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Abstract Background Venous air trap chamber designs vary considerably to suit specific continuous renal replacement therapy circuits, with key variables including inflow design and filter presence. Nevertheless, intrachamber flow irregularities do occur and can promote blood coagulation. Therefore, this study employed computational fluid dynamics (CFD) simulations to better understand how venous air trap chamber designs affect flow. Methods The flow within a venous air trap chamber was analyzed through numerical calculations based on CFD, utilizing large eddy simulation. The working fluid was a 33% glycerin solution, and the flow rate was set at 150 ml/min. A model of a venous air trap chamber with a volume of 15 ml served as the computational domain. Calculations were performed for four conditions: horizontal inflow with and without a filter, and vertical inflow with and without a filter. Streamline plots and velocity contour plots were generated to visualize the flow. Results In the horizontal inflow chamber, irrespective of filter presence, ultimately the working fluid exhibited a downstream vortex flow along the chamber walls, dissipating as it progressed, and being faster near the walls than in the chamber center. In the presence of a filter, the working fluid flowed uniformly toward the outlet, while in the absence of a filter the flow became turbulent before reaching the outlet. These observations indicate a streamlining effect of the filter. In the vertical inflow chamber, irrespective of filter presence, the working fluid flowed vertically from the inlet into the main flow direction. Part of the working fluid bounced back at the chamber bottom, underwent upward and downward movements, and eventually flowed out through the outlet. Stagnation was observed at the top of the chamber. Without a filter, more working fluid bounced back from the bottom of the chamber. Conclusions CFD analysis estimated that the flow in a venous air trap chamber is affected by inflow method and filter presence. The “horizontal inflow chamber with filter” was identified as the design creating a smooth and uninterrupted flow throughout the chamber.

Abstract Background Sepsis 3 definitions have shifted the focus from nonspecific inflammation to sepsis as an organ dysfunction caused by a dysregulated host response to infection. Neutrophils have become therapeutic targets because of their intimate but complex involvement in sepsis. We conducted ex vivo and animal experiments to apply a granulocyte and monocyte adsorption column, which is clinically used for inflammatory bowel disease, in sepsis. In this study, the biocompatibility was evaluated in sepsis-like hypercytokinemia. Methods Six female outbred pigs were anesthetized. Extracorporeal direct hemoperfusion (DHP) with an Adacolumn or a sham column was initiated after lipopolysaccharide (LPS) administration. The DHP was performed for 2 h at a blood flow rate (QB) of 30 or 60 mL/min. Blood samples were collected before and during the DHP (30, 60, 90, and 120 min). The percentage change in white blood cell count, platelet count, and cytokine concentration was compared between the Adacolumn and sham columns. Results The percentage change in white blood cells were 96 (95–98)% and 106 (101–108)% in the Adacolumn and sham groups, respectively, at QB = 60 mL/min (p

Abstract Background Infective endocarditis (IE) is a rare cardiovascular complication in patients with coronavirus disease 2019 (COVID-19). IE after COVID-19 can also be complicated by acute respiratory distress syndrome (ARDS); however, the guidelines for the treatment of such cases are not clear. Here, we report a case of perioperative management of post-COVID-19 IE with ARDS using veno-venous extracorporeal membrane oxygenation (V-V ECMO). Case presentation The patient was a 40-year-old woman who was admitted on day 18 of COVID-19 onset and was administered oxygen therapy, remdesivir, and dexamethasone. The patient’s condition improved; however, on day 24 of hospitalization, the patient developed hypoxemia and was admitted to the intensive care unit (ICU) due to respiratory failure. Blood culture revealed Corynebacterium striatum, and transesophageal echocardiography revealed vegetation on the aortic and mitral valves. Valve destruction was mild, and the cause of respiratory failure was thought to be ARDS. Despite continued antimicrobial therapy, ARDS did not improve the patient’s condition, and valve destruction progressed; therefore, surgical treatment was scheduled on day 13 of ICU admission. After preoperative consultation with the team, a decision was made to initiate V-V ECMO after the patient was weaned from CPB, with concerns about further worsening of her respiratory status after surgery. The patient returned to the ICU with transition to V-V ECMO, and her circulation remained stable. The patient was weaned off V-V ECMO on postoperative day 33 and discharged from the ICU on postoperative day 47. Conclusions ARDS may occur in patients with IE after COVID-19. Owing to concerns about further exacerbation of pulmonary damage, the timing of surgery should be comprehensively considered. Preoperatively, clinicians should discuss perioperative ECMO introduction and configuration.

