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Abstract Keloids are characterized by abnormal wound healing with excessive accumulation of extracellular matrix. Myofibroblasts are the primary contributor to extracellular matrix secretion, playing an essential role in the wound healing process. However, the differences between myofibroblasts involved in keloid formation and normal wound healing remain unclear. To identify the specific characteristics of keloid myofibroblasts, we initially assessed the expression levels of well-established myofibroblast markers, α-smooth muscle actin (α-SMA) and transgelin (TAGLN), in scar and keloid tissues (n = 63 and 51, respectively). Although myofibroblasts were present in significant quantities in keloids and immature scars, they were absent in mature scars. Next, we conducted RNA sequencing using myofibroblast-rich areas from keloids and immature scars to investigate the difference in RNA expression profiles among myofibroblasts. Among significantly upregulated 112 genes, KN motif and ankyrin repeat domains 4 (KANK4) was identified as a specifically upregulated gene in keloids. Immunohistochemical analysis showed that KANK4 protein was expressed in myofibroblasts in keloid tissues; however, it was not expressed in any myofibroblasts in immature scar tissues. Overexpression of KANK4 enhanced cell mobility in keloid myofibroblasts. Our results suggest that the KANK4-mediated increase in myofibroblast mobility contributes to keloid pathogenesis.

Abstract Background The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients. Methods Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3. Results In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77–1.14; I 2 = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76–1.20), clinical cure (RR 1.23, 95% CI: 0.91–1.67), length of stay in the ICU (mean difference 0, 95% CI: − 2.18–2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88–1.48) and day 3 (RR 1.35, 95% CI: 0.90–2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes. Conclusion TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required. Trial registration: Clinical trial registration; PROSPERO ( https://www.crd.york.ac.uk/prospero/ ), registry number: CRD 42022371959. Registered 24 November 2022.

Abstract Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the “Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit” to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions. Graphical Abstract

Abstract Background Super-enhancers (SEs), which activate genes involved in cell-type specificity, have mainly been defined as genomic regions with top-ranked enrichment(s) of histone H3 with acetylated K27 (H3K27ac) and/or transcription coactivator(s) including a bromodomain and extra-terminal domain (BET) family protein, BRD4. However, BRD4 preferentially binds to multi-acetylated histone H4, typically with acetylated K5 and K8 (H4K5acK8ac), leading us to hypothesize that SEs should be defined by high H4K5acK8ac enrichment at least as well as by that of H3K27ac. Results Here, we conducted genome-wide profiling of H4K5acK8ac and H3K27ac, BRD4 binding, and the transcriptome by using a BET inhibitor, JQ1, in three human glial cell lines. When SEs were defined as having the top ranks for H4K5acK8ac or H3K27ac signal, 43% of H4K5acK8ac-ranked SEs were distinct from H3K27ac-ranked SEs in a glioblastoma stem-like cell (GSC) line. CRISPR-Cas9–mediated deletion of the H4K5acK8ac-preferred SEs associated with MYCN and NFIC decreased the stem-like properties in GSCs. Conclusions Collectively, our data highlights H4K5acK8ac’s utility for identifying genes regulating cell-type specificity.

Abstract Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

Abstract Background The efficacies of fresh frozen plasma and coagulation factor transfusion have been widely evaluated in trauma-induced coagulopathy management during the acute post-injury phase. However, the efficacy of red blood cell transfusion has not been adequately investigated in patients with severe trauma, and the optimal hemoglobin target level during the acute post-injury and resuscitation phases remains unclear. Therefore, this study aimed to examine whether a restrictive transfusion strategy was clinically non-inferior to a liberal transfusion strategy during the acute post-injury phase. Methods This cluster-randomized, crossover, non-inferiority multicenter trial was conducted at 22 tertiary emergency medical institutions in Japan and included adult patients with severe trauma at risk of major bleeding. The institutions were allocated a restrictive or liberal transfusion strategy (target hemoglobin levels: 7–9 or 10–12 g/dL, respectively). The strategies were applied to patients immediately after arrival at the emergency department. The primary outcome was 28-day survival after arrival at the emergency department. Secondary outcomes included transfusion volume, complication rates, and event-free days. The non-inferiority margin was set at 3%. Results The 28-day survival rates of patients in the restrictive (n = 216) and liberal (n = 195) strategy groups were 92.1% and 91.3%, respectively. The adjusted odds ratio for 28-day survival in the restrictive versus liberal strategy group was 1.02 (95% confidence interval: 0.49–2.13). Significant non-inferiority was not observed. Transfusion volumes and hemoglobin levels were lower in the restrictive strategy group than in the liberal strategy group. No between-group differences were noted in complication rates or event-free days. Conclusions Although non-inferiority of the restrictive versus liberal transfusion strategy for 28-day survival was not statistically significant, the mortality and complication rates were similar between the groups. The restrictive transfusion strategy results in a lower transfusion volume. Trial registration number: umin.ac.jp/ctr: UMIN000034405, registration date: 8 October 2018.

