaSR agonist (etelcalcetide) and/or a VDRA (calcitriol or maxacalcitol) in all the adjusted models., Conclusions: Bone responsiveness to PTH is negatively correlated with the intravenous administration of a CaSR agonist and/or a VDRA in patients undergoing chronic HD., (© 2021. The Author(s).)

Background and Aim: Either clipping or band ligation will become the most common endoscopic treatment for colonic diverticular bleeding (CDB). Rebleeding is a significant clinical outcome of CDB, but there is no cumulative evidence comparing reduction of short-term and long-term rebleeding between them. Thus, we conducted a systematic review and meta-analysis to determine which endoscopic treatment is more effective to reduce recurrence of CDB., Methods: A comprehensive search of the databases PubMed/MEDLINE and Embase was performed through December 2019. Main outcomes were early and late rebleeding rates, defined as bleeding within 30 days and 1 year of endoscopic therapy for CDB. Initial hemostasis, need for transcatheter arterial embolization, or surgery were also assessed. Overall pooled estimates were calculated., Results: Sixteen studies fulfilled the eligibility criteria, and a total of 790 participants were included. The pooled prevalence of early rebleeding was significantly lower for band ligation than clipping (0.08 vs 0.19; heterogeneity test, P = 0.012). The pooled prevalence of late rebleeding was significantly lower for band ligation than clipping (0.09 vs 0.29; heterogeneity test, P = 0.024). No significant difference of initial hemostasis rate was noted between the two groups. Pooled prevalence of need for transcatheter arterial embolization or surgery was significantly lower for band ligation than clipping (0.01 vs 0.02; heterogeneity test, P = 0.031). There were two cases with colonic diverticulitis due to band ligation but none in clipping., Conclusion: Band ligation therapy was more effective compared with clipping to reduce recurrence of colonic diverticular hemorrhage over short-term and long-term durations., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: The present study aimed to clarify the safety and efficacy of the noncessation method of antithrombotic agents after emergency endoscopic hemostasis in patients with nonvariceal upper gastrointestinal bleeding (UGIB)., Methods: In this multicenter, prospective, pilot study, we performed emergency endoscopic hemostasis for nonvariceal UGIB in patients taking antithrombotic agents and resumed the medications without a cessation period (group A). The clinical characteristics, types of antithrombotic agents, UGIB etiology, treatment outcome, and adverse events were evaluated. We used propensity score matching to compare treatment outcomes and adverse events with our previous cohort (group B) in whom antithrombotic agents were transiently discontinued after emergency endoscopic hemostasis., Results: Forty-three consecutive patients were prospectively enrolled. The main antithrombotic agents were low-dose aspirin and direct oral anticoagulants; 11 patients (25.6%) were taking multiple antithrombotics. Peptic ulcers were the main cause of bleeding (95.4%). Endoscopic hemostasis was successful in all patients and the incidence of rebleeding within a month was 7.0%. Propensity score matching created 40 matched pairs. Endoscopic hemostasis was performed by soft coagulation significantly more frequently in group A than in group B (97.5% versus 60.0%, P  < 0.001). Neither the rebleeding rate within a month nor thromboembolic event rate was different between the two groups. However, the mean duration of hospitalization was significantly shorter in group A than in group B (8.6 ± 5.2 d versus 14.4 ± 7.1 d, P  < 0.001)., Conclusions: Antithrombotic agents possibly can be continued after successful emergency endoscopic hemostasis for nonvariceal UGIB., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Daisuke Yamaguchi et al.)

