Tumour-derived exosomes promote the induction of monocytic myeloid-derived suppressor cells from peripheral blood mononuclear cells by delivering miR-106a-5p and miR-146a-5p in multiple myeloma.

The shift of the tumour immune microenvironment to a suppressive state promotes not only the development and progression of the disease in multiple myeloma (MM) but also the development of resistance to immunotherapy. We previously demonstrated that myeloma cells can induce monocytic myeloid-derived suppressor cells (M-MDSCs) from healthy peripheral blood mononuclear cells (PBMCs) via the concomitant secretion of CC motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF), but an unknown mediator also promotes M-MDSC induction. This study demonstrates that miR-106a-5p and miR-146a-5p delivered by tumour-derived exosomes (TEXs) from myeloma cells play essential roles in M-MDSC induction in MM. MiR-106a-5p and miR-146a-5p upregulate various immunosuppressive/inflammatory molecules in PBMCs, such as IDO1, CD38, programmed death-ligand 1, CCL5 or MYD88, which are involved in interferon (IFN)-α response, IFN-γ response, inflammatory response, tumour necrosis factor-α signalling and Interleukin-6-JAK-STAT3 signalling. These molecular features mirror the increases in myeloid cellular compartments of PBMCs when co-cultured with myeloma cells. MiR-106a-5p and miR-146a-5p have a compensatory relationship, and these two miRNAs collaborate with CCL5 and MIF to promote M-MDSC induction. Collectively, novel therapeutic candidates may be involved in TEX-mediated sequential cellular and molecular events underlying M-MDSC induction, potentially improving the efficacy of immunotherapy.

Clinical Significance of Elevated Xanthine Dehydrogenase Levels and Hyperuricemia in Patients with Sepsis.

Patient outcomes for severe sepsis and septic shock remain poor. Excessive oxidative stress accelerates organ dysfunction in severe acute illnesses. Uric acid (UA) is the most abundant antioxidant. We hypothesized that UA and related molecules, which play a critical role in antioxidant activity, might be markers of oxidative stress in sepsis. The study aimed to clarify the clinical significance of UA and the relationship between UA, molecules related to UA, and outcomes by measuring blood UA, xanthine dehydrogenase (XDH), and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels over time. Blood UA levels in septic patients were correlated with the SOFA score (ρ = 0.36, p < 0.0001) and blood XDH levels (ρ = 0.27, p < 0.0001). Blood XDH levels were correlated with the SOFA score (ρ = 0.59, p < 0.0001) and blood 8-OHdG levels (ρ = -0.32, p < 0.0001). Blood XDH levels were persistently high in fatal cases. Blood XDH level (OR 8.84, 95% CI: 1.42-91.2, p = 0.018) was an independent factor of poor outcomes. The cutoff of blood XDH level was 1.38 ng/mL (sensitivity 92.8%, specificity 61.9%), and those 1.38 ng/mL or higher were associated with a significantly reduced survival rate (blood XDH level > 1.38 ng/mL: 23.7%, blood XDH level < 1.38 ng/mL: 96.3%, respectively, p = 0.0007). Elevated UA levels due to elevated blood XDH levels in sepsis cases may reduce oxidative stress. Countermeasures against increased oxidative stress in sepsis may provide new therapeutic strategies.

Prognostic implication of CTLA-4, PD-1, and PD-L1 expression in aggressive adult T-cell leukemia-lymphoma.

The prognosis of patients with aggressive adult T cell leukemia-lymphoma (ATLL) is dismal even with intensive chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a promising option for patients with aggressive ATLL, but the posttransplant outcome remains unsatisfactory. Hence, to further improve clinical outcomes, novel therapeutic approaches are needed. The clinical significance of immune checkpoint protein expression has not been well-established in aggressive ATLL. This study aims to identify the association between the expression profile of immune checkpoint proteins on ATLL cells and clinical outcomes. This retrospective study cohort included 65 patients with aggressive ATLL diagnosed between 2001 and 2015 at the National Cancer Center Hospital, Tokyo, Japan. Formalin-fixed paraffin-embedded tissue was used to immunohistochemically determine the expression of immune checkpoint proteins and assess the impact of expression profile on the probability of overall survival from diagnosis or HSCT. The current analysis shows that cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) expressions were adverse prognostic factors in patients with aggressive ATLL. Experiments that assess the efficacy of immune checkpoint inhibitors are warranted to alleviate the adverse impacts associated with negative immune checkpoints.