Abstract Background Rituximab, high‐dose methotrexate (HD‐MTX), procarbazine and vincristine (R‐MPV), has significantly prolonged the survival of patients with primary central nervous system lymphoma (PCNSL), but predictive factors for response to R‐MPV have not yet been investigated. Herein, we investigated the correlation of MYD88 L265P and CD79B Y196 mutations, which are the most frequently found molecular alterations in PCNSL, with prognosis of patients with PCNSL treated with R‐MPV. Methods We investigated the long‐term clinical course and status of MYD88 and CD79B genes in 85 patients with PCNSL treated with R‐MPV or HD‐MTX treatment, and the correlation of these genetic mutations with prognosis. Results R‐MPV achieved an excellent tumor control rate (61.6% and 69.9% of 5‐year progression‐free and overall survival rates, respectively). While MYD88 L265P mutation had no significant effect on survival, patients with CD79B Y196 mutations exhibited prolonged survival (p

Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-β1 (TGF-β1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-β1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. In situ hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF.

Abstract Dysregulation of transcriptional programs that are tightly regulated by DNA methylation during placental and fetal development at different gestational stages, may cause recurrent miscarriage. Here, we examined genome-wide DNA methylation in chorionic villi and decidual tissues from patients suffering RM and from healthy women who had undergone artificial abortion (n = 5 each). We found that 13,426 and 5816 CpG sites were differentially methylated in chorionic villi and decidua, respectively. DNA methylation profiles of chorionic villi, but not decidua, in RM patients was clearly distinct from AA controls. Among the differentially methylated genes, the enhancer region of SPATS2L was significantly more highly methylated in RM patients (n = 19) than AA controls (n = 19; mean methylation level, 52.0%-vs.-28.9%, P

Abstract Background The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. Methods The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. Results Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4–8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). Conclusions This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

For patients with unstable abdominal trauma unresponsive to initial transfusion, the damage control strategy includes prompt hemostasis by open surgery and packing. Recently, a hybrid treatment that combines packing and transcatheter arterial embolization as a damage control strategy was reported to be effective; however, the indications and techniques are yet to be established. A 25-year-old male patient who was in shock due to severe liver injury after a traffic accident was brought to our emergency room by emergency services. After initial resuscitation, including resuscitative endovascular balloon occlusion of the aorta and blood transfusion, preoperative contrast-enhanced computed tomography indicated grade IV liver injury with active bleeding from the right hepatic artery. Damage control strategy with packing and subsequent transcatheter arterial embolization was determined to be useful. During treatment, bile leakage was observed. An endoscopic nasobiliary drainage tube was inserted, and the patient was treated conservatively. He was discharged on day 83 of hospitalization. Although using preoperative contrast-enhanced computed tomography before damage control surgery remains controversial, it can provide useful information to determine damage control strategy, including morphological evaluation of the injured area and the presence of active bleeding.

Abstract Aim Multicenter collaborative research accelerates patient recruitment and strengthens evidence. Nevertheless, the factors influencing emergency and critical care physicians’ involvement in such research in Japan remain unclear. Methods A nationwide web‐based survey conducted in early 2023 targeted emergency physicians working a minimum of 3 days per week in Japan. The survey descriptively assessed their backgrounds, work and research environments, experiences, and perceived impediments and motivators for multicenter research. Results Of the 387 respondents, 348 were included in the study, yielding a 5.1% response rate. Women comprised 11% of the participants; 33% worked in university hospitals, 65% served in both emergency departments and intensive care units, and 54% did shift work. Only 12% had designated research time during working hours, with a median of 1 hour per week (interquartile range 0–5 h), including time outside of work. While 73% had participated in multicenter research, 58% noted barriers to participation. The key obstacles were excessive data entry (72%), meeting time constraints (59%), ethical review at each facility (50%), and unique sample collection, such as bronchoalveolar lavage specimens or pathological tissues (51%). The major incentives were networking (70%), data sets reuse (65%), feedback on research results (63%), and recognition from academic societies (63%). Financial rewards were not highly prioritized (38%). Conclusions While valuing clinical research, emergency physicians face barriers, especially data entry burden and limited research time. Networking and sharing research findings motivate them. These insights can guide strategies to enhance collaborative research in emergency and critical care in Japan.

Abstract Objective Burnout negatively affects the wellness and performance of emergency physicians (EPs). This study aimed to clarify the actual prevalence of burnout and its associated factors among Japanese EPs. Methods We conducted a cross‐sectional questionnaire study of selected 27 Japanese emergency departments (EDs). We examined the Maslach Burnout Inventory‐Human Services Survey score and its associations with ED‐level‐ and EP‐level factors in a multivariable analysis. Results A total of 267 EPs (81.9%) completed survey. Of these, 43 EPs (16.1%) scored severe emotional exhaustion (EE), 53 (19.8%) scored severe depersonalization (DP), and 179 (67.0%) scored severe personal accomplishment (PA), and 24 (8.9%) scored severely in all three domains. In our multivariable analysis, emergency medical service centers were associated with severe PA scores (odds ratio [OR], 10.56; 95% confidence interval [CI], 1.78–62.66; p = 0.009). A 3 to 6 hour‐sleep period was associated with severe EE scores (OR, 2.04; 95% CI, 1.04–3.98; p = 0.036), and EPs in their 20s were associated with severe DP scores (OR, 7.37; 95% CI, 1.41–38.38; p = 0.018). Conclusion Our results suggest that 8.9% of Japanese EPs are in higher degrees of burnout. In particular, Japanese EPs scored more severely on PA. To avoid burnout in Japanese EPs, it is important to improve the working environment by ensuring more than 6 h of sleep, providing more support for young EPs, and taking effective action to combat low EP self‐esteem.

Both coronavirus disease 2019 (COVID‐19) and heat stroke have symptoms of fever or hyperthermia and the difficulty in distinguishing them could lead to a strain on emergency medical care. To mitigate the potential confusion that could arise from actions for preventing both COVID‐19 spread and heat stroke, particularly in the context of record‐breaking summer season temperatures, this work offers new knowledge and evidence that address concerns regarding indoor ventilation and indoor temperatures, mask wearing and heat stroke risk, and the isolation of older adults. Specifically, the current work is the second edition to the previously published guidance for handling heat stroke during the COVID‐19 pandemic, prepared by the “Working group on heat stroke medical care during the COVID‐19 epidemic,” composed of members from four organizations in different medical and related fields. The group was established by the Japanese Association for Acute Medicine Heatstroke and Hypothermia Surveillance Committee. This second edition includes new knowledge, and conventional evidence gleaned from a primary selection of 60 articles from MEDLINE, one article from Cochrane, 13 articles from Ichushi, and a secondary/final selection of 56 articles. This work summarizes the contents that have been clarified in the prevention and treatment of infectious diseases and heat stroke to provide guidance for the prevention, diagnosis, and treatment of heat stroke during the COVID‐19 pandemic.

Abstract Emissions of black carbon (BC) particles from anthropogenic and natural sources contribute to climate change and human health impacts. Therefore, they need to be accurately quantified to develop an effective mitigation strategy. Although the spread of the emission flux estimates for China have recently narrowed under the constraints of atmospheric observations, consensus has not been reached regarding the dominant emission sector. Here, we quantified the contribution of the residential sector, as 64% (44–82%) in 2019, using the response of the observed atmospheric concentration in the outflowing air during Feb–Mar 2020, with the prevalence of the COVID-19 pandemic and restricted human activities over China. In detail, the BC emission fluxes, estimated after removing effects from meteorological variability, dropped only slightly (− 18%) during Feb–Mar 2020 from the levels in the previous year for selected air masses of Chinese origin, suggesting the contributions from the transport and industry sectors (36%) were smaller than the rest from the residential sector (64%). Carbon monoxide (CO) behaved differently, with larger emission reductions (− 35%) in the period Feb–Mar 2020, suggesting dominance of non-residential (i.e., transport and industry) sectors, which contributed 70% (48–100%) emission during 2019. The estimated BC/CO emission ratio for these sectors will help to further constrain bottom-up emission inventories. We comprehensively provide a clear scientific evidence supporting mitigation policies targeting reduction in residential BC emissions from China by demonstrating the economic feasibility using marginal abatement cost curves.