Equine estrogens (EEs) are widely used in hormone replacement therapy pharmaceuticals for postmenopausal women. Previous studies have shown that EEs occur in the aquatic environment; however, the potential estrogenicity and risk of EEs in aquatic organisms, including fish, have yet to be studied in detail. Therefore, we evaluated the estrogenic potential of major EEs, namely equilin (Eq), 17α-dihydroequilin (17α-Eq), 17β-dihydroequilin (17β-Eq), equilenin (Eqn), 17α-dihydroequilenin (17α-Eqn), and 17β-dihydroequilenin (17β-Eqn), on medaka (Oryzias latipes) using in vivo and in silico assays. Quantitative real-time RT-PCR analyses revealed that expression levels of choriogenin L (ChgL) and choriogenin H (ChgH) in medaka embryos responded to various types and concentrations of EEs in a concentration-dependent manner, whereas transcription levels of vitellogenin 1 were not significantly affected by any of the EEs in the concentration range tested. The order of the in vivo estrogenic potencies of EEs was as follows: 17β-Eq > Eq > 17β-Eqn > Eqn > 17α-Eqn > 17α-Eq. Additionally, the 50% effective concentrations (EC 50 ) of 17β-Eq was lower than that of 17β-estradiol. We also investigated the interaction potential of EEs with medaka estrogen receptor (ER) subtypes in silico using a three-dimensional model of the ligand-binding domain (LBD) for each ER and docking simulations. All six EEs were found to interact with the LBDs of ERα, ERβ1, and ERβ2. The order of the in silico interaction potentials of EEs with each ER LBD was as follows: 17β-Eq > 17α-Eq > Eq > 17β-Eqn > 17α-Eqn > Eqn. Furthermore, we identified the key amino acids that interact with EEs in each ER LBD; our findings suggest that amino acids and/or their hydrogen bonding may be responsible for the ligand-specific interactions with each ER. This study is the first to comprehensively analyze the estrogenic potential of EEs in medaka both in vivo and in silico., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A 23-year-old woman was admitted to our hospital because of rapidly developing lower abdominal pain. Computed tomography revealed ascites, splenomegaly, and a huge mass that occupied the pouch of Douglas and surrounded her uterus. A markedly elevated white blood cell count of 495×10 9 /l and the identification of the BCR-ABL1 fusion gene led to the diagnosis of chronic myeloid leukemia (CML). Although neither an increase in the blast percentage nor any additional chromosomal abnormality was observed in the patient, CML was considered in the blast phase because of extramedullary disease infiltration. Dasatinib was administered with the temporal use of hydroxyurea and VP-16, which resulted in rapid disappearance of her intrapelvic mass and complete hematologic response within 1 month. She refused to undergo allogeneic hematopoietic stem cell transplantation and continued to take dasatinib, achieving complete cytogenetic and major molecular responses within 5 and 11 months, respectively. CML cases initially presenting with extramedullary tumors are rare. Furthermore, in our case, a mutational analysis at diagnosis revealed an in-frame exon 4 deletion in ABL1, which is reported to decrease cell proliferation. This fact is intriguing because her clinical outcome was relatively favorable.

Introduction: Patients with chronic kidney disease (CKD) exhibit a higher probability of having cognitive impairment or dementia than those without CKD. The beneficial effects of physical exercise on cognitive function are known in the general older population, but more research is required in older adults with CKD., Methods: Eighty-one outpatients (aged ≥65 years) with CKD stage G3-G4 were assessed for eligibility. Among them, 60 were randomized (single-center, unblinded, and stratified) and 53 received the allocated intervention (exercise n = 27, control n = 26). Patients in the exercise group undertook group-exercise training at our facility once weekly and independent exercises at home twice weekly or more, for 24 weeks. Patients in the control group received general care. General and specific cognitive functions (memory, attention, executive, and verbal) were measured, and differences in their scores at baseline and at the 24-week follow-up visit were assessed between the 2 groups., Results: Forty-four patients completed the follow-up at 24 weeks (exercise n = 23, control n = 21). Patients in the exercise group showed significantly greater changes in Wechsler Memory Scale-Revised Logical Memory delayed recall (exercise effect: 2.82, 95% CI: 0.46-5.19, p = 0.03), and immediate and delayed recall (exercise effect: 5.97, 95% CI: 1.13-10.81, p = 0.02) scores than those in the control group., Conclusions: The 24-week exercise intervention significantly improved the memory function in older adults with pre-dialysis CKD. This randomized controlled trial suggests that physical exercise is a useful nonpharmacological strategy for preventing cognitive decline in these patients., (© 2021 S. Karger AG, Basel.)

