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.

Diphenhydramine overdose detected early by integration of toxidrome and electrocardiography and treated with venoarterial extracorporeal membrane oxygenation: a case report.

Drug overdose can lead to a range of symptoms, including potentially life-threatening cardiac arrhythmias. However, identifying the specific causative drug upon admission can be challenging in many cases. The toxidrome approach is a method that utilizes toxidromes, which are collections of findings obtained from physical examination and ancillary tests, that may be caused by a specific toxin. In this particular case, a man presented with an unknown drug overdose that caused symptoms indicative of anticholinergic effects and abnormal electrocardiogram (ECG) findings. The ECG revealed an R wave in lead aVR, S waves in leads I and aVL, and wide QRS tachycardia with a Brugada pattern. Shortly after arrival, the patient developed cardiac arrest due to a lethal arrhythmia. Prompt initiation of venoarterial extracorporeal cardiopulmonary membrane oxygenation (VA-ECMO) was performed. Fortunately, the patient achieved full neurological recovery, and the overdosed drug was identified as diphenhydramine. When diagnosing and treating drug overdose caused by an unidentified substance, diphenhydramine toxicity should be considered when an anticholinergic toxidrome is present and a Brugada pattern is observed on the ECG. VA-ECMO demonstrates potential as a viable treatment option when initial interventions prove ineffective.

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.

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.

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.

Achievement of Target Glycemic Goal with Simple Basal Insulin Regimen in Women with Gestational Diabetes: A Prospective Cohort Study.

There is little evidence concerning the need to treat gestational diabetes (GDM) in the same way as pregestational diabetes. We evaluated the efficacy of the simple insulin injection (SII) regimen for achieving the target glucose goal without increasing adverse perinatal outcomes in singleton pregnant women with GDM. All subjects underwent self-monitoring of blood glucose (SMBG), and insulin therapy was indicated according to the SMBG profile. Insulin was initially started with the SII regimen, in which one daily injection of NPH insulin before breakfast was used, and another NPH injection was added at bedtime, if necessary. We used the target glucose as <95 mg/dL at fasting and <120 mg/dL postprandial and accepted <130 mg/dL for the latter. If the target glucose did not reach with the regimen, we switched to the multiple daily injection (MDI) with additional prandial insulin aspart. We compared the SMBG profile before delivery as well as the perinatal outcomes between the SII and MDI groups. Among 361 women (age 33.7 years, nullipara 41%, prepregnancy body mass index 23.2 kg/m2) with GDM, 59%, 18%, and 23% were in the diet-alone, SII, and MDI groups, respectively. Consequently, regarding women requiring insulin therapy, 43% were treated with the SII regimen throughout pregnancy. The severity of baseline hyperglycemia according to the SMBG data at baseline was the MDI>the SII>the diet group. The rate of achieving target glucose levels before delivery in the SII group at fasting, postprandial < 120 mg/dL and <130 mg/dL were 93%, 54% and 87%, respectively, which were similar to that in the MDI group (93%, 57%, and 93%, respectively), with no significant differences in perinatal outcomes. In conclusion, more than 40% of women with GDM requiring insulin therapy achieved the target glucose goal with this simple insulin regimen without any increase in adverse effects.

Relationship between brain volume reduction during the acute phase of sepsis and activities of daily living in elderly patients: A prospective cohort study.

Brain damage in acute sepsis may be associated with poor long-term outcomes that impair reintegration into society. We aimed to clarify whether brain volume reduction occurs during the acute phase of sepsis in patients with acute brain damage. In this prospective, noninterventional observational study, brain volume reduction was evaluated by comparing head computed tomography findings at admission with those obtained during hospitalization. We examined the association between brain volume reduction and performance of the activities of daily living in 85 consecutive patients (mean age, 77 ± 12.7 years) with sepsis or septic shock. The bicaudate ratio increased in 38/58 (65.5%) patients, Evans index increased in 35/58 (60.3%) patients, and brain volume by volumetry decreased in 46/58 (79.3%) patients from the first to the second measurement, with significant increases in the bicaudate ratio (P < 0.0001) and Evans index (P = 0.0005) and a significant decrease in the brain volume by volumetry (P < 0.0001). The change rate for brain volume by volumetry was significantly correlated with the Katz index (ρ = -0.3790, P = 0.0094). In the acute phase of sepsis in this sample of older patients, 60-79% of patients showed decreased brain volumes. This was associated with a decreased capacity for performing activities of daily living.

"The eyes are the windows of the soul": Portable automated pupillometry to monitor autonomic nervous activity in CO2 narcosis: A case report.