Abstract 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

Abstract Post-trauma patients are at great risk of pulmonary embolism (PE), however, data assessing specific risk factors for post-traumatic PE are scarce. This was a nested case–control study using the Japan Trauma Data Bank between 2004 and 2017. We enrolled patients aged ≥ 16 years, Injury Severity Score ≥ 9, and length of hospital stay ≥ 2 days, with PE and without PE, using propensity score matching. We conducted logistic regression analyses to examine risk factors for PE. We included 719 patients with PE and 3595 patients without PE. Of these patients, 1864 [43.2%] were male, and their median Interquartile Range (IQR) age was 73 [55–84] years. The major mechanism of injury was blunt (4282 [99.3%]). Median [IQR] Injury Severity Score (ISS) was 10 [9–18]. In the multivariate analysis, the variables spinal injury [odds ratio (OR), 1.40 (1.03–1.89)]; long bone open fracture in upper extremity and lower extremity [OR, 1.51 (1.06–2.15) and OR, 3.69 (2.89–4.71), respectively]; central vein catheter [OR, 2.17 (1.44–3.27)]; and any surgery [OR, 4.48 (3.46–5.81)] were independently associated with PE. Spinal injury, long bone open fracture in extremities, central vein catheter placement, and any surgery were risk factors for post-traumatic PE. Prompt initiation of prophylaxis is needed for patients with such trauma.

OBJECTIVES:. Although multiple organ dysfunction syndrome (MODS) is the main cause of death in patients with heat-related illnesses, its underlying pathophysiological mechanism remains elusive. Complement activation is considered one of the main causes of MODS in patients with sepsis and trauma. Considering the pathophysiological similarity of heat related-illnesses with sepsis and trauma, the complement system might be activated in patients with heat-related illnesses as well. Our aim was to investigate whether excessive complement activation occurs in patients with heat-related illnesses. DESIGN:. Prospective observational study. SETTING:. Emergency department in the university hospital. PATIENTS:. Thirty-two patients with heat-related illnesses and 15 age-matched healthy controls were enrolled in this study. INTERVENTIONS:. Blood samples were collected from the study subjects for the measurement of complement factors. MEASUREMENTS AND MAIN RESULTS:. Complement component 3a (C3a), complement component 5a (C5a), C5b-9, complement factor B (Ba), Factor H, and soluble CD59 in plasma were measured. The levels of C3a, C5a, C5b-9, and Ba significantly increased in patients with heat-related illnesses on day 0 compared with those in the healthy controls. Soluble CD59 was significantly high in patients with heat-related illnesses on day 0 and showed a correlation with the severity of the condition (Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and staging scores), Japanese Association for Acute Medicine disseminated intravascular coagulation scores, and the coagulation system (prothrombin time and fibrin degradation products). CONCLUSIONS:. The complement system was activated in patients with heat-related illnesses, suggesting that it is one of the causes of MODS. Soluble CD59 may be a potent biomarker for the severity of heat-related illnesses.

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. The pathways associated with the ubiquitin–proteasome and autophagy systems are particularly activated in the muscle tissues during sepsis and may lead to muscle wasting. Additionally, expression of muscle atrophy-related genes Atrogin-1 and MuRF-1 are seemingly increased via the ubiquitin–proteasome pathway. In clinical settings, electrical muscular stimulation, physiotherapy, early mobilization, and nutritional support are used for patients with sepsis to prevent or treat SAMW. However, there are no pharmacological treatments for SAMW, and the underlying mechanisms are still unknown. Therefore, research is urgently required in this field.

Delirium is characterized by an acutely altered mental status accompanied by reductions in cognitive function and attention. Delirium in septic patients, termed sepsis-associated delirium (SAD), differs in several specific aspects from the other types of delirium that are typically encountered in intensive care units. Since sepsis and delirium are both closely associated with increased morbidity and mortality, it is important to not only prevent but also promptly diagnose and treat SAD. We herein reviewed the etiology, pathogenesis, risk factors, prevention, diagnosis, treatment, and prognosis of SAD, including coronavirus disease 2019 (COVID-19)-related delirium. Delirium by itself not only worsens long-term prognosis, but it is also regarded as an important factor affecting the outcome of post-intensive care syndrome. In COVID-19 patients, the difficulties associated with adequately implementing the ABCDEF bundle (Assess, prevent, and manage pain; Both spontaneous awakening and breathing trials: Choice of analgesia and sedation; Delirium assess, prevent, and manage; Early mobility and exercise; Family engagement/empowerment) and the need for social isolation are issues that require the development of conventional care for SAD.

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.

Aim Status epilepticus (SE) is a life‐threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients with benzodiazepine‐refractory convulsive SE. Therefore, this study aimed to evaluate intravenous phenytoin (PHT) and other intravenous antiepileptic medications for SE. Methods We searched PubMed, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for published randomized controlled trials (RCTs) in humans up to August 2019. We compared outcomes between intravenous PHT and other intravenous medications. The important primary composite outcomes were the successful clinical cessation of seizures, mortality, and neurological outcomes at discharge. The reliability of the level of evidence for each outcome was compared using the Grading of Recommendations Assessment, Development, and Evaluation approach. Results A total of 1,103 studies were identified from the databases, and 10 RCTs were included in the analysis. The ratio of successful clinical seizure cessation was significantly lower (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.82–0.97) for patients treated with intravenous PHT than with other medications. When we compared mortality and neurological outcomes at discharge, we observed no significant differences between patients treated with PHT and those treated with other medications. The RRs were 1.07 (95% CI, 0.55–2.08) and 0.91 (95% CI, 0.72–1.15) for mortality and neurological outcomes at discharge, respectively. Conclusions Our findings showed that intravenous PHT was significantly inferior to other medications in terms of the cessation of seizures. No significant differences were observed in mortality or neurological outcomes between PHT and other medications.

Optimal energy and protein delivery goals for critically ill patients remain unknown. The purpose of this systematic review and meta-analysis was to compare the impact of energy and protein delivery during the first 4 to 10 days of an ICU stay on physical impairments. We performed a systematic literature search of MEDLINE, CENTRAL, and ICHUSHI to identify randomized controlled trials (RCTs) that compared energy delivery at a cut-off of 20 kcal/kg/day or 70% of estimated energy expenditure or protein delivery at 1 g/kg/day achieved within 4 to 10 days after admission to the ICU. The primary outcome was activities of daily living (ADL). Secondary outcomes were physical functions, changes in muscle mass, quality of life, mortality, length of hospital stay, and adverse events. Fifteen RCTs on energy delivery and 14 on protein were included in the analysis. No significant differences were observed in any of the outcomes included for energy delivery. However, regarding protein delivery, there was a slight improvement in ADL (odds ratio 21.55, 95% confidence interval (CI) −1.30 to 44.40, p = 0.06) and significantly attenuated muscle loss (mean difference 0.47, 95% CI 0.24 to 0.71, p < 0.0001). Limited numbers of RCTs were available to analyze the effects of physical impairments. In contrast to energy delivery, protein delivery ≥1 g/kg/day achieved within 4 to 10 days after admission to the ICU significantly attenuated muscle loss and slightly improved ADL in critically ill patients. Further RCTs are needed to investigate their effects on physical impairments.

Despite the increasing threat of heatstroke with global warming, pathophysiologic injury continues to be defined. In addition, morphological changes of the peripheral blood cells in heatstroke have not been well characterized. We evaluated pathophysiologic changes in bone marrow and blood cells in a rat heatstroke model using a 39.5 °C climate chamber. After three hours of incubation, blood and bone marrow samples were collected for morphology, and the direct effects of heat on leukocytes in vitro were evaluated using time-lapse observation. The blood cell count and peripheral/bone marrow smear were examined either in a lethal model (core body temperature exceeded 42.5 °C) or in a sublethal model (35% and >20% decreases, respectively) and changes were less in the sublethal model. Platelet clumping with the appearance of large platelets was observed. The neutrophils often demonstrated hyper-segmented nuclei, and lymphocytes showed reactive or blast-like changes. Further, the direct effect of heat on leukocytes noted apoptotic cell death at 41.5 °C, but subsequent necrosis at 43 °C. In summary, our rodent model showed that heatstroke causes platelet aggregation, leukocyte injury, and aponecrotic cell death. Such changes were milder and reversible in sublethal heatstroke. The appearance of immature cells may result from damage to the bone marrow microenvironment. These findings may provide useful information for potential diagnostic and therapeutic considerations.

Blue light imaging (BLI) and narrow-band imaging (NBI) are two modalities that enable narrow-band light observation. We aimed to compare the diagnostic ability of magnifying endoscopy with BLI (ME-BLI) and NBI (ME-NBI) for determining the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) by the Japanese Esophageal Society’s intrapapillary capillary loop (IPCL) classification. We enrolled 81 patients between 2014 and 2018, and the still endoscopic images for diagnosing the invasion depth at the same part in ME-BLI and ME-NBI were registered. Two blinded investigators reviewed them and diagnosed the invasion depth by the IPCL classification. Subsequently, the diagnostic yields in two modalities were compared. The overall accuracies for the invasion depth by the IPCL classification in ME-BLI and ME-NBI did not differ significantly (67.9–71.6% vs. 72.8–74.1%). In the analysis based on the invasion depth, the sensitivities and positive predictive values in tumors invading the muscularis mucosa or submucosa ≤200 µm were low (23.1–30.8% and 16.7–25.0%, respectively) in both modalities. In conclusion, the diagnostic ability for determining the invasion depth of SESCC by the IPCL classification was relatively similar in ME-BLI and ME-NBI, but diagnosis by magnifying endoscopy alone might not be satisfactory.

Ice cores can provide long-term records of black carbon (BC), an important aerosol species closely linked to the climate and environment. However, previous studies of ice cores only analysed BC particles with diameter of <600-850 nm, which could have led to underestimation of BC mass concentrations. Information on the size distribution of BC particles is very limited, and there are no Arctic ice core records of the temporal variation in BC size distribution. In this study, we applied a recently developed improved technique to analyse the BC concentration in an ice core drilled at the SIGMA-D site in northwest Greenland. The improved technique, which uses a modified Single-Particle Soot Photometer and a high-efficiency nebulizer, widens the measurable range of BC particle size. For high-resolution continuous analyses of ice cores, we developed a continuous flow analysis (CFA) system (resolution: 10-40 mm). Coupling of the improved BC measurement technique with the CFA system allows accurate high-resolution measurements of the size distribution and concentration of BC particles with diameter between 70 nm and 4 µm, with minimal particle losses. Using this technique, we reconstructed the size distributions and the number and mass concentrations of BC particles during the past 350 years. On the basis of the size distributions, we assessed the underestimation of BC mass concentrations measured using the conventional method. For the period 2003-2013, the underestimation of the average mass concentration would have been 12%-17% for the SIGMA-D core. [ABSTRACT FROM AUTHOR]

The roles and impacts of black carbon (BC), an important aerosol species affecting Earth's radiation budget, are not well understood owing to lack of accurate long-term observations. To study the temporal changes in BC since the pre-industrial period, we analysed BC in an ice core drilled in northwest Greenland. Using an improved technique for BC measurement and a continuous flow analysis system, we obtained accurate and high temporal resolution records of BC particle size and mass/number concentrations for the past 350 years. Number and mass concentrations, which both started to increase in the 1870s associated with inflow of anthropogenically derived BC, reached their maxima in the 1910s-1920s and then subsequently decreased. On the basis of backward trajectory analyses, we found that North America was the dominant source region of the anthropogenic BC in the ice core. The increase in anthropogenic BC shifted the annual concentration peaks of BC from summer to winter-early spring. After BC concentrations diminished to pre-industrial levels, the annual peak concentration of BC returned to the summer. We found that anthropogenic BC particles were larger than biomass burning BC particles. By separating the BC in winter and summer, we reconstructed the temporal variations in BC that originated from biomass burning, including the period with large anthropogenic input. The BC that originated from biomass burning showed no trend of increase until the early 2000s. Finally, possible albedo reductions due to BC are discussed. Our new data provide key information for validating aerosol and climate models, thereby supporting improved projections 31 of future climate and environment. [ABSTRACT FROM AUTHOR]