Background: Vitamin D deficiency is often observed in patients undergoing maintenance hemodialysis and is associated with significantly increased risk of overall mortality. Despite reports of poor nutrition/intake, vitamin D status among patients on maintenance hemodialysis receiving welfare remains unknown. This study investigated the vitamin D status in welfare recipients undergoing maintenance hemodialysis., Methods: This cross-sectional study investigated vitamin D status among 106 outpatients undergoing maintenance hemodialysis at two medical facilities in Japan. Patients were divided into welfare and non-welfare groups based on their status as of September 2018. Patients were divided into two categories: serum vitamin D deficiency, defined as serum 25(OH)D concentrations < 12 ng/mL, or non-deficiency. Vitamin D deficiency was used as a dependent variable, while welfare receipt was used as the main predictor variable., Results: Mean [± standard deviation] patient age, median [interquartile range] body mass index, and hemodialysis duration were 66.9 [± 10.8] years, 21.5 [19.6, 24.3] kg/m 2 , and 7.9 [2.9, 12.3] years, respectively. Among 106 patients, 45 were women (42.5%) and 16 (15.1%) were receiving welfare. The welfare group had a higher diabetes prevalence ( P  = 0.003) and significantly lower median serum 25-hydroxyvitamin D concentrations (11.5 [8.7, 14.0] vs. 14.8 [11.2, 19.9] ng/mL, P  = 0.005). Multiple logistic regression analysis revealed that welfare receipt was a significant risk factor for vitamin D deficiency (odds ratio [95% confidence interval], 4.41 [1.08, 18.07])., Conclusions: Welfare recipients undergoing maintenance hemodialysis are at significantly increased risks of vitamin D deficiency compared with patients not receiving welfare., Competing Interests: Competing InterestsThere are no financial or other potential conflicts of interest to disclose regarding this study., (© The Author(s) 2021.)

Mercury (Hg), cadmium (Cd), and lead (Pb) concentrations in marketed cigarettes from South Korea, Vietnam, Japan, Indonesia, Taiwan, Thailand, the United Kingdom (UK), Belgium, Italy, Finland, and France were investigated. The cigarettes from Vietnam and Thailand had the highest trend of Hg. Meanwhile, Cd was found higher in cigarettes from Thailand, the UK, and Belgium. Pb concentrations in cigarettes from Belgium, the UK, and Korea were higher than others. The average of these heavy metals concentrated in cigarettes was in the order of Pb > Cd > Hg. Furthermore, the contents of these heavy metals in cigarette leaves were much higher than in filter and rolling paper. There was a significant positive correlation between Hg and Cd, but no correlation between Cd and Pb and between Hg and Pb. Significant positive correlations of nicotine with Hg and Cd but not Pb in the cigarette were observed. Activated carbon filters (Ce-C) absorb Cd and Pb from cigarette leaves and rolling paper indicated a higher trapping trend than cellulose acetate filter without activated carbon (Ce). The trapping ratios of Ce-C (Cd: 5.53%, Pb:5.41%) were higher than Ce (Cd:3.09%, Pb:5.49%). On the other hand, Hg had lower absorption by both types of filters (Ce:0.15%, Ce-C:0.02%). This revealed that Hg, Cd and Pb absorption ability by both filters was relatively lower to the total concentration of these metals in tobacco leaves and rolling paper. The concern was that the higher concentrations of metals such as Hg, Cd and Pb in cigarettes might exist in mainstream smoke.

Juvenile hormone (JH) is an important endocrine factor regulating many biological activities in arthropods. In daphnids, methoprene-tolerant (Met) belongs to a basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) family protein which has recently been confirmed as a JH receptor and can bind and be activated by JHs and JH agonists. Although the activation of the JH signaling pathway causes many physiological effects, the molecular basis for the structural feature and ligand binding properties of Daphnia Met are not fully understood. To study the ligand preference in terms of structural features of Daphnia Met, we built in silico homology models of the PAS-B domain of Daphnia Mets from cladoceran crustaceans, Daphnia pulex and D. magna . Structural comparison of two Daphnia Met PAS-B domain models revealed that the volume in the main cavity of D. magna Met was larger than that of D. pulex Met. Compared with insect Met, Daphnia Met had a less hydrophobic cavity due to polar residues in the core-binding site. Molecular docking simulations of JH and its analogs with Daphnia Met indicated that the interaction energies were correlated with each of the experimental values of in vivo JH activities based on male induction and in vitro Met-mediated transactivation potencies. Furthermore, in silico site-directed mutagenesis supported experimental findings that Thr292 in D. pulex Met and Thr296 in D. magna Met substitution to valine contribute to JH selectivity and differential species response. This study demonstrates that in silico simulations of Daphnia Met and its ligands may be a tool for predicting the ligand profile and cross species sensitivity.