RATIONALE: Altered autonomic responses can be observed in patients in the intensive care unit (ICU), and these changes in abnormal autonomic responses are known to be associated with patient prognosis. Therefore, it is important to monitor autonomic nervous system activity in these critically ill patients. While the utility of monitoring critically ill patients using heart rate (HR) variability measurements has been reported, portable automated pupillometers are small, lightweight, and easy-to-operate medical devices that may be more easily evaluated for autonomic nervous system function. PATIENT CONCERNS: An unconscious 80-year-old female patient with chronic obstructive pulmonary disease was brought to the medical emergency department after a call from her caregiver. DIAGNOSIS: On arrival, the patient's Glasgow coma scale score was 7, her blood pressure was 140/80 mm Hg, her HR was 114 bpm, and her respiratory rate was 27 breaths/minutes with increased breathing effort. Oxygen saturation was 90% on a venturi mask (3 L of supplemental oxygen). The arterial blood gas analysis showed a pH of 7.196, a partial pressure of carbon dioxide (CO2) of 89.6 mm Hg, a partial pressure of oxygen of 87.5 mm Hg, and a bicarbonate level of 29.4 mmol/L. Other than CO2 narcosis, there were no abnormal findings to induce impaired consciousness. The patient did not respond to support with a bag-valve mask and was intubated. One hour after intubation, her impaired consciousness improved. The patient was extubated 20 hours later and discharged on Day 3. INTERVENTIONS: The patient was admitted to the ICU after being intubated, where vital signs and blood gas analysis were monitored every 2 hours, and consciousness was assessed using the Glasgow coma scale. Using a portable automated pupillometer (NeurOptics NPi™-200, Neuroptics Inc., Irvine, CA), pupillary responses, including pupil size or light reflex, were measured every 2 hours during ICU stay. OUTCOMES: Changes in respiratory rate and partial pressure of CO2 values correlated with pupil size and constriction velocity, but HR changes were contrary. LESSONS: Pupillary responses exhibited by automated pupillometers observed in patients with CO2 narcosis may be linked to vital signs and allow for autonomic evaluation.

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.

Undernutrition Scored Using the CONUT Score with Hypoglycemic Status in ICU-Admitted Elderly Patients with Sepsis Shows Increased ICU Mortality.

This study aimed to clarify whether the influence of undernutrition status and the degree of glycemic disorders affected the prognosis of patients with sepsis. A total of 307 adult patients with sepsis were retrospectively enrolled and analyzed. Characteristics, including nutrition status, calculated according to the Controlling Nutritional Status (CONUT) score of survivors and non-survivors, were examined. The independent prognostic factors of these patients with sepsis were extracted using multivariable logistic regression analysis. The CONUT scores in three glycemic categories were compared. Most patients with sepsis (94.8%) in the study had an undernutrition status according to their CONUT scores. High CONUT scores (odds ratio, 1.214; p = 0.002), indicating a poor nutritional status, were associated with high mortality. The CONUT scores in the hypoglycemic group were significantly higher than those in other groups with an undernutrition status (vs. hyperglycemic, p < 0.001; vs. intermediate glycemic, p = 0.006). The undernutrition statuses of patients with sepsis in the study scored using the CONUT were independent predictors of prognostic factors.

Current status of active cooling, deep body temperature measurement, and face mask wearing in heat stroke and heat exhaustion patients in Japan: a nationwide observational study based on the Heatstroke STUDY 2020 and 2021.

Aim: The study aimed to determine the current status of face mask use, deep body temperature measurement, and active cooling in patients suffering from heat stroke and heat exhaustion in Japan. Methods: This was a prospective, observational, multicenter study using data from the Heatstroke STUDY 2020-2021, a nationwide periodical registry of heat stroke and heat exhaustion patients. Based on the Bouchama heatstroke criteria, we classified the patients into two groups: severe and mild-to-moderate. We compared the outcomes between the two groups and reclassified them into two subgroups according to the severity of the illness, deep body temperature measurements, and face mask use. Cramer's V was used to determine the effect sizes for a comparison between groups. Results: Almost all patients in this study were categorized as having degree III based on the Japanese Association for Acute Medicine heatstroke criteria (JAAM-HS). However, the severe group was significantly worse than the mild-to-moderate group in outcomes like in-hospital death and modified Rankin Scale scores, when discharged. Heat strokes had significantly higher rates of active cooling and lower mortality rates than heat stroke-like illnesses. Patients using face masks often use them during labor, sports, and other exertions, had less severe conditions, and were less likely to be young male individuals. Conclusions: It is suggested that severe cases require a more detailed classification of degree III in the JAAM-HS criteria, and not measuring deep body temperature could have been a factor in the nonperformance of active cooling and worse outcomes.

The Characteristics of Patients with Severe COVID-19 Pneumonia Treated with Direct Hemoperfusion Using Polymyxin B-Immobilized Fiber Column (PMX-DHP).

