Protective Effects of Hydrogen Gas Inhalation for Hindlimb Ischaemia-Reperfusion Injury in a Mouse Model.

OBJECTIVE: Ischaemia-reperfusion (I/R) injury is a severe post-operative complication that triggers an inflammatory response and causes severe damage. Hydrogen gas has anti-oxidant and anti-apoptotic properties and has been shown to be safe in humans. The study aimed to investigate whether hydrogen gas protects against skeletal muscle I/R injury. METHODS: Experimental basic research using mice. A total of 160 eight to 10 week old albino laboratory bred strain of house mice (25.8 ± 0.68 g) were used in this study. The mice were cable tied to the hindlimb under anaesthesia and then placed in an anaesthesia box filled with air and 2% isoflurane (control group); 80 mice were additionally subjected to 1.3% hydrogen gas in this mix (hydrogen group). After two hours, the cable ties were removed to initiate reperfusion, and hydrogen inhalation lasted for six hours in the hydrogen group. After six hours, the mice were taken out of the box and kept in cages under standard conditions until time for observation at 16 different time points after reperfusion: zero, two, four, six, eight, and 10 hours and one, two, three, four, five, six, seven, 14, 21, and 28 days. Five mice were sacrificed using excess anaesthesia at each time point, and the bilateral hindlimb tissues were harvested. The inflammatory effects of the I/R injury were assessed by evaluating serum interleukin-6 concentrations using enzyme linked immunosorbent assay, as well as histological and immunohistochemical analyses. Untreated mice with I/R injury were used as controls. RESULTS: Hydrogen gas showed protective effects associated with a reduction in inflammatory cell infiltration (neutrophils, macrophages, and lymphocytes), a reduced area of damaged muscle, maintenance of normal muscle cells, and replacement of damaged muscle cells with neoplastic myocytes. CONCLUSION: Inhalation of hydrogen gas had a protective effect against hindlimb I/R injury in mice, in part by reducing inflammatory cell infiltration and in part by preserving normal muscle cells.

Early symptoms preceding post-infectious irritable bowel syndrome following COVID-19: a retrospective observational study incorporating daily gastrointestinal symptoms.

BACKGROUND: Intestinal microinflammation with immune dysfunction due to severe acute respiratory syndrome coronavirus 2 reportedly precipitates post-infectious irritable bowel syndrome. This study aimed to elucidate potential risk factors for subsequent development of irritable bowel syndrome, hypothesizing that it is associated with specific symptoms or patient backgrounds. METHODS: This single-center retrospective observational study (2020-2021) included adults with confirmed coronavirus disease requiring hospital admission and was conducted using real-world data retrieved from a hospital information system. Patient characteristics and detailed gastrointestinal symptoms were obtained and compared between patients with and without coronavirus disease-induced irritable bowel syndrome. Multivariate logistic models were used to validate the risk of developing irritable bowel syndrome. Moreover, daily gastrointestinal symptoms during hospitalization were examined in patients with irritable bowel syndrome. RESULTS: Among the 571 eligible patients, 12 (2.1%) were diagnosed with irritable bowel syndrome following coronavirus disease. While nausea and diarrhea during hospitalization, elevated white blood cell count on admission, and intensive care unit admission were associated with the development of irritable bowel syndrome, nausea and diarrhea were identified as risk factors for its development following coronavirus disease, as revealed by the adjusted analyses (odds ratio, 4.00 [1.01-15.84] and 5.64 [1.21-26.31], respectively). Half of the patients with irritable bowel syndrome had both diarrhea and constipation until discharge, and constipation was frequently followed by diarrhea. CONCLUSIONS: While irritable bowel syndrome was rarely diagnosed following coronavirus disease, nausea and diarrhea during hospitalization precede the early signs of irritable bowel syndrome following coronavirus disease.

Frailty and Neurologic Outcomes of Patients Resuscitated From Nontraumatic Out-of-Hospital Cardiac Arrest: A Prospective Observational Study.