Abstract Background During continuous kidney replacement therapy (CKRT) in patients with sepsis and critical conditions, circuit coagulation can occur, often for unclear reasons. In this study, we investigate how the structure of the venous air trap chamber may contribute to venous air trap chamber coagulation. Clinical data were evaluated and experiments were performed. Methods The clinical evaluation involved patients who underwent continuous hemofiltration (CHF) using an acrylonitrile-co-methallyl sulfonate surface-treated (AN69ST) hemofilter (AN69ST-CHF) and either an ACH-Σ or Prismaflex CKRT machine in our ICU from April to July 2019. The patient data were divided into two groups based on CKRT machine and the percentage of CHF procedures that could continuously be performed for 22 h (CHF target achievement rate), and coagulation sites were evaluated. Statistical analysis was performed by the Mann–Whitney U test and Pearson’s chi-square test. For in vitro experiments, a system was constructed to circulate a 33% glycerol solution at a flow rate of 150 ml/min. In a venous air trap chamber, fluid dye disappearance times and fluid movements were visually evaluated. Results The clinical evaluation included 22 procedures (8 patients) in the ACH-Σ group and 22 procedures (11 patients) in the Prismaflex group, without significant differences in patient backgrounds between the groups. The CHF target achievement rate was 72.7% (16/22) in the ACH-Σ group and 77.3% (17/22) in the Prismaflex group, revealing no significant difference (p = 0.73). However, significantly fewer venous air trap chamber coagulations were observed in the Prismaflex group (1/5) than in the ACH-Σ group (5/6) (p

Key Clinical Message In younger patients, including those with extensive infarction involving the anterior and middle cerebral artery regions of the right hemisphere, appropriate treatment for rare causes and goal‐oriented long‐term rehabilitation could improve severe hemiplegia and higher brain dysfunction, and allow for further education and employment. Abstract Although the number of young stroke patients is small, many have serious sequelae and rare causes. In addition to independence in activities of daily living, education and employment are desired. We present two cases of extensive infarction in the right cerebrum in patients who underwent rehabilitation with good outcomes.

Abstract Background Chest computed tomography findings are helpful for understanding the pathophysiology of severe acute respiratory distress syndrome (ARDS). However, there is no large, multicenter, chest computed tomography registry for patients requiring veno-venous extracorporeal membrane oxygenation (V-V ECMO). The aim of this study was to describe chest computed tomography findings at V-V ECMO initiation and to evaluate the association between the findings and outcomes in severe ARDS. Methods This multicenter, retrospective cohort study enrolled patients with severe ARDS on V-V ECMO, who were admitted to the intensive care units of 24 hospitals in Japan between January 1, 2012, and December 31, 2022. Results The primary outcome was 90-day in-hospital mortality. The secondary outcomes were the successful liberation from V-V ECMO and the values of static lung compliance. Among the 697 registry patients, of the 582 patients who underwent chest computed tomography at V-V ECMO initiation, 394 survived and 188 died. Multivariate Cox regression showed that traction bronchiectasis and subcutaneous emphysema increased the risk of 90-day in-hospital mortality (hazard ratio [95% confidence interval] 1.77 [1.19–2.63], p = 0.005 and 1.97 [1.02–3.79], p = 0.044, respectively). The presence of traction bronchiectasis was also associated with decreased successful liberation from V-V ECMO (odds ratio: 0.27 [0.14–0.52], p