Background: The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task., Methods: Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy., Results: TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of "Stance" category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252)., Conclusion: TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia)., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Thrombomodulin functions as an anticoagulant through thrombin binding and protein C activation. We herein report the first case of hereditary functional thrombomodulin deficiency presenting with recurrent subcutaneous hemorrhage and old cerebral infarction. The patient had a homozygous substitution of glycine by aspartate at amino acid residue 412 (Gly412Asp) in the thrombin-binding domain of the thrombomodulin gene (designated thrombomodulin-Nagasaki). In vitro assays using a recombinant thrombomodulin with the same mutation as the patient showed a total lack of thrombin binding and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Marked clinical and laboratory improvement was obtained with recombinant human soluble thrombomodulin therapy., (© 2020 by The American Society of Hematology.)

This study assessed the transcription levels of estrogen-responsive genes, such as vitellogenins (Vtg1 and Vtg2), choriogenins (ChgL, ChgH, and ChgHm), cytochrome P450 aromatase (CYP19a1b), and ER subtypes (ERα, ERβ1, and ERβ2), in 7 days-post-fertilization (dpf) embryos and 9 and 12 dpf larvae of medaka (Oryzias latipes) exposed to estrogenic endocrine-disrupting chemicals (EDCs). The <5 h-post-fertilization embryos were exposed to EDCs such as 17β-estradiol (E2), p-n-nonylphenol (NP), and bisphenol A (BPA). In E2 (0.10-222 nM)-treated 7 dpf embryos and 9 or 12 dpf larvae, ChgL, ChgH, and ChgHm expression was up-regulated in a concentration-dependent manner. By contrast, interestingly, Vtg1 and Vtg2 expression was not induced in E2-treated 7 dpf embryos but was significantly induced in 9 and 12 dpf larvae, suggesting a developmental-stage-specific regulatory mechanism underlying Vtg expression. The maximum concentrations of NP (0.09-1.5 μM) and BPA (1.8-30 μM) up-regulated Chg expression in 9 or 12 dpf larvae, and the relative estrogenic potencies (REPs) of E2, NP, and BPA were 1, 2.1 × 10 -4 , and 1.0 × 10 -5 , respectively. Chg messenger RNA (mRNA) in medaka embryos and larvae can be used as a sensitive biomarker for screening potential estrogenic EDCs. Our assay system using embryos and larvae can be used as an in vivo alternative model because independent feeding stages (e.g., embryonic and early larval stages) are suitable alternatives., (Copyright © 2020. Published by Elsevier Inc.)