STUDY OBJECTIVE: To elucidate the clinical utility of the Clinical Frailty Scale score for predicting poor neurologic functions in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: This was a prospective, multicenter, observational study conducted between 2019 and 2021. The study included adults with nontraumatic OHCA admitted to the intensive care unit after return of spontaneous circulation (ROSC). Pre-arrest high Clinical Frailty Scale score was defined as 5 or more. Favorable neurologic outcomes defined as a Cerebral Performance Category score of 2 or less at 30 days after admission were compared between patients with and without high Clinical Frailty Scale scores. Multivariable logistic regression analyses fitted with generalized estimating equations were performed to adjust for patient characteristics, out-of-hospital information, and resuscitation content and account for within-institution clustering. RESULTS: Of 9,909 patients with OHCA during the study period, 1,216 were included, and 317 had a pre-arrest high Clinical Frailty Scale score. Favorable neurologic outcomes were fewer among patients with high Clinical Frailty Scale scores. The high Clinical Frailty Scale score group showed a lower percentage of favorable neurologic outcomes after OHCA than the low Clinical Frailty Scale score group (6.1% vs 24.4%; adjusted odds ratio, 0.45 [95% confidence interval 0.22 to 0.93]). This relationship remained in subgroups with cardiogenic OHCA, with ROSC after hospital arrival, and without a high risk of dying (Clinical Frailty Scale score of 7 or less), whereas the neurologic outcomes were comparable regardless of pre-arrest frailty in those with noncardiogenic OHCA and with ROSC before hospital arrival. CONCLUSIONS: Pre-arrest high Clinical Frailty Scale score was associated with unfavorable neurologic functions among patients resuscitated from OHCA. The Clinical Frailty Scale score would help predict clinical consequences following intensive care after ROSC.

Healthcare costs for hospitalized COVID-19 patients in a Japanese university hospital: a cross-sectional study.

BACKGROUND: A health-economic evaluation related to COVID-19 is urgently needed to allocate healthcare resources efficiently; however, relevant medical cost data in Japan concerning COVID-19 are scarce. METHODS: This cross-sectional study investigated the healthcare cost for hospitalized COVID-19 patients in 2021 at Keio University Hospital. We calculated the healthcare costs during hospitalization using hospital claims data and investigated the variables significantly related to the healthcare cost with multivariable analysis. RESULTS: The median healthcare cost per patient for the analyzed 330 patients was Japanese yen (JPY) 1,304,431 (US dollars ~ 11,871) (interquartile range: JPY 968,349-1,954,093), and the median length of stay was 10 days. The median healthcare cost was JPY 798,810 for mild cases; JPY 1,113,680 for moderate I cases; JPY 1,643,909 for moderate II cases; and JPY 6,210,607 for severe cases. Healthcare costs increased by 4.0% for each additional day of hospitalization; 1.26 times for moderate I cases, 1.64 times for moderate II cases, and 1.84 times for severe cases compared to mild cases; and 2.05 times for cases involving ICU stay compared to those not staying in ICU. CONCLUSIONS: We clarified the healthcare cost for hospitalized COVID-19 patients by severity in a Japanese university hospital. These costs contribute as inputs for forthcoming health economic evaluations for strategies for preventing and treating COVID-19.

Early intubation and decreased in-hospital mortality in patients with coronavirus disease 2019.

BACKGROUND: Some academic organizations recommended that physicians intubate patients with COVID-19 with a relatively lower threshold of oxygen usage particularly in the early phase of pandemic. We aimed to elucidate whether early intubation is associated with decreased in-hospital mortality among patients with novel coronavirus disease 2019 (COVID-19) who required intubation. METHODS: A multicenter, retrospective, observational study was conducted at 66 hospitals in Japan where patients with moderate-to-severe COVID-19 were treated between January and September 2020. Patients who were diagnosed as COVID-19 with a positive reverse-transcription polymerase chain reaction test and intubated during admission were included. Early intubation was defined as intubation conducted in the setting of ≤ 6 L/min of oxygen usage. In-hospital mortality was compared between patients with early and non-early intubation. Inverse probability weighting analyses with propensity scores were performed to adjust patient demographics, comorbidities, hemodynamic status on admission and time at intubation, medications before intubation, severity of COVID-19, and institution characteristics. Subgroup analyses were conducted on the basis of age, severity of hypoxemia at intubation, and days from admission to intubation. RESULTS: Among 412 patients eligible for the study, 110 underwent early intubation. In-hospital mortality was lower in patients with early intubation than those with non-early intubation (18 [16.4%] vs. 88 [29.1%]; odds ratio, 0.48 [95% confidence interval 0.27-0.84]; p = 0.009, and adjusted odds ratio, 0.28 [95% confidence interval 0.19-0.42]; p < 0.001). The beneficial effects of early intubation were observed regardless of age and severity of hypoxemia at time of intubation; however, early intubation was associated with lower in-hospital mortality only among patients who were intubated later than 2 days after admission. CONCLUSIONS: Early intubation in the setting of ≤ 6 L/min of oxygen usage was associated with decreased in-hospital mortality among patients with COVID-19 who required intubation. Trial Registration None.