Abstract Background Tumor lysis syndrome is an oncological emergency triggered by the rapid release of intracellular materials from lysed malignant cells. Intensive chemotherapy is challenging for patients with severe renal dysfunction and a high risk of tumor lysis syndrome. Sustained high-efficiency daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA) could work not only as a renal replacement therapy, but also as a novel method to control intracellular materials, including cytokines and damage-associated molecular patterns. We aimed to describe two cases of patients with Burkitt’s lymphoma with a very high risk of tumor lysis syndrome who were successfully treated with a combination of chemotherapy and SHEDD-fA. Case presentation The first case was of a 67-year-old man who was admitted to the intensive care unit for respiratory failure and diagnosed with Burkitt’s lymphoma. Extremely high lactate dehydrogenase levels and anuria, indicating severe acute kidney injury, are considered to be associated with a very high risk of tumor lysis syndrome. SHEDD-fA was initiated prophylactically to prevent exacerbation of tumor lysis syndrome. To ensure the blood concentration of antitumor drugs, SHEDD-fA was stopped temporarily and restarted 6 h after the completion of chemotherapy. No tumor lysis syndrome-related complications were observed. The second case involved a 68-year-old man who was admitted to the intensive care unit due to exacerbation of Burkitt’s lymphoma complicated by severe pneumonia and disseminated intravascular coagulation. The patient exhibited metabolic acidosis, hyperkalemia, hyperuricemia, and anuria. SHEDD-fA was performed immediately. As in the first case, we temporarily discontinued SHEDD-fA before chemotherapy and restarted it 6 h after the completion of chemotherapy. No tumor lysis syndrome-associated complications were observed and renal function recovered. Interleukin-6, interleukin-8, and high-mobility group box-1 protein levels in the blood were lower on the outlet side than on the inlet side. Conclusions SHEDD-fA allows safe and effective administration of chemotherapy in patients with severe renal dysfunction and a very high risk of tumor lysis syndrome. Our findings indicate that blood purification modality may need to be selected according to tumor lysis syndrome severity.

Abstract Background Hemodynamic management during anesthesia in liver transplantation for patients with polycystic liver disease (PLD) can be more challenging because of the bleeding and hemodynamic alterations due to the markedly enlarged liver. We hereby report a case of PLD wherein transesophageal echocardiography (TEE) was employed for optimal hemodynamic monitoring during liver transplantation. Case presentation A 61-year-old man was scheduled to undergo liver transplantation for massive PLD. Hemodynamic instability was associated with mechanical displacement of the giant cystic liver. TEE results revealed the collapse of the inferior vena cava due to liver displacement. TEE also detected intrathoracic hemorrhage triggered by detachment from the markedly enlarged liver. Conclusion TEE is a valuable monitoring tool for sharing information with surgeons and diagnostic modality for finding the source of bleeding in liver transplantation for PLD and may contribute majorly to the quality of perioperative management.

Objectives: Sepsis is a life-threatening condition characterized by multi-organ dysfunction due to host immune system dysregulation in response to an infection. During sepsis, neutrophils release neutrophil extracellular traps (NETs) as part of the innate immune response. However, excessive NETs play a critical role in the development of organ failure during sepsis. Although recombinant human soluble thrombomodulin (rTM) can inhibit NET formation in the lungs and liver of a mouse model of endotoxin shock, its effects on the kidneys are unclear. Methods: The specific effects of NETs and rTM on the renal cortex and renal medulla were examined in a mouse model of endotoxin shock generated by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), followed by i.p. injection of rTM or an identical volume of saline 1 h later. Results: LPS injection increased serum creatinine, blood urea nitrogen, and histone H3 levels. However, rTM administration significantly decreased histone H3 and citrullinated histone H3 (citH3) levels. Immunohistochemical analysis revealed no significant changes in citH3 quantity in the renal cortex of any group. However, in the renal medulla, the increase in citH3 induced by LPS was abolished in the LPS+rTM group. Conclusions: Our findings demonstrate that rTM can suppress NETs in the renal medulla of mice with endotoxin-induced acute kidney injury.

Objectives: Perioperative venous thromboembolism (VTE) is a potentially fatal complication, making preoperative VTE diagnosis and secondary thromboprophylaxis important. This study was performed to investigate the impact of promotion of a preoperative VTE protocol at a perioperative management center (PMC) on detecting the preoperative VTE rate and subsequent treatment. Methods: This retrospective study involved patients aged ≥20 years who underwent elective anesthesia. The patients were divided into two groups: the pre-PMC group (January to October 2014, before the opening of the PMC) and the post-PMC group (January to December 2019, after the opening of the PMC). The rates of preoperative lower-limb compression ultrasonography (CUS), VTE detection, anticoagulation therapy, and new postoperative pulmonary embolism (PE) were compared between the two groups. Results: The pre-PMC and post-PMC groups comprised 3737 and 5388 patients, respectively. The preoperative CUS and VTE detection rates were significantly higher in the post-PMC than pre-PMC group (7.2% and 1.43% vs. 25.6% and 3.93%, respectively; P

Abstract Background The recently developed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). Methods We retrospectively measured serum SARS‐CoV‐2 antibodies against the spike protein (S‐IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S‐IgG titers ≥300 antibody units/mL). Results Although active anti‐myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B‐cell maturation antigen‐targeted therapy. Dose 3 (booster vaccination) led to significantly higher S‐IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine‐induced cellular immune response in patients using T‐spot Discovery SARS‐CoV‐2 kit, revealed an enhanced cellular immune response after Dose 3. Conclusions This study highlighted the significance of booster SARS‐CoV‐2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine‐induced humoral immune response.