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are widely distributed in air, water, and sediments; however, limited data are available regarding their potential adverse effects on the early life stages of fish. In this study, we evaluated the embryonic teratogenicity and developmental toxicity of BaP in Japanese medaka (Oryzias latipes) using a nanosecond pulsed electric field (nsPEF) technique and predicted their molecular mechanisms via transcriptome analysis. The gas chromatography/mass spectrometry analyses revealed that the BaP was efficiently incorporated into the embryos by nsPEF treatment. The embryos incorporating BaP presented typical teratogenic and developmental effects, such as cardiovascular abnormalities, developmental abnormalities, and curvature of backbone. DNA microarray analysis revealed several unique upregulated genes, such as those involved in cardiovascular diseases, various cellular processes, and neural development. Furthermore, the gene set enrichment and network analyses found several genes and hub proteins involved in the developmental effects of BaP on the embryos. These findings suggest a potential mechanism of teratogenicity and developmental toxicity caused by exposure to BaP. The nsPEF and transcriptome analyses in combination can be effective for evaluating the potential effects of chemical substances on medaka embryos., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Extracellular vesicles (EVs) from cancer are delivered both proximal and distal organs. EVs are highly glycosylated at the surface where EVs interact with cells and therefore has an impact on their properties and biological functions. Aberrant glycosylation in cancer is associated with cancer progression and metastasis. However, the biological function of glycosylation on the surface of EV is uncovered. We first demonstrated differential glycosylation profiles of EVs and their originated cells, and distinct glycosylation profiles in a brain-metastatic subline BMD2a from its parental human breast cancer cell line, MDA-MB-231-luc-D3H2LN by lectin blot. We then investigated the roles of surface glycoconjugates on EV uptake. N- and/or O-glycosylation removal of fluorescent-labelled BMD2a EVs enhanced cellular uptake to endothelial cells, suggesting that surface glycosylation has inhibitory effects on cellular uptake. Biodistribution of glycosylation-deprived BMD2a EVs administrated intravenously into mice was further analysed ex vivo using near-infrared lipophilic dye. EVs treated with O-deglycosylation enzymes enhanced the accumulation of EVs to the lungs after 24 h from the injection, while N-deglycosylation did not markedly alter biodistribution. As the lungs are first organs in which intravenous blood flows, we suggest that surface glycosylation of cancer-derived EVs avoid promiscuous adhesion to proximal tissues to be delivered to distant organs., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)

The lycopene content of tomatoes is important because of its effects on vital physiological functions such as improvement of glucose tolerance and non-alcoholic fatty liver disease. To investigate the influence of the lycopene content of tomatoes on glucose tolerance and hepatic lipid content, homogenates of lycopene-rich (LR) or lycopene-free negative control (NC) tomato varieties were administrated to normal rats for 4 weeks. At the end of the experiment, an oral glucose tolerance test (OGTT) was performed. Rats were fed once and then dissected. According to the OGTT results, plasma glucose levels in the LR group were 10% and 9% lower at 15 min and 30 min, respectively, than those in the NC group, whereas plasma insulin levels did not differ between the groups at either time point. Upon dissection, plasma leptin levels in the LR group were higher than those in the NC group, while plasma adiponectin levels did not differ between groups. With the exception of retinol palmitate, no carotenoids were detected in the liver by HPLC analysis. Hepatic retinol palmitate levels and hepatic triacyl glyceride levels did not differ between the groups. We concluded that in normal rats, a lycopene-rich tomato variety improved glucose tolerance via an increase in plasma leptin levels that enhanced insulin sensitivity but did not affect carotenoid accumulation or lipid metabolism.

Introduction/aims: Immune checkpoint inhibitors (ICIs) sometimes cause immune-related adverse events (irAEs), of which there is little information in the literatures. The objective of this study was to characterize the clinical features of gastrointestinal irAEs (GI irAEs)., Materials and Methods: From a total of 250 patients who were administered anti-PD-1 antibodies (nivolumab and pembrolizumab), we retrospectively identified 9 patients with grade 2 or higher GI irAE based on medical records. Patient characteristics, clinical features, imaging and pathological findings, and treatment course were evaluated., Results: Grade 2 or higher GI irAEs were observed in 9 (3.6%) patients. Of the 9 patients who experienced GI irAE, 8 were male, and mean age was 63.2 years. Five patients received nivolumab and 4 received pembrolizumab. The GI irAEs observed were diarrhea in 7 patients and bloody stool in 2 patients. Grade 2 GI irAEs were identified in 3 patients and grade 3 GI irAEs in 6 patients. The average time from ICI administration to the onset of GI irAEs was 22.2 weeks (range 7-56 weeks) for nivolumab and 19.7 weeks (range 11-28 weeks) for pembrolizumab. Endoscopic findings showed ulcerative colitis-like findings in 3 of 7 patients, and pathological examination revealed crypt epithelial cell apoptosis in 6 of 7 patients. Eight of the 9 patients received steroids, and 2 patients received infliximab additionally. All GI irAEs were manageable., Conclusions: Because of the lack of specific clinical, imaging, and pathological findings, information of ICI use was indispensable for diagnosis. Although GI irAEs are controllable by steroid and infliximab, further studies regarding management strategy will be needed., (© 2019 S. Karger AG, Basel.)