Association between frailty and mortality among patients with accidental hypothermia: a nationwide observational study in Japan.

BACKGROUND: Frailty has been associated with a risk of adverse outcomes, and mortality in patients with various conditions. However, there have been few studies on whether or not frailty is associated with mortality in patients with accidental hypothermia (AH). In this study, we aim to determine this association in patients with AH using Japan's nationwide registry data. METHODS: The data from the Hypothermia STUDY 2018&19, which included patients of ≥18 years of age with a body temperature of ≤35 °C, were obtained from a multicenter registry for AH conducted at 120 institutions throughout Japan, collected from December 2018 to February 2019 and December 2019 to February 2020. The clinical frailty scale (CFS) score was used to determine the presence and degree of frailty. The primary outcome was the comparison of mortality between the frail and non-frail patient groups. RESULTS: In total, 1363 patients were included in the study, of which 920 were eligible for the analysis. The 920 patients were divided into the frail patient group (N = 221) and non-frail patient group (N = 699). After 30-days of hospitalization, 32.6% of frail patients and 20.6% of non-frail patients had died (p < 0.001). Frail patients had a significantly higher risk of 90-day mortality (Hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.25-2.17; p < 0.001). Based on the Cox proportional hazards analysis using multiple imputation, after adjustment for age, potassium level, lactate level, pH value, sex, CPK level, heart rate, platelet count, location of hypothermia incidence, and rate of tracheal intubation, the HR was 1.69 (95% CI, 1.25-2.29; p < 0.001). CONCLUSIONS: This study showed that frailty was associated with mortality in patients with AH. Preventive interventions for frailty may help to avoid death caused by AH.

Be careful of splenic rupture caused by hit by a pitch during a baseball game: a case report.

BACKGROUND: To the best of our knowledge, splenic rupture caused by hit by a pitch (HBP) has not been previously reported. We present a patient who underwent emergency laparotomy for splenic rupture after being HBP during a baseball game. CASE PRESENTATION: A 41-year-old male was HBP in the left abdomen during his first at-bat during a baseball game. During the operation, vascular injury of the splenic hilum and a deeply extending parenchymal injury were observed, and splenectomy was performed. Histologic findings were consistent with splenic rupture. CONCLUSIONS: The patient's postoperative course was uneventful. Although extremely rare, the possibility of intra-abdominal organ injury should be considered in batters who are hit in the abdomen by a pitched baseball, as illustrated by our patient.

Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma.

An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.

Increased oxidative stress and renal injury in patients with sepsis.

Sepsis remains one of the leading causes of death in intensive care units. The early phase of sepsis is characterized by a massive formation of reactive oxygen and nitrogen species such as superoxide and nitric oxide. However, few comprehensive studies on plasma antioxidants have been reported. Increased oxidative stress was confirmed in sepsis patients (n = 18) at the time of hospitalization by a significant decrease in plasma ascorbic acid and a significant increase in the percentage of oxidized form of coenzyme Q10 in total coenzyme Q10 compared to age-matched healthy controls (n = 62). Tissue oxidative damage in patients was suggested by a significant decrease in polyunsaturated fatty acid contents and a significant increase in oleic acid contents in total free fatty acids. Thus, it is reasonable that plasma uric acid (end product of purines) would be significantly elevated. However, uric acid levels were continuously decreased during hospitalization for 7 days, indicating a continuous formation of peroxynitrite. A greater decrease in free cholesterol (FC) compared to cholesterol esters (CE) was observed. Thus, the FC/CE ratio significantly increased, suggesting deficiency of lecithin-cholesterol acyltransferase secreted from the liver. Plasma levels of prosaposin, a coenzyme Q10 binding protein, significantly decreased as compared to healthy controls. This may be correlated with renal injury in sepsis patients, since the kidney is thought to be a major secretor of prosaposin.

Systemic impact on secondary brain aggravation due to ischemia/reperfusion injury in post-cardiac arrest syndrome: a prospective observational study using high-mobility group box 1 protein.