The SWI/SNF chromatin remodeling complex consists of more than ten component proteins that form a large protein complex of >1 MDa. The catalytic proteins Smarca4 or Smarca2 work in concert with the component proteins to form a chromatin platform suitable for transcriptional regulation. However, the mechanism by which each component protein works synergistically with the catalytic proteins remains largely unknown. Here, we report on the function of Smarce1, a component of the SWI/SNF complex, through the phenotypic analysis of homozygous mutant embryonic stem cells (ESCs). Disruption of Smarce1 induced the dissociation of other complex components from the SWI/SNF complex. Histone binding to DNA was loosened in homozygous mutant ESCs, indicating that disruption of Smarce1 decreased nucleosome stability. Sucrose gradient sedimentation analysis suggested that there was an ectopic genomic distribution of the SWI/SNF complex upon disruption of Smarce1, accounting for the misregulation of chromatin conformations. Unstable nucleosomes remained during ESC differentiation, impairing the heterochromatin formation that is characteristic of the differentiation process. These results suggest that Smarce1 guides the SWI/SNF complex to the appropriate genomic regions to generate chromatin structures adequate for transcriptional regulation. [ABSTRACT FROM AUTHOR]

In this paper the Photoacoustic Aerosol Absorption Spectrometer PAAS-4λ is introduced. PAAS-4λ was specifically developed for long-term monitoring tasks in (unattended) air quality stations. It uses four wavelengths coupled to a single acoustic resonator in a compact and robust set-up. The instrument has been thoroughly characterized and carefully calibrated in the laboratory using NO2/air mixtures and Nigrosin aerosol. It has an ultimate 1σ detection limit below 0.1 Mm-1 at a measurement precision and accuracy of 3% and 10%, respectively. In order to demonstrate the PAAS-4λ suitability for long-term monitoring tasks, the instrument is currently validated at the air quality monitoring station Pallas in Finland, about 140 km north of the Arctic circle. Eleven months of PAAS-4λ data from this deployment are presented and discussed in terms of instrument performance. Intercomparisons with the filter-based photometers COSMOS, MAAP, and AE33 demonstrate the capabilities and value of PAAS-4λ, also for the validation of the widely used filter-based instruments. [ABSTRACT FROM AUTHOR]

Rationale: Extracorporeal membrane oxygenation (ECMO) treatment is widely used worldwide, and many hospitals consider using antibiotics to prevent nosocomial infection in patients receiving ECMO treatment. However, the efficacy of antimicrobial prophylaxis for patients receiving ECMO treatment remains unclear. Objectives: To evaluate the efficacy of prophylactic antibiotics for patients receiving ECMO treatment. Methods: This retrospective cohort study was performed using data recorded in the Japanese Diagnosis Procedure Combination database from July 1, 2010, to March 31, 2017. We compared in-hospital mortality, nosocomial pneumonia, acute kidney injury, and diarrhea between patients receiving prophylactic antibiotics (prophylaxis group) and those not receiving antibiotics (control group) using propensity score matching. For in-hospital mortality and nosocomial pneumonia, multivariable logistic regression models fitted using a generalized estimating equation, stabilized inverse probability of treatment weighting, and instrumental variable analysis were performed. Results: We identified 9,615 eligible patients and classified them into the prophylaxis (n = 5,552) and control (n = 4,063) groups. In the propensity score-matched analysis, 3,650 pairs were generated. Significant differences between the prophylaxis group and the control group were detected in the in-hospital mortality (56.4% vs. 59.8%; risk difference, -3.7%; 95% confidence interval [CI], -6.0 to -1.3) and nosocomial pneumonia (12.9% vs. 15.3%; risk difference, -2.4%; 95% CI: -4.3 to -0.6). In the multivariable logistic regression models fitted using a generalized estimating equation, stabilized inverse probability of treatment weighting, and instrumental variable analysis, the point estimates suggested a direction similar to that found in the propensity score analysis. The proportions of patients with acute kidney injury or diarrhea did not significantly increase with the use of prophylactic antibiotics. Conclusions: Using prophylactic antibiotics during ECMO treatment was associated with reduced in-hospital mortality and lower proportions of patients with nosocomial pneumonia. Future prospective studies are needed to validate these results. [ABSTRACT FROM AUTHOR]

The article presents the discussion on investigating the efficacy of prophylactic antibiotics during extracorporeal membrane oxygenation (ECMO) in a Japanese nationwide database.