Background/aims: The present study was performed to compare the safety of sedation with propofol during endoscopic submucosal dissection (ESD) for gastric tumors under sedation in the endoscopy room by an endoscopist versus sedation in the operation room by an anesthesiologist., Methods: In total, 638 patients with gastric tumors who underwent ESD from January 2011 to August 2017 at Ureshino Medical Center and Saga Medical Center Koseikan were retrospectively reviewed. The patients were divided into 2 groups: those who underwent ESD in the endoscopy room (Group E, n = 532) and those who underwent ESD in the operation room (Group O, n = 106). Propensity score matching was applied for evaluation. The treatment outcome of ESD and the adverse events of sedation during ESD (desaturation, hypotension, bradycardia, and arrhythmia) were compared between the 2 groups to consider the safety of ESD., Results: The propensity score-matching analysis created 82 matched pairs. Adjusted comparisons between Groups E and O showed similar treatment outcomes of ESD for gastric tumors. There were no significant differences in the treatment outcomes, anesthesia time, and mean propofol dose between the 2 groups. With respect to adverse events, desaturation occurred more often in Group E than Group O (18.3 vs. 3.7%, respectively; p = 0.005). There were no significant differences in other adverse events (hypotension, bradycardia, and arrhythmia) between the 2 groups., Conclusion: Sedation with propofol in the operation room might be required to ensure safer application of ESD for gastric tumors. However, a decrease in the desaturation rate was the only disadvantage of sedation in the endoscopy room., (© 2019 S. Karger AG, Basel.)

Background: Patients with permanent postsurgical hypoparathyroidism, a complication of total thyroidectomy, often require high calcium supplementation with vitamin D to maintain serum calcium levels. The epidemiology of calcium-alkali syndrome (CAS) in patients with hypoparathyroidism after total thyroidectomy remains unclear. This study aimed to investigate the incidence of hypercalcemia, renal impairment, metabolic alkalosis, and CAS in patients treated for presumed hypoparathyroidism after total thyroidectomy., Methods: Twenty-seven patients with neck cancers who underwent total thyroidectomy without parathyroid autotransplantation between January 2010 and October 2013 at our hospital were consecutively included. All patients received calcium lactate and alfacalcidol for postsurgical hypocalcemia. We defined hypercalcemia as a corrected serum calcium level (cCa) ≥10.5 mg/dL, metabolic alkalosis as a difference in serum sodium and serum chloride ([sNa-sCl]) ≥39 mEq/L, and renal impairment as a ≥50% increase in serum creatine and/or ≥35% decrease in estimated glomerular filtration rate (eGFR) compared to baseline., Results: cCa peaked (11.1 ± 1.5 mg/dL) at a median of 326 days (interquartile range 78-869) after surgery. At peak cCa, [sNa-sCl] was significantly higher (p < 0.01), and eGFR was significantly lower (p < 0.01) than that at baseline. Fifteen patients (55.6%) had hypercalcemia, 19 (70.3%) had alkalosis, 12 (44.4%) had renal impairment, and 9 (33.3%) had CAS. Patients with CAS (mean age 67.1 ± 10.8 years) were older than those without CAS (56.7 ± 13.6 years, p = 0.06). The mean dose of alfacalcidol in the CAS group (3.1 ± 1.2 μg/day) was significantly larger than that in the non-CAS group (2.1 ± 1.0 μg/day, p = 0.03)., Conclusions: This retrospective study reveals the high incidence of CAS in patients with hypoparathyroidism after total thyroidectomy. Furthermore, these findings suggest that the serum calcium level, acid-base balance, and renal function should be closely monitored in patients with postsurgical hypoparathyroidism who receive large doses of active vitamin D., (© 2020 S. Karger AG, Basel.)