Extracorporeal cardiopulmonary resuscitation in adult patients with out-of-hospital cardiac arrest: a retrospective large cohort multicenter study in Japan.

BACKGROUND: The prevalence of extracorporeal cardiopulmonary resuscitation (ECPR) in patients with out-of-hospital cardiac arrest (OHCA) has been increasing rapidly worldwide. However, guidelines or clinical studies do not provide sufficient data on ECPR practice. The aim of this study was to provide real-world data on ECPR for patients with OHCA, including details of complications. METHODS: We did a retrospective database analysis of observational multicenter cohort study in Japan. Adult patients with OHCA of presumed cardiac etiology who received ECPR between 2013 and 2018 were included. The primary outcome was favorable neurological outcome at hospital discharge, defined as a cerebral performance category of 1 or 2. RESULTS: A total of 1644 patients with OHCA were included in this study. The patient age was 18-93 years (median: 60 years). Shockable rhythm in the initial cardiac rhythm at the scene was 69.4%. The median estimated low flow time was 55 min (interquartile range: 45-66 min). Favorable neurological outcome at hospital discharge was observed in 14.1% of patients, and the rate of survival to hospital discharge was 27.2%. The proportions of favorable neurological outcome at hospital discharge in terms of shockable rhythm, pulseless electrical activity, and asystole were 16.7%, 9.2%, and 3.9%, respectively. Complications were observed during ECPR in 32.7% of patients, and the most common complication was bleeding, with the rates of cannulation site bleeding and other types of hemorrhage at 16.4% and 8.5%, respectively. CONCLUSIONS: In this large cohort, data on the ECPR of 1644 patients with OHCA show that the proportion of favorable neurological outcomes at hospital discharge was 14.1%, survival rate at hospital discharge was 27.2%, and complications were observed during ECPR in 32.7%.

Hydrogen gas with extracorporeal cardiopulmonary resuscitation improves survival after prolonged cardiac arrest in rats.

BACKGROUND: Despite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats. METHODS: Rats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated. RESULTS: The survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan-Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in D-glutamine and D-glutamate metabolism. CONCLUSIONS: H2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia-reperfusion injury in critically ill patients who require ECMO support.

The Effects of Hydrogen Gas Inhalation on Adverse Left Ventricular Remodeling After Percutaneous Coronary Intervention for ST-Elevated Myocardial Infarction　- First Pilot Study in Humans.

BACKGROUND: Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI).Methods and Results:The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m2; control: -1.4±7.2 mL/m2; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). CONCLUSIONS: The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).

Podocyte-specific NF-κB inhibition ameliorates proteinuria in adriamycin-induced nephropathy in mice.

BACKGROUND: Podocytes play a central role in the formation of the glomerular filtration barrier in the kidney, and their dysfunction has been shown to result in proteinuria. In the present study, we sought to determine the cell-autonomous role of NF-κB, a proinflammatory signaling, within podocytes in proteinuric kidney disease. METHODS: Podocyte-specific IκBΔN transgenic (Pod-IκBΔN) mice, in which NF-κB was inhibited specifically in podocytes, were generated by the Cre-loxP technology, and their phenotype was compared with control mice in adriamycin-induced nephropathy. RESULTS: Pod-IκBΔN mice were phenotypically normal and did not exhibit proteinuria at the physiological condition. By the intravenous administration of adriamycin, overt proteinuria appeared in Pod-IκBΔN mice, as well as in control mice. However, of interest, the amount of proteinuria was significantly lower in adriamycin-injected Pod-IκBΔN mice (373 ± 122 mg albumin/g creatinine), compared with adriamycin-injected control mice (992 ± 395 mg albumin/g creatinine). Expression of podocyte-selective slit diaphragm-associated proteins, such as nephrin and synaptopodin, was markedly decreased by adriamycin injection in control mice, whereas the reduction was attenuated in Pod-IκBΔN mice. Adriamycin-induced reduction in synaptopodin expression was also seen in cultured podocytes derived from control mice, but not in those from Pod-IκBΔN mice. CONCLUSIONS: Because nephrin and synaptopodin are essential for the maintenance of the slit diaphragm in podocytes, these results suggest that proteinuria in adriamycin-induced nephropathy is caused by the reduction in expression of these proteins. The results also suggest that the NF-κB signalling in podocytes cell-autonomously contributes to proteinuria through the regulation of these proteins.