Purpose: The characteristics of patients with severe COVID-19 pneumonia who underwent direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP), in addition to steroids and immunomodulators, remain unclear. Patients and Methods: We conducted a retrospective observational study on 31 patients with severe COVID-19 pneumonia treated with PMX-DHP in an intensive care unit (ICU) from December 2020 to September 2021. Results: Outcomes 28 days after admission to the ICU were 20 in the survival group and 11 in the death group. Parameters significantly different between the survival and death group before PMX-DHP were percentage of invasive mechanical ventilation (25% vs 72.7%, P = 0.0209), PaO2/FIO2 (P/F) ratio (104.5 vs 75, P = 0.0317), and sequential organ failure assessment (SOFA) score (2 vs 3, P = 0.0356). Invasive mechanical ventilation avoidance rate was significantly different between the survival (100%) and death group (0%) (P = 0.0012). P/F ratio, respiratory ratio (RR), and lymphocyte counts improved significantly after PMX-DHP for all patients. The lymphocyte counts changed significantly in the survival (P < 0.0001), but not the death group (P = 0.7927). Conclusion: PMX-DHP, in addition to steroids and immunomodulators, may improve oxygenation and alleviate tachypnea by modulating the lymphocyte numbers and levels of various mediator against severe COVID-19 pneumonia. It may be better to perform PMX-DHP before multi organ dysfunction and lung injury has progressed. Furthermore, the early increase in lymphocyte counts after PMX-DHP might be an indicate a positive outcome.

Influence of the coronavirus disease 2019 (COVID-19) pandemic on the incidence of heat stroke and heat exhaustion in Japan: a nationwide observational study based on the Heatstroke STUDY 2019 (without COVID-19) and 2020 (with COVID-19).

AIM: To assess heat stroke and heat exhaustion occurrence and response during the coronavirus disease 2019 pandemic in Japan. METHODS: This retrospective, multicenter, registry-based study describes and compares the characteristics of patients between the months of July and September in 2019 and 2020. Factors affecting heat stroke and heat exhaustion were statistically analyzed. Cramér's V was calculated to determine the effect size for group comparisons. We also investigated the prevalence of mask wearing and details of different cooling methods. RESULTS: No significant differences were observed between 2019 and 2020. In both years, in-hospital mortality rates just exceeded 8%. Individuals >65 years old comprised 50% of cases and non-exertional onset (office work and everyday life) comprised 60%-70%, respectively. The recommendations from the Working Group on Heat Stroke Medicine given during the coronavirus disease pandemic in 2019 had a significant impact on the choice of cooling methods. The percentage of cases, for which intravascular temperature management was performed and cooling blankets were used increased, whereas the percentage of cases in which evaporative plus convective cooling was performed decreased. A total of 49 cases of heat stroke in mask wearing were reported. CONCLUSION: Epidemiological assessments of heat stroke and heat exhaustion did not reveal significant changes between 2019 and 2020. The findings suggest that awareness campaigns regarding heat stroke prevention among the elderly in daily life should be continued in the coronavirus disease 2019 pandemic. In the future, it is also necessary to validate the recommendations of the Working Group on Heatstroke Medicine.

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.

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.

Accidental hypothermia: characteristics, outcomes, and prognostic factors-A nationwide observational study in Japan (Hypothermia study 2018 and 2019).

AIM: This study describes the clinical characteristics and outcomes as well as the prognostic factors of patients with accidental hypothermia (AH) using Japan's nationwide registry data. METHODS: The Hypothermia study 2018 and 2019, which included patients aged 18 years or older with a body temperature of 35°C or less, was a multicenter registry conducted at 87 and 89 institutions throughout Japan, with data collected from December 2018 to February 2019 and December 2019 to February 2020, respectively. RESULTS: In total, 1363 patients were enrolled in the registry, of which 1194 were analyzed in this study. The median (interquartile range) age was 79 (68-87) years, and the median (interquartile range) body temperature at the emergency department was 30.8°C (28.4-33.6°C). Forty-three percent of patients with AH had a mild condition, 35.2% moderate, and 21.9% severe. AH occurred in an indoor setting in 73.4% and was caused by acute medical illness in 49.3% of patients. A total of 101 (8.5%) patients suffered from cardiopulmonary arrest on arrival at the hospital. The overall 30-day mortality rate was 24.5%, the median (interquartile range) intensive care unit stay was 4 (2-7) days, and the median (interquartile range) hospital stay was 13 (4-27) days. In the multivariable logistic analysis, the prognostic factors were age (≥75 years old), male, activities of daily living (needing total assistance), cause of AH (trauma, alcohol), Glasgow Coma Scale score, and potassium level (>5.5 mEq/L). CONCLUSION: The mortality rate of AH was 24.5% in Japan. The prognostic factors developed in this study may be useful for the early prediction, prevention, and awareness of severe AH.

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.

Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.

Machine learning-based mortality prediction model for heat-related illness.

In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017-2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 [95% confidence interval (CI) 0.336-0.494], 0.395 [CI 0.318-0.472], 0.426 [CI 0.346-0.506], and 0.528 [CI 0.442-0.614], respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 [CI 0.222-0.351] as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses.