Association of excess visceral fat and severe illness in hospitalized COVID-19 patients in Japan: a retrospective cohort study.

BACKGROUND/OBJECTIVES: Obesity, defined by body mass index (BMI), is a well-known risk factor for the severity of coronavirus disease 2019 (COVID-19). Adipose tissue distribution has also been implicated as an important factor in the body's response to infection, and excess visceral fat (VF), which is prevalent in Japanese, may contribute significantly to the severity. Therefore, this study aimed to evaluate the association of obesity and VF with COVID-19 severe illness in Japan. SUBJECTS/METHODS: This retrospective cohort study involved 550 COVID-19 patients admitted to a tertiary care hospital with BMI and body composition data, including VF. The primary endpoint was severe illness, including death, due to COVID-19 during hospitalization. Logistic regression analysis was applied to examine the quartiles of BMI and VF on severe illness after adjusting for covariates such as age, sex, subcutaneous fat, paraspinal muscle radiodensity, and comorbidities affecting VF (COPD, cancer within 5 years, immunosuppressive agent use). RESULTS: The median age was 56.0 years; 71.8% were males. During hospitalization, 82 (14.9%) experienced COVID-19 severe illness. In the multivariate logistic regression analysis, Q4 of BMI was not significantly associated with severe illness compared to Q1 of BMI (OR 1.03; 95% CI 0.37-2.86; p = 0.95). Conversely, Q3 and Q4 of VF showed a higher risk for severe illness compared to Q1 of VF (OR 2.68; 95% CI 1.01-7.11; p = 0.04, OR 3.66; 95% CI 1.30-10.26; p = 0.01, respectively). Stratified analysis by BMI and adjusted for covariates showed the positive association of VF with severe illness only in the BMI < 25 kg/m2 group. CONCLUSIONS: High BMI was not an independent risk factor for COVID-19 severe illness in hospitalized patients in Japan, whereas excess VF significantly influenced severe illness, especially in patients with a BMI < 25 kg/m2.

Action protocol of medical staff for airway obstruction after anterior cervical spine surgery: A systematic review of case reports.

BACKGROUND: Postoperative airway obstruction after anterior cervical spine surgery (ACSS) can be a fatal complication. Occasionally, it rapidly progresses to complete obstruction. There are no established standardized protocols on how medical staff should assess for signs and symptoms, seek help, or facilitate airway management after ACSS to prevent unfavorable events. This study aimed to primarily describe a systematic approach by assessing the signs and treatment outcomes of airway compromise in patients who underwent ACSS. Further, it recommended an action protocol after extubation for medical staff according to patients' symptoms to prevent unfavorable outcomes. METHODS: An extensive literature search was performed on PubMed, Web of Science, and the Cochrane Library to identify case reports, case series, and cohort studies restricted to English and published between January 1990 and March 2023. We included cases that described the signs, symptoms, and treatment of airway obstruction after ACSS. Meanwhile, cases involving complications of other known causes, cases of trauma or occipital-cervical fixation, or those using bone morphogenetic protein were excluded. RESULTS: Twenty cases from 17 studies were obtained, and their study quality was acceptable. Four patients died, and two presented with hypoxic ischemic encephalopathy. Further, five of six patients had fatal complications that initially developed within 7 h after surgery. Then, 9 (69%) of 13 patients with evidence of hematoma (69%) showed initial symptoms within 12 h after surgery. Finally, 9 of 11 patients with early-stage symptoms had favorable outcomes, and patients who developed late-stage symptoms commonly had unfavorable outcomes. CONCLUSION: The early identification of signs and symptoms and immediate treatment are important, particularly within 12 h postoperatively. We suggest a novel action protocol for medical staff according to symptom urgency, which includes the measurement of neck circumference using a string for evaluating neck swelling.

Effectiveness of remdesivir with corticosteroids for COVID-19 patients in intensive care unit: A hospital-based observational study.

The effectiveness of remdesivir on survival in coronavirus disease 2019 (COVID-19), especially in cases treated in the intensive care unit (ICU), is controversial. We investigated the effectiveness of remdesivir with corticosteroids on the survival of COVID-19 patients in a real ICU clinical practice. For laboratory-confirmed COVID-19 patients admitted to the ICU of a tertiary hospital in Tokyo (April 2020-November 2021) and who received corticosteroids, the effectiveness of remdesivir for survival, stratified by interval length (within 9 or 10+ days), was retrospectively analyzed using Cox regression model. A total of 168 patients were included: 35 with no remdesivir use (control), 96 with remdesivir use within 9 days, and 37 with remdesivir use with an interval of 10+ days. In-hospital mortality was 45.7%, 10.4%, and 16.2%, respectively. After adjusting for possible covariates including comorbidities, laboratory data, oxygen demand, or level of pneumonia, remdesivir use within 9 days from symptom onset reduced mortality risk (hazard ratio [HR]: 0.10; 95% confidence interval (CI): 0.025-0.428) compared to the control group. However, remdesivir use with an interval of 10+ days showed no significant association with mortality (HR: 0.42; 95% CI: 0.117-1.524). Among COVID-19 patients who received corticosteroids in ICU, remdesivir use within 9 days from symptom onset was associated with reduced in-hospital mortality risk.

Instruments to assess post-intensive care syndrome assessment: a scoping review and modified Delphi method study.

BACKGROUND: The assessment of post-intensive care syndrome (PICS) is challenging due to the numerous types of instruments. We herein attempted to identify and propose recommendations for instruments to assess PICS in intensive care unit (ICU) survivors. METHODS: We conducted a scoping review to identify PICS follow-up studies at and after hospital discharge between 2014 and 2022. Assessment instruments used more than two times were included in the modified Delphi consensus process. A modified Delphi meeting was conducted three times by the PICS committee of the Japanese Society of Intensive Care Medicine, and each score was rated as not important (score: 1-3), important, but not critical (4-6), and critical (7-9). We included instruments with ≥ 70% of respondents rating critical and ≤ 15% of respondents rating not important. RESULTS: In total, 6972 records were identified in this scoping review, and 754 studies were included in the analysis. After data extraction, 107 PICS assessment instruments were identified. The modified Delphi meeting reached 20 PICS assessment instrument recommendations: (1) in the physical domain: the 6-min walk test, MRC score, and grip strength, (2) in cognition: MoCA, MMSE, and SMQ, (3) in mental health: HADS, IES-R, and PHQ-9, (4) in the activities of daily living: the Barthel Index, IADL, and FIM, (5) in quality of life: SF-36, SF-12, EQ-5D-5L, 3L, and VAS (6), in sleep and pain: PSQI and Brief Pain Inventory, respectively, and (7) in the PICS-family domain: SF-36, HADS, and IES-R. CONCLUSION: Based on a scoping review and the modified Delphi method, 20 PICS assessment instruments are recommended to assess physical, cognitive, mental health, activities of daily living, quality of life, sleep, and pain in ICU survivors and their families.

Overexpressed angiotensin-converting enzyme in neutrophils suppresses glomerular damage in crescentic glomerulonephritis.

While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin system, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance to infection. Here, we investigate if such neutrophils protect against renal injury in immune complex (IC)-mediated crescentic glomerulonephritis (GN) through complement. Nephrotoxic serum nephritis (NTN) was induced in wild-type and NeuACE mice that overexpress ACE in neutrophils. Glomerular injury of NTN in NeuACE mice was attenuated with much less proteinuria, milder histological injury, and reduced IC deposits, but presented with more glomerular neutrophils in the early stage of the disease. There were no significant defects in T and B cell functions in NeuACE mice. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expression of FcγRII/III and complement receptor CR1/2. IC uptake in neutrophils was enhanced by NeuACE serum containing elevated complement C3b. Given no significant complement activation by ACE, this suggests that neutrophil ACE indirectly preactivates C3 and that the C3b-CR1/2 axis and elevated FcγRII/III play a central role in IC elimination by neutrophils, resulting in reduced glomerular injury. The present study identified a novel renoprotective role of ACE in glomerulonephritis; elevated neutrophilic ACE promotes elimination of locally formed ICs in glomeruli via C3b-CR1/2 and FcγRII/III, ameliorating glomerular injury.NEW & NOTEWORTHY We studied immune complex (IC)-mediated crescentic glomerulonephritis in NeuACE mice that overexpress ACE only in neutrophils. Such mice show no significant defects in humoral immunity but strongly resist nephrotoxic serum nephritis (less proteinuria, milder histological damage, reduced IC deposits, and more glomerular neutrophils). NeuACE neutrophils enhanced IC uptake via increased surface expression of CR1/2 and FcgRII/III, as well as elevated serum complement C3b. These results suggest neutrophil ACE as a novel approach to reducing glomerulonephritis.

Rapid and sensitive SARS-CoV-2 detection using a homogeneous fluorescent immunosensor Quenchbody with crowding agents.

Antigen tests for SARS-CoV-2 are widely used by the public during the ongoing COVID-19 pandemic, which demonstrates the societal impact of homogeneous immunosensor-related technologies. In this study, we used the PM Q-probe and Quenchbody technologies to develop a SARS-CoV-2 nucleocapsid protein (N protein) homogeneous immunosensor based on a human anti-N protein antibody. For the first time, we uncovered the crowding agent's role in improving the performance of the double-labeled Quenchbody, and the possible mechanisms behind this improvement are discussed. The 5% polyethylene glycol 6000 significantly improved both the response speed and sensitivity of SARS-CoV-2 Quenchbodies. The calculated limit of detection for recombinant N protein was 191 pM (9 ng mL-1) within 15 min of incubation, which was 9- to 10-fold lower than the assay without adding crowding agent. We also validated the developed immunosensor in a point-of-care test by measuring specimens from COVID-19-positive patients using a compact tube fluorometer. In brief, this work shows the feasibility of Quenchbody homogeneous immunosensors as rapid and cost-efficient tools for the diagnosis and high-throughput analysis of swab samples in large-scale monitoring and epidemiological studies of COVID-19 or other emerging infectious diseases.

Comparison of Two Different Intensive Care Unit Systems for Severely Ill Children in Japan: Data from the JaRPAC Registry.

The importance of centralizing treatment services for severely ill children has been well established, but such entralization remains difficult in Japan. We aimed to compare the trauma and illness severity and mortality of children admitted to two common types of ICUs for children. According to the type of management and disposition of the medical provider, we classified ICUs as pediatric ICUs [PICUs] or general ICUs, and analyzed differences in endogenous and exogenous illness settings between them. Overall, 1,333 pediatric patients were included, with 1,143 patients admitted to PICUs and 190 patients to general ICUs. The Pediatric Cerebral Performance Category score (PCPC) at discharge was significantly lower in the PICU group (adjusted OR: 0.45; 95%CI: 0.23-0.88). Death and unfavorable neurological outcomes occurred less often in the PICU group (adjusted OR: 0.29; 95%CI: 0.14-0.60). However, when limited to exogenous illness, PCPC scores (adjusted OR: 0.38; 95%CI: 0.07-1.99) or death/unfavorable outcomes (adjusted OR: 0.72; 95%CI: 0.08-6.34) did not differ between the groups. PCPC deterioration and overall sequelae/death rates were lower in PICUs for children with endogenous illnesses, although the outcomes of exogenous illness were similar between the 2 unit types. Further studies on the necessity of centralization are warranted.

Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice.

Human pandemic H1N1 2009 influenza virus causes significant morbidity and mortality with severe acute lung injury due to the excessive inflammatory reaction, even with neuraminidase inhibitor use. The anti-inflammatory effect of anti-high-mobility group box-1 (HMGB1) monoclonal antibody (mAb) against influenza pneumonia has been reported. In this study, we evaluated the combined effect of anti-HMGB1 mAb and peramivir against pneumonia induced by influenza A (H1N1) virus in mice. Nine-week-old male C57BL/6 mice were inoculated with H1N1 and treated with intramuscularly administered peramivir at 2 and 3 days post-infection (dpi). The anti-HMGB1 mAb or a control mAb was administered at 2, 3, and 4 dpi. Survival rates were assessed, and lung lavage and pathological analyses were conducted at 5 and 7 dpi. The combination of peramivir with the anti-HMGB1 mAb significantly improved survival rate whereas the anti-HMGB1 mAb alone did not affect virus proliferation in the lungs. This combination therapy also significantly ameliorated histopathological changes, neutrophil infiltration, and macrophage aggregation by inhibiting HMGB1, inflammatory cytokines, and oxidative stress. Fluorescence immunostaining showed that the anti-HMGB1 mAb inhibited HMGB1 translocation from type I alveolar epithelial cells. In summary, combining anti-HMGB1 with conventional anti-influenza therapy might be useful against severe influenza virus infection.

Anti-high mobility group box-1 monoclonal antibody treatment of brain edema induced by influenza infection and lipopolysaccharide.

Encephalopathy is a major cause of influenza-associated child death and severe neurological sequelae in Japan, highlighting the urgent need for new therapeutic strategies. In this study, we evaluated the effects of anti-high mobility group box-1 monoclonal antibody (α-HMGB1) treatment on brain edema induced by influenza A virus (IAV) and lipopolysaccharide in 4-week-old BALB/c female mice. The results showed that administration of 7.5 mg/kg α-HMGB1 1 h after IAV (A/Puerto Rico/8/34) inoculation significantly alleviated brain edema at 48 h after IAV inoculation, as confirmed by the suppression of Evans Blue dye leakage and matrix metallopeptidase-9 mRNA expression in the brain. Moreover, we also observed suppression of oxidative stress and different cytokines in IAV-inoculated mice. The expression of plasminogen activator inhibitor-1 was also attenuated following treatment with α-HMGB1. Notably, α-HMGB1 treatment had no effect on virus propagation in the lung. In summary, anti-HMGB1 treatment may improve the prognosis in cases with influenza-associated encephalopathy by attenuating brain edema and reducing the inflammatory responses induced by HMGB1.

Medical equipment deployment in pediatric emergency prehospital medical units in Japan.

The deployment status of pediatric emergency equipment in ambulances in Japan is unknown. To investigate the status of and issues associated with prehospital emergency medical care for pediatric patients, we conducted a descriptive epidemiological study. We carried out a Web-based survey of 767 fire defense headquarters in Japan, of which 671 responded (valid response rate, 88%). Most of the fire defense headquarters equipped all of their ambulances with oxygen masks (82%), bag-valve masks (for neonates, 83%; for children, 84%), straight laryngoscope blades (for neonates, 47%; for children 68%), blood pressure cuffs for children (91%), oximeter probes (78%), and stiff neck collars (91%); but despite the need for other equipment such as nasopharyngeal and oropharyngeal airways, and Magill forceps, they were insufficiently deployed. In Japan, prehospital emergency medical equipment deployment does not meet the needs of pediatric patients. Minimum equipment standards need to be established for pediatric prehospital care.

Epidemiology of Pediatric Acute Encephalitis/Encephalopathy in Japan.

We studied the etiology of pediatric acute encephalitis/encephalopathy (pAEE) using epidemiological data obtained from a nationwide survey in Japan. Two-step questionnaires were sent to the pediatric departments of hospitals throughout the country in 2007, querying the number of the cases during 2005-2006 as the first step, and asking for the details of clinical information as the second step. In all, 636 children with pAEE (age ≤ 15 years) were enrolled. For the known etiology of pAEE (63.5% of the total cases), 26 microbes and 2 clinical entities were listed, but the etiology of 36.5% remained unknown. Influenza virus (26.7%), exanthem subitum (12.3%), and rotavirus (4.1%) were the most common, and the incidence of pAEE peaked at the age of 1 year. This trend was common among all etiologies. Among the neurological symptoms observed at the onset of pAEE, seizures were observed more often in patients aged ≤ 3 years, although abnormal speech and behavior were also common in older children. Undesirable outcomes (death and neurological sequelae) occurred at high rates in patients with any known etiology other than mycoplasma. In conclusion, these findings provide comprehensive insight into pAEE in Japan.

Metabolic pathway catalyzed by Vanin-1 pantetheinase plays a suppressive role in influenza virus replication in human alveolar epithelial A549 cells.

Our previous analysis of gene expression profiles in the peripheral blood from patients with influenza A (H1N1) pdm09 pneumonia revealed elevated transcription levels of the vanin-1 (vascular non-inflammatory molecule 1, VNN1) gene, which encodes an epithelial ectoenzyme with pantetheinase activity involved in recycling coenzyme A. Here, to elucidate the role of VNN1 in influenza A virus (IAV) H1N1 infection, we investigated the change of VNN1 expression in the context of IAV infection and the effects of its related substances, i.e., its direct substrate pantetheine and its two metabolites pantothenic acid and cysteamine on the replication of IAV in the human alveolar epithelial carcinoma cell line A549. The messenger RNA expression of VNN1 in A549 cells was significantly increased (by 4.9-fold) after IAV infection under an elevated concentration of pantetheine. Moreover, VNN1 mRNA levels were elevated by > 100-fold in response to pro-inflammatory cytokines, especially TNF-α and IL-1ß. Pantetheine significantly reduced the IAV replication and IAV Matrix 1 (M1) mRNA levels when it was administered prior to and during infection. In addition, cysteamine treatment during IAV infection significantly reduced the viral replication and IAV M1 mRNA levels, whereas pantothenic acid did not. These findings suggest that the metabolic pathway catalyzed by VNN1 pantetheinase plays a suppressive role in IAV infection in the respiratory tract, especially in severe conditions under hypercytokinemia.

New age-based weight estimation formulae for Japanese children.