miR-363 induces transdifferentiation of human kidney tubular cells to mesenchymal phenotype.

BACKGROUND: microRNAs (miRNAs) are non-coding small RNAs that regulate embryonic development, cell differentiation and pathological processes via interaction with mRNA. Epithelial-mesenchymal transition (EMT) is pathological process that involves in a variety of diseases such as cancer or fibrosis. METHODS: In this study, we identified miR-363 as a potent inducer of EMT by microarray analysis in human kidney tubular cells, and analyzed the function and mechanisms of miR-363. RESULTS: Overexpression of miR-363 induced mesenchymal phenotypes with loss of epithelial phenotypes in human kidney tubular cells. In addition, in vitro scratch assay demonstrated that miR-363 promotes cell migration of primary culture of human kidney tubular cells. We identified TWIST/canonical WNT pathway as the downstream effecter of miR-363, and inhibition of canonical WNT by small molecule, IWR-1, attenuated EMT induced by miR-363. CONCLUSION: miR-363 induces transdifferentiation of human kidney tubular cells via upregulation of TWIST/canonical WNT pathway.

Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats.

Background: The present study aimed at investigating the effect of a novel antioxidant, hydrogen (H2) gas, on the severity of contrast-induced acute kidney injury (CIAKI) in a rat model. Methods: CIAKI was induced in rats by intravenous injection of a contrast medium, Ioversol, in addition to reagents inhibiting prostaglandin and nitric oxide synthesis. During the injection of these reagents, the rats inhaled H2 gas or control gas. Results: One day after the injection, serum levels of urea nitrogen were significantly lower in H2 gas-inhaling CIAKI rats (17.6 ± 2.3 mg/dl) than those in control gas-treated CIAKI rats (36.0 ± 7.3 mg/dl), although they both were elevated as compared to untreated rats (14.9 ± 0.9 mg/dl). Consistently, creatinine clearance in H2 gas-treated CIAKI rats was higher than that in control gas-treated counterparts. Renal histological analysis revealed that the formation of proteinaceous casts and tubular necrosis was improved by H2 gas inhalation. Mechanistic analyses showed that inhalation of H2 gas significantly reduced renal cell apoptosis, expression of cleaved caspase 3, and expression of an oxidative stress marker, 8-hydroxydeoxyguanosine, in injured kidneys. Conclusion: Results suggest that H2 gas inhalation is effective in ameliorating the severity of CIAKI in rats by reducing renal cell apoptosis and oxidative stress. © 2015 S. Karger AG, Basel.

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

Door-to-Needle Time for Extracorporeal Cardiopulmonary Resuscitation and Neurological Outcomes in Out-of-Hospital Cardiac Arrest: A Nationwide Study.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is an option for refractory cardiac arrest, and immediate initiation after indication is recommended. However, the practical goals of ECPR preparation (such as the door-to-needle time) remain unclear. This study aimed to elucidate the association between the door-to-needle time and neurological outcomes of out-of-hospital cardiac arrest. METHODS AND RESULTS: This is a post hoc analysis of a nationwide multicenter study on out-of-hospital cardiac arrest treated with ECPR at 36 institutions between 2013 and 2018 (SAVE-J [Study of Advanced Cardiac Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan] II study). Adult patients without hypothermia (≥32 °C) in whom circulation was not returned at ECPR initiation were included. The probability of favorable neurological function at 30 days (defined as Cerebral Performance Category ≤2) was estimated using a generalized estimating equations model, in which institutional, patient, and treatment characteristics were adjusted. Estimated probabilities were then calculated according to the door-to-needle time with 3-minute increments, and a clinical threshold was assumed. Among 1298 patients eligible for this study, 136 (10.6%) had favorable neurological function. The estimated probability of favorable outcomes was highest in patients with 1 to 3 minutes of door-to-needle time (12.9% [11.4%-14.3%]) and remained at 9% to 10% until 27 to 30 minutes. Then, the probability dropped gradually with each 3-minute delay. A 30-minute threshold was assumed, and shorter door-to-extracorporeal membrane oxygenation/low-flow time and fewer adverse events related to cannulation were observed in patients with door-to-needle time <30 minutes. CONCLUSIONS: The probability of favorable functions after out-of-hospital cardiac arrest decreased as the door-to-needle time for ECPR was prolonged, with a rapid decline after 27 to 30 minutes. REGISTRATION: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041577; Unique identifier: UMIN000036490.