BACKGROUND: Ischemia/reperfusion injury (I/R) is an important pathophysiology of post-cardiac arrest syndrome (PCAS) against multiple organ dysfunction and mortality. The inflammatory response in PCAS causes systemic I/R. The purpose of this study was to demonstrate the pathophysiology of systemic I/R for secondary brain damage using the biomarkers high-mobility group box 1 (HMGB1), neuron-specific enolase (NSE), and interleukin-6 (IL-6). METHODS: This study was designed as a single-institution prospective observational study. Subjects were observed for 90 days, and neurological outcome was classified according to the Glasgow-Pittsburgh Cerebral Performance Categories Scale (CPC). Serum HMGB1, NSE, and IL-6 were evaluated for variability, correlation with each biomarker, or the Sequential Organ Function Assessment (SOFA) score and CPC at return of spontaneous circulation at 0, 24, 48, and 168 h. RESULTS: A total of 128 patients were enrolled in this study. Initial HMGB1 correlated with CPC (ρ = 0.27, p = 0.036) and SOFA score (ρ = 0.33, p < 0.001). The early phase of HMGB1 (0-24 h), all phases of IL-6, and the delayed phase of NSE (24-168 h) manifested poor neurological outcome. HMGB1 showed a significant correlation with NSE (ρ = 0.29, p = 0.002 at 0 h; ρ = 0.42, p < 0.001 at 24 h) and IL-6 (ρ = 0.36, p < 0.001 at 24 h). CONCLUSIONS: Serum HMGB1 for first 24 h after cardiac arrest was significantly correlated with SOFA score, NSE, and IL-6. This result suggests that systemic I/R may contribute to secondary brain aggravation. It is expected that research on HMGB1 focused on systemic I/R will help prevent aggravating neurological outcomes.

Development of DS-5573a: A novel afucosylated mAb directed at B7-H3 with potent antitumor activity.

B7-H3 is highly overexpressed in a variety of human clinical tumors, and its expression is significantly associated with poor outcomes. In our study, we aimed to develop new antitumor mAbs by employing cancer cell immunization, and succeeded in generating a mouse anti-human B7-H3 antibody (M30) that shows antitumor activity. M30 was humanized (Hu-M30), and an afucosylated Hu-M30 (DS-5573a) was also generated. To assess the potency of DS-5573a as a therapeutic mAb, we characterized this mAb and evaluated its antitumor activity in vitro and in vivo. Flow cytometry analysis showed that B7-H3 proteins were expressed on various types of cancer cell lines broadly, and DS-5573a binds to IgC1 and IgC2 domains of human B7-H3. Antibody-dependent cellular cytotoxicity activity of DS-5573a was drastically enhanced against medium to high B7-H3-expressing cancer cell lines MDA-MB-231 and NCI-H322. DS-5573a also induced high antibody-dependent cellular cytotoxicity activity against low B7-H3-expressing cancer cell line COLO205, whereas Hu-M30 induced little activity against it. In addition, DS-5573a was found to be a novel anti-B7-H3 antibody which showed antibody-dependent cellular phagocytosis activity. Furthermore, DS-5573a showed dose-dependent and significant antitumor efficacy (0.03-3 mg/kg) in MDA-MB-231-bearing SCID mice (which have functional natural killer cells and macrophages), but little antitumor efficacy in NOG mice (which lack natural killer cells and have reduced macrophage function). These results suggest that antitumor activity of DS-5573a is mediated by effector cells, and this mAb could be a promising antitumor therapy for patients with a wide range of B7-H3-expressing tumors.

Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads.

Trastuzumab conjugates consisting of exatecan derivatives were prepared and their biological activities and physicochemical properties were evaluated. The ADCs showed strong efficacy and a low aggregation rate. The exatecan derivatives were covalently connected via a peptidyl spacer (Gly-Gly-Phe-Gly), which is assumed to be stable in circulation, and were cleaved by lysosomal enzymes following ADC internalization into tumor tissue. These anti-HER2 ADCs exhibited a high potency, specifically against HER2-positive cancer cell lines in vitro. The ADCs, bearing exatecan derivatives which have more than two methylene chains, exhibited superior cytotoxicity. It was speculated that steric hindrance of the cleavable amide moiety could be involved in the drug release. The adequate alkyl lengths of exatecan derivatives (13, 14, 15) were from two to four in terms of aggregation rate. The ADC having a hydrophilic moiety showed good efficacy in a HER2-positive and Trastuzumab-resistant breast carcinoma cell model in mice.

Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology.

To establish a novel and widely applicable payload-linker technology for antibody-drug conjugates (ADCs), we have focused our research on applying exatecan mesylate (DX-8951f), a potent topoisomerase I inhibitor, which exhibits extensive antitumor activity as well as significant myelotoxicity, as the payload part. Through this study, we discovered a promising exatecan derivative (DX-8951 derivative, DXd), that has the characteristics of low membrane permeability and shows considerably less myelotoxicity than that shown by exatecan mesylate in an in vitro human colony forming unit-granulocyte macrophage assay. DXd was further used for drug conjugation by using commercially or clinically useful monoclonal antibodies to evaluate the potency of the ADC. The result revealed that the DXd-ADCs targeting CD30, CD33, and CD70 were effective against each of their respective target-expressing tumor cell lines. Moreover, a novel DXd-ADC targeting B7-H3, which is a new target for ADCs, also showed potent antitumor efficacy both in vitro and in vivo. In conclusion, this study showed that this novel topoisomerase I inhibitor-based ADC technology is widely applicable to a diverse number of antibodies and is expected to mitigate myelotoxicity, thereby possibly resulting in better safety profiles than that of existing ADC technologies.

Effects of oral administration of Lactobacillus acidophilus L-92 on the symptoms and serum cytokines of atopic dermatitis in Japanese adults: a double-blind, randomized, clinical trial.

OBJECTIVES: Several studies on lactobacilli have demonstrated they are effective against atopic dermatitis (AD) in children, but there are very few reports of their effects in adults. We investigated the changes in AD symptoms in adults after the ingestion of the Lactobacillus acidophilus strain L-92 (L-92), which has been shown to have a curative effect on AD in children. METHODS: A double-blind, parallel-group, placebo-controlled comparison was performed on 49 AD patients aged ≥16 years using heat-killed L-92. Skin lesions were assessed using the SCORing AD (SCORAD) index before the start of L-92 ingestion and 4 and 8 weeks after ingestion. Serum cytokine and blood marker levels were measured 8 weeks after the start of L-92 ingestion. RESULTS: The group that ingested L-92 had lower SCORAD scores than the controls (p = 0.002). The L-92 group also had decreased ratios of change for eosinophil count (p = 0.03) and increased ratios of change for serum TGF-ß (p = 0.03). Ratios of change for serum TGF-ß rose significantly (p = 0.04) in patients showing mitigated symptoms with L-92 administration. CONCLUSIONS: Administration of heat-killed L-92 was effective for AD symptoms in adults. L-92 may contribute to the suppression of Th2-dominant inflammation. Our preliminary trial is the first to report the effects of L-92 on adult AD.

Shorter time until return of spontaneous circulation is the only independent factor for a good neurological outcome in patients with postcardiac arrest syndrome.

OBJECTIVE: Few studies have reported factors that result in a better neurological outcome in patients with postcardiac arrest syndrome (PCAS) following return of spontaneous circulation (ROSC). We investigated the factors affecting neurological outcome in terms of both prehospital care and treatments after arrival at hospital in patients with PCAS. METHODS: The study enrolled patients with cardiogenic cardiac arrest who were admitted to an intensive care unit after ROSC with PCAS. We investigated the association of the following factors with outcome: age, gender, witness to event present, bystander cardiopulmonary resuscitation (CPR) performed, ECG waveform at the scene, time interval from receipt of call to arrival of emergency personnel, time interval from receipt of call to arrival at hospital, prehospital defibrillation performed, special procedures performed by emergency medical technician, and time interval from receipt of call to ROSC, coronary angiography/percutaneous coronary intervention (PCI) and therapeutic hypothermia performed. RESULTS: The study enrolled 227 patients with PCAS. Compared with the poor neurological outcome group, the good neurological outcome group had a statistically significant higher proportion of the following factors: younger age, male, witness present, bystander CPR performed, first ECG showed ventricular fibrillation/pulseless ventricular tachycardia, defibrillation performed during transportation, short time interval from receipt of call to ROSC, coronary angiography/PCI and therapeutic hypothermia performed. Of these factors, the only independent factor associated with good neurological outcome was the short time interval from receipt of the call to ROSC. CONCLUSIONS: In the present study, shortening time interval from receipt of call to ROSC was the only important independent factor to achieve good neurological outcome in patients with PCAS.

Patients with Severe Trauma Having an Injury Severity Score of 24 and above Develop Nutritional Disorders.

In this single-center, retrospective, observational study, we aimed to assess the severity at which patients with trauma tend to develop metabolic disturbances that worsen their Controlling Nutritional Status (CONUT) scores. Participants were general adult patients with trauma hospitalized for at least one week. Injury Severity Scores (ISSs) at admission and CONUT scores one week later were calculated, and correlation coefficients were examined. The receiver operating characteristic (ROC) curve was used to calculate the ISS cutoff value for a CONUT score of 5 or more on day 7 of hospitalization. The ISS was assessed using multiple logistic regression analysis to determine whether it predicts worse nutritional status. Forty-nine patients were included. ISSs correlated with CONUT scores on day 7 (r = 0.373, p = 0.008). Using the ROC curve, the cutoff value for the ISS was 23.5. Multiple logistic regression analyses showed that a high ISS (odds ratio [OR], 1.158; 95% confidence interval [CI], 1.034-1.296; p = 0.011) and older age (OR, 1.094; 95% CI, 1.027-1.165; p = 0.005) were associated with a CONUT score 5 or more on day 7 of hospitalization. Patients with trauma with an ISS of 24 or higher have worsening CONUT scores during hospitalization; these patients require careful nutritional management.

Blockade of SIRPα-CD47 axis by anti-SIRPα antibody enhances anti-tumor activity of DXd antibody-drug conjugates.

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.

Secondary prevention of new vascular events with lifestyle intervention in patients with noncardioembolic mild ischemic stroke: a single-center randomized controlled trial.

BACKGROUND: Lifestyle modification is associated with a substantially decreased risk of cardiovascular events. However, the role of lifestyle intervention for secondary prevention in patients with noncardioembolic ischemic stroke is inadequately defined. We assessed the hypothesis that lifestyle intervention can reduce the onset of new vascular events in patients with noncardioembolic mild ischemic stroke. METHODS: We conducted an observer-blind randomized controlled trial that enrolled 70 patients (48 men, mean age 63.5 years) with acute noncardioembolic mild ischemic stroke. The patients were allocated in equal numbers to a lifestyle intervention group or a control group. We performed lifestyle interventions, which comprised exercise training, salt restriction and nutrition advice for 24 weeks. Then all patients were prospectively followed up for occurrence of the primary endpoints, including hospitalization due to stroke recurrence and the onset of other vascular events. We also evaluated systolic blood pressure (SBP) at the clinic and at home, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hemoglobin A1c (HbA1c) and high-sensitivity C-reactive protein (hs-CRP) to compare the efficacy of the lifestyle interventions. RESULTS: This trial was terminated earlier than expected because of the prespecified early stopping rule for efficacy. After the 24-week intervention period, the intervention group showed a significant increase in daily physical activity and a significant decrease in salt intake (physical activity, p = 0.012; salt intake, p < 0.001), with a significant difference between the randomized groups (physical activity, p < 0.001; salt intake, p = 0.018). Similarly, blood pressure was decreased and the HDL-C levels were increased in the intervention group (SBP, p < 0.001; HDL-C, p = 0.018), with significant differences between the randomized groups (SBP, p < 0.001; HDL-C, p = 0.022). In contrast, LDL-C, HbA1c and hs-CRP tended to decrease in the intervention group, but this decrease did not achieve significance. After a median follow-up period of 2.9 years, 12 patients allocated to the control group and 1 patient in the lifestyle intervention group experienced at least 1 vascular event. A sequential plans analysis indicated the superiority of the lifestyle intervention in interim analysis. Kaplan-Meier survival curves after the log-rank test showed a significant prognostic difference between the randomized groups (p = 0.005). CONCLUSIONS: Lifestyle intervention with appropriate medication is beneficial for reducing the incidence of new vascular events and improving vascular risk factors in patients with noncardioembolic mild ischemic stroke.

Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the Berlin definition.

INTRODUCTION: The Berlin definition divides acute respiratory distress syndrome (ARDS) into three severity categories. The relationship between these categories and pulmonary microvascular permeability as well as extravascular lung water content, which is the hallmark of lung pathophysiology, remains to be elucidated. The aim of this study was to evaluate the relationship between extravascular lung water, pulmonary vascular permeability, and the severity categories as defined by the Berlin definition, and to confirm the associated predictive validity for severity. METHODS: The extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPI) were measured using a transpulmonary thermodilution method for three consecutive days in 195 patients with an EVLWi of ≥10 mL/kg and who fulfilled the Berlin definition of ARDS. Collectively, these patients were seen at 23 ICUs. Using the Berlin definition, patients were classified into three categories: mild, moderate, and severe. RESULTS: Compared to patients with mild ARDS, patients with moderate and severe ARDS had higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores on the day of enrollment. Patients with severe ARDS had higher EVLWi (mild, 16.1; moderate, 17.2; severe, 19.1; P <0.05) and PVPI (2.7; 3.0; 3.2; P <0.05). When categories were defined by the minimum PaO2/FIO2 ratio observed during the study period, the 28-day mortality rate increased with severity categories: moderate, odds ratio: 3.125 relative to mild; and severe, odds ratio: 4.167 relative to mild. On independent evaluation of 495 measurements from 195 patients over three days, negative and moderate correlations were observed between EVLWi and the PaO2/FIO2 ratio (r = -0.355, P<0.001) as well as between PVPI and the PaO2/FIO2 ratio (r = -0.345, P <0.001). ARDS severity was associated with an increase in EVLWi with the categories (mild, 14.7; moderate, 16.2; severe, 20.0; P <0.001) in all data sets. The value of PVPI followed the same pattern (2.6; 2.7; 3.5; P <0.001). CONCLUSIONS: Severity categories of ARDS described by the Berlin definition have good predictive validity and may be associated with increased extravascular lung water and pulmonary vascular permeability. TRIAL REGISTRATION: UMIN-CTR ID UMIN000003627.

The threat of a new tetanus outbreak due to urban flooding disaster requires vigilance: a narrative review.

Vaccines for tetanus prevention have rapidly progressed, and the number of outbreaks, especially the incidence of tetanus in developed countries, has decreased dramatically. However, the mortality rate associated with severe tetanus remains high. Tetanus eradication is difficult owing to the widespread presence of the spores of tetanus bacteria in the environment, but tetanus can be prevented by acquired immunity from vaccines. Older people, intravenous drug users, and migrants are at a high risk of tetanus in developed countries owing to the lack of booster vaccination programs. Natural disasters, especially floods, often cause an increase in the prevalence of tetanus because of the associated injuries. Precautions should be taken to combat the threat of a new tetanus outbreak due to floods in urban areas owing to global warming. In particular, Japan is facing a high risk of urban flooding-induced tetanus, despite its status as a developed country. This review aims to highlight the data on the epidemiology, causes, treatment, and prevention of tetanus and problems associated with tetanus countermeasures during future floods.

An Easy-to-Use Prehospital Indicator to Determine the Severity of Suspected Heat-Related Illness: An Observational Study in the Tokyo Metropolitan Area.

Rapid hospital arrival decreases mortality risk in heat-related illnesses. We investigated an easy-to-use indicator of life-threatening severity of heat-related illnesses in a community setting to enable quick hospitalization by using data extracted from prehospital transportation records of a database from 2016 that included information on the clinical severity of suspected heat-related illnesses in patients (n = 2528) upon hospital arrival. Patient-related risk factors (adjusted odds ratio, aOR [95% confidence interval, CI]) included age, vital signs, location of the patient, and illness severity, and respiratory rate (3.34 [1.80-6.22]), heart rate (2.88 [1.57-5.29]), axillary body temperature (7.79 [4.02-15.1]), and consciousness level (38.3 [5.22-281.1]) were independent risk factors for heat-related illness severity. On-site blood pressure was not an independent factor for illness severity. Heart rate > 120 beats/min, respiratory rate > 24 breaths/min, and temperature > 38.6 °C (highest areas under the receiver operating characteristic curves [95% CI]: 0.80 [0.75-0.87]; 0.73 [0.67-0.81]; and 0.83 [0.77-0.91], respectively) predicted life-threatening illness severity. Changes in the vital signs of patients with heat-related illnesses, particularly tachycardia and tachypnea, constitute sensitive, easy-to-use indicators that facilitate rapid identification of severity by laypersons and transport of patients before aggravation to a life-threatening situation.