BACKGROUND: Although dosing and sizing of resuscitation drugs and equipment are mostly weight based, time is usually insufficient to weigh critically ill children. Many age-based weight estimation formulae for emergency use have been developed worldwide, but there is no specific formula for Japanese children. The aim of this study was therefore to develop and validate age-based formulae for estimating the bodyweight of children living in Japan. METHODS: A total of 370 980 measurements of bodyweight were obtained from 39 547 participants aged 12-155 months. They participated in a national survey, called the Longitudinal Survey of Babies in the 21st Century, which started in 2001. We created the new original weight estimation formulae for children living in Japan, called the Japanese Pediatric Assessment of Normal weight (JAPAN) formulae, using 75% of measurements that were randomly selected from the total measurements. To check the validity of the formulae, we applied the JAPAN formulae, the Park et al. formula for Korean children, and the commonly used Nelson formula for the remaining 25% of measurements. The mean absolute error and the root mean square error (RMSE) were calculated for each scale. RESULTS: The JAPAN formulae performed better than the two other formulae among Japanese children, with a mean absolute error and RMSE of 0.83 and 1.08 (kg), respectively. The performance of the Park et al. formulae for Korean children was poor for children living in Japan. CONCLUSIONS: The newly developed JAPAN formulae for age-based weight estimation are appropriate for children living in Japan.

Effects of Therapeutic Hypothermia for Neuroprotection from the Viewpoint of Redox Regulation.

Redox regulation has recently been recognized as an important factor in acute illnesses as well as in chronic diseases. It has also become a target for neuroprotection in acute intensive care. Despite its well-known therapeutic effects, therapeutic hypothermia has recently been re-evaluated for its potential use in emergency and critical care medicine. Hypothermia is an undesirable physiological condition that can increase oxidative stress and decrease anti-oxidative potency. However, many studies have shown that under ischemia/reperfusion conditions, therapeutic hypothermia actually suppresses enhanced oxidative stress and maintains or increases anti-oxidative potency. This review provides an overview and outlook for the future of therapeutic hypothermia for neuroprotection from the perspective of redox regulation in patients with post-cardiac arrest syndrome and traumatic brain injury.

Intracranial Pressure Monitoring for Pediatric Acute Encephalopathy.

Newly published clinical practice guidelines recommend intracranial pressure (ICP) monitoring in critical care for the management of pediatric acute encephalopathy (pAE), but the utility of ICP monitoring for pAE has been poorly studied. We recently performed direct ICP monitoring for two patients. We observed that although the direct ICP monitoring had clinical benefits with less body weight gain and no vasopressor use in both cases, this monitoring technique is still invasive. Future studies should determine the utility of non-invasive ICP monitoring systems in pAE to further improve the quality of intensive-care management.

Validity of Mothers' Reports of Children's Weight in Japan.

Estimation methods for pediatric weight have not been evaluated for Japanese children. This study aimed to assess the accuracy of mothers' reports of their children's weight in Japan. We also evaluated potential alternatives to the estimation of weight, including the Broselow tape (BT), Advanced Pediatric Life Support (APLS), and Park's formulae. We prospectively collected cross-sectional data on a convenience sample of 237 children aged less than 10 years who presented to a general pediatric outpatient clinic with their mothers. Each weight estimation method was evaluated using Bland- Altman plots and by calculating the proportion within 10% and 20% of the measured weight. Mothers' reports of weight were the most accurate method, with 94.9% within 10% of the measured weight, the lowest mean difference (0.27kg), and the shortest 95% limit of agreement (－1.4 to 1.9kg). The BT was the most reliable alternative, followed by APLS and Park's formulae. Mothers' reports of their children 's weight are more accurate than other weight estimation methods. When no report of a child's weight by the mother is available, BT is the best alternative. When an aged-based formula is the only option, the APLS formula is preferred.

The Clinical Application of Hydrogen as a Medical Treatment.

In recent years, it has become evident that molecular hydrogen is a particularyl effective treatment for various disease models such as ischemia-reperfusion injury; as a result, research on hydrogen has progressed rapidly. Hydrogen has been shown to be effective not only through intake as a gas, but also as a liquid medication taken orally, intravenously, or locally. Hydrogen's effectiveness is thus multifaceted. Herein we review the recent research on hydrogen-rich water, and we examine the possibilities for its clinical application. Now that hydrogen is in the limelight as a gaseous signaling molecule due to its potential ability to inhibit oxidative stress signaling, new research developments are highly anticipated.