Delta Shock Index and higher incidence of emergency surgery in older adults with blunt trauma.

PURPOSE: Vital signs are important for predicting clinical outcomes in patients with trauma. However, their accuracy can be affected in older adults because hemodynamic changes are less obvious. This study aimed to examine the usefulness of changes in vital signs during transportation in predicting the need for hemostatic treatments in older patients with trauma. METHODS: This retrospective cohort study was conducted using data from the Japan Trauma Data Bank (2004-2019). Patients aged ≥ 65 years who were hemodynamically stable at the scene were included in this study. The incidence of emergency surgery within 12 h after hospital arrival was compared between patients with delta Shock Index (dSI) > 0.1 and those with dSI ≤ 0.1. Predicting ability was examined after adjusting for patient demographics, comorbidities, vital signs at the scene and on hospital arrival, Injury Severity Score, and abbreviated injury scale in each region. RESULTS: Among the 139,242 patients eligible for the study, 3,701 underwent urgent hemostatic surgery within 12 h. Patients with dSI > 0.1 showed a significantly higher incidence of emergency surgery than those with dSI ≤ 0.1 (871/16,549 [5.3%] vs. 2,830/84,250 [3.4%]; odds ratio (OR), 1.60 [1.48-1.73]; adjusted OR, 1.22 [1.08-1.38]; p = 0.001). The relationship between high dSI and a higher incidence of intervention was observed in patients with hypertension and those with decreased consciousness on arrival. CONCLUSION: High dSI > 0.1 was significantly associated with a higher incidence of urgent hemostatic surgery in older patients.

Therapeutic Apheresis Using a ß2-Microglobulin Removal Column Reduces Circulating Tumor Cell Count.

An elevated serum ß2-microglobulin (ß2M) level is indicative of impaired glomerular filtration and prerenal diseases, such as malignant tumors, autoimmune disorders, and liver diseases. An elevated serum ß2M level has been shown to promote metastasis via the induction of epithelial-mesenchymal transition (EMT) in cancer cells. However, the therapeutic potential of targeting ß2M remains unclear. Here, we aimed to investigate the efficacy of Filtor, a small polymethyl methacrylate fiber-based ß2M removal column, in reducing the ß2M level and suppressing cancer cell-induced EMT and metastasis. We assessed the effects of Filtor on the changes in metastasis based on the number of circulating tumor cells (CTCs), which reflects the post-EMT cancer cell population. We performed therapeutic apheresis using Filtor on a male patient with sinonasal neuroendocrine carcinoma, a female patient with a history of colorectal cancer, and another female patient with a history of pancreatic ductal adenocarcinoma. Significantly low serum ß2M levels and CTC counts were observed immediately and 4 weeks after treatment compared with those in the pretreatment phase. Moreover, the CTC count immediately after therapeutic intervention was markedly reduced, likely because Filtor had trapped CTCs directly. These findings suggest that therapeutic apheresis with Filtor can prevent cancer metastasis and recurrence by directly removing CTCs.

Skew of plasma low- and high-density lipoprotein distributions to less dense subfractions in normotriglyceridemic chronic kidney disease patients on maintenance hemodialysis treatment.

BACKGROUND: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. METHODS: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. RESULTS: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL2 in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL3 were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. CONCLUSION: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients.

Efficacy of inhaled hydrogen on neurological outcome following brain ischaemia during post-cardiac arrest care (HYBRID II): a multi-centre, randomised, double-blind, placebo-controlled trial.

Background: Inhaled molecular hydrogen gas (H2) has been shown to improve outcomes in animal models of cardiac arrest (CA). H2 inhalation is safe and feasible in patients after CA. We investigated whether inhaled H2 would improve outcomes after out-of-hospital CA (OHCA). Methods: HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20-80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H2 or oxygen (control) for 18 h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352). Findings: The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H2 (n = 39) or control (n = 34) groups. The primary outcome, i.e., a CPC of 1 or 2 at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46-1.13; P = 0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0-5) and 5 (1-6) in the H2 and control groups, respectively (P = 0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H2 and control groups, respectively (P = 0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H2 and control groups, respectively (P = 0.02). Interpretation: The increase in participants with good neurological outcomes following post-OHCA H2 inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H2 inhalation may increase 90-day survival without neurological deficits. Funding: Taiyo Nippon Sanso Corporation. Translation: For the Japanese translation of the abstract see Supplementary Materials section.

Persistent and Late-Onset Disseminated Intravascular Coagulation Are Closely Related to Poor Prognosis in Patients with Sepsis.

BACKGROUND: Septic-associated disseminated intravascular coagulation (DIC) is heterogeneous regarding prognosis and responsiveness to anticoagulant therapy. OBJECTIVES: To investigate the relationship between the timing of development and recovery of DIC, its prognosis, and the difference in response to anticoagulant therapy in sepsis-associated DIC patients. METHODS: This study was performed with a dataset from a multicenter nationwide retrospective cohort study (J-Septic DIC registry) in Japan between 2011 and 2013 to reveal the subgroup "high risk of death in DIC" and investigate the relationship between anticoagulant use and mortality. Patients were assigned to four groups based on the International Society on Thrombosis and Haemostasis-overt DIC status at days 1 and 3: non-DIC (-/-), early-recovered DIC (+/-), late-onset DIC (-/+), and persistent DIC (+/+). RESULTS: A total of 1,922 patients were included. In-hospital mortality in persistent and late-onset DIC patients was significantly higher than in patients with non-DIC and early-recovered DIC. This finding indicates that persistent DIC and late-onset DIC were a poor-prognosis subgroup, "high-risk" DIC. Meanwhile, patients with high-risk DIC treated with anticoagulants had significantly better outcomes than those without anticoagulants after adjusting for confounding factors. CONCLUSION: This study showed that individuals with a high risk of death, persistent DIC, and late-onset DIC were a poor-prognostic subgroup in septic DIC; however, high-risk DIC is also a subgroup that can obtain more benefits from anticoagulant therapy.

Hypotension at Hospital Presentation and Post-Contrast Acute Kidney Injury following Computed Tomography with Contrast Media.

INTRODUCTION: Post-contrast acute kidney injury (PC-AKI) is a major complication of contrast media usage; risks for PC-AKI are generally evaluated before computed tomography (CT) with contrast at the emergency department (ED). Although persistent hypotension (systolic blood pressure [sBP] <80 mm Hg for 1 h) is associated with increased PC-AKI incidence, it remains unclear whether transient hypotension that is haemodynamically stabilized before CT is a risk of PC-AKI. We hypothesized that hypotension on ED arrival would be associated with higher PC-AKI incidence even if CT with contrast was performed after patients are appropriately resuscitated. METHODS: This multicentre retrospective observational study was conducted at three tertiary care centres during 2013-2014. We identified 280 patients who underwent CT with contrast at the ED. Patients were classified into two groups based on sBP on arrival (<80 vs. ≥80 mm Hg); hypotension was considered as transient because CT with contrast has always been performed after patients were stabilized at participating hospitals. PC-AKI incidence was compared between the groups; inverse probability weighting (IPW) was conducted to adjust background characteristics. RESULTS: Eighteen patients were excluded due to chronic haemodialysis, cardiac arrest on arrival, or death within 72 h; 262 were eligible for this study. PC-AKI incidence was higher in the transient hypotension group than the normotension group {7/27 (28.6%) vs. 24/235 (10.2%), odds ratio (OR) 3.08 (95% confidence interval [CI] 1.18-8.03), p = 0.026}, which was confirmed by IPW (OR 3.25 [95% CI 1.99-5.29], p < 0.001). CONCLUSION: Transient hypotension at the ED was associated with PC-AKI development.

Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).