Background: Endoscopic mucosal resection (EMR) to remove colon polyps is increasingly common in patients taking antithrombotic agents. The safety of EMR with submucosal saline injection has not been clearly demonstrated in this population., Aims: The present study aimed to evaluate the efficacy and safety of submucosal injection of saline-epinephrine versus hypertonic saline in colorectal EMR of patients taking antithrombotic agents., Methods: This study enrolled 204 patients taking antithrombotic agents among 995 consecutive patients who underwent colonic EMR from April 2012 to March 2018 at Ureshino Medical Center. Patients were divided into two groups according to the injected solution: saline-epinephrine or hypertonic (10%) saline (n = 102 in each group). Treatment outcomes and adverse events were evaluated in each group and risk factors for immediate and post-EMR bleeding were investigated., Results: There were no differences between groups in patient or polyp characteristics. The main antithrombotic agents were low-dose aspirin, warfarin, and clopidogrel. Propensity-score matching created 80 matched pairs. Adjusted comparisons between groups showed similar en bloc resection rates (95.1% with saline-epinephrine vs. 98.0% with hypertonic saline). There were no significant differences in adverse events (immediate EMR bleeding, post-EMR bleeding, perforation, or mortality) between groups. Multivariate analyses revealed that polyp size over 10 mm was associated with an increased risk of immediate EMR bleeding (odds ratio 12.1, 95% confidence interval 2.0-74.0; P = 0.001)., Conclusions: Two tested solutions in colorectal EMR were considered to be both safe and effective in patients taking antithrombotic agents.

In aqueous media, the introduction of additional metal species into polyoxometalates (POMs) with multiple vacant sites, such as a hexavacant Dawson-type phosphotungstate, which is of interest for the synthesis of novel metal oxide clusters, is generally difficult because they easily undergo self-condensation and/or structural decomposition. In this study, we succeeded in developing a novel synthetic method to obtain metal-substituted γ-Dawson-type phosphotungstate monomers by introducing metal species into an organic solvent-soluble lacunary phosphotungstate, TBA4H10[α-P2W12O48] (I) (TBA = tetra-n-butylammonium), in organic media. The reaction of I, which possessed two types of vacant sites, i.e. middle and edge sites, with divalent metal species such as Mn2+, Co2+, Ni2+, Cu2+, or Zn2+ in acetonitrile afforded a series of isostructural POMs M2 (TBA5[γ-P2W12O44M2(OAc)(CH3CONH)2]·nH2O·mCH3CN; M = Mn2+, Co2+, Ni2+, Cu2+, or Zn2+; OAc = acetate) with an edge-sharing bis(square-pyramidal) {O2M(μ3-O)2(μ-OAc)MO2} core. The bis(square-pyramidal) core was selectively placed at the middle site of the hexavacant lacunary phosphotungstate, and the two metals in the core were bridged by two phosphate units and one acetate species. Meanwhile, the edge sites were capped by acetimidate ligands, which protect the reactive lacunary POM from self-condensation. To the best of our knowledge, this is the first report describing the synthesis and characterization of metal-substituted hexavacant γ-Dawson-type POM monomers.

Tomato ( Solanum lycopersicum ) is a rich source of lycopene, a carotenoid that confers various positive biological effects such as improved lipid metabolism. Here, we conducted a randomized, double-blind, placebo-controlled, parallel-group comparative study to investigate the effects of regular and continuous intake of a new high-lycopene tomato, a variety named PR-7, for 12 weeks, based on 74 healthy Japanese subjects with low-density lipoprotein cholesterol (LDL-C) levels ≥120 to <160 mg/dL. The subjects were randomly assigned to either the high-lycopene tomato or placebo (lycopene-free tomato) group. Each subject in the high-lycopene group ingested 50 g of semidried PR-7 (lycopene, 22.0-27.8 mg/day) each day for 12 weeks, while subjects in the placebo group ingested placebo semidried tomato. Medical interviews were conducted, vital signs were monitored, body composition was determined, and blood and saliva samples were taken at weeks 0 (baseline), 4, 8, and 12. The primary outcome assessed was LDL-C. The intake of high-lycopene tomato increased lycopene levels in this group compared to levels in the placebo group ( p < 0.001). In addition, high-lycopene tomato intake improved LDL-C ( p = 0.027). The intake of high-lycopene tomato, PR-7, reduced LDL-C and was confirmed to be safe.