Over one-third of stroke survivors develop aphasia, and language dysfunction persists for the remainder of their lives. Brain language network changes in patients with aphasia. Recently, it has been reported that phase synchrony within a low beta-band (14–19 Hz) frequency between Broca's area and the homotopic region of the right hemisphere is positively correlated with language function in patients with subacute post-stroke aphasia, suggesting that synchrony is important for language recovery. Here, we employed amplitude-modulated transcranial alternating current stimulation (AM-tACS) to enhance synchrony within the low beta band frequency between Broca's area and the right homotopic area, and to improve language function in a case of chronic post-stroke aphasia. According to an N-of-1 study design, the patient underwent short-term intervention with a one-time intervention of 15 Hz-AM-tACS with Broca's and the right homotopic areas (real condition), sham stimulation (sham condition), and 15 Hz-AM-tACS with Broca's and the left parietal areas (control condition) and long-term intervention with sham and real conditions (10 sessions in total, each). In the short-term intervention, the reaction time and accuracy rate of the naming task improved after real condition, not after sham and control conditions. The synchrony between the stimulated areas evaluated by coherence largely increased after the real condition. In the long-term intervention, naming ability, verbal fluency and overall language function improved, with the increase in the synchrony, and those improvements were sustained for more than a month after real condition. This suggests that AM-tACS on Broca's area and the right homotopic areas may be a promising therapeutic approach for patients with poststroke aphasia.

Objective: To examine the effect of in-bed leg cycling exercise on patients with intensive care unit-acquired weakness (ICU-AW). Design: Single-center retrospective study. Subjects/Patients: Patients admitted to the ICU between January 2019 and March 2023 were enrolled in the ergometer group, and those admitted to the ICU between August 2017 and December 2018 were enrolled in the control group. Methods: The ergometer group performed in-bed leg cycling exercises 5 times per week for 20 min from the day of ICU-AW diagnosis. Furthermore, the ergometer group received 1 early mobilization session per day according to the early mobilization protocol, whereas the control group received 1 or 2 sessions per day. The number of patients with recovery from ICU-AW at ICU discharge and improvement in physical functions were compared. Results: Significantly more patients in the ergometer group recovered from ICU-AW than in the control group (87.0% vs 60.6%, p = 0.039). Regarding physical function, the ergometer group showed significantly higher improvement efficiency in Medical Research Council sum score (1.0 [0.7–2.1] vs 0.1 [0.0–0.2], p

Abstract Background Patients with severe acute kidney injury (AKI) who require continuous venovenous hemodiafiltration (CVVHDF) in intensive care unit (ICU) are at high mortality risk. Little is known about clinical biomarkers for risk prediction, optimal initiation, and optimal discontinuation of CVVHDF. Methods This prospective observational study was conducted in seven university-affiliated ICUs. For urinary neutrophil gelatinase-associated lipocalin (NGAL) and plasma IL-6 measurements, samples were collected at initiation, 24 h, 48 h after, and CVVHDF discontinuation in adult patients with severe AKI. The outcomes were deaths during CVVHDF and CVVHDF dependence. Results A total number of 133 patients were included. Twenty-eight patients died without CVVHDF discontinuation (CVVHDF nonsurvivors). Urinary NGAL and plasma IL-6 at the CVVHDF initiation were significantly higher in CVVHDF nonsurvivors than in survivors. Among 105 CVVHDF survivors, 70 patients were free from renal replacement therapy (RRT) or death in the next 7 days after discontinuation (success group), whereas 35 patients died or needed RRT again (failure group). Urinary NGAL at CVVHDF discontinuation was significantly lower in the success group (93.8 ng/ml vs. 999 ng/ml, p

Objectives: Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients. Methods: Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients’ illness severity score, was examined. Results: Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels. Conclusions: Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.

Introduction While limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute respiratory distress syndrome (ARDS) is widely accepted, the best setting for positive end-expiratory pressure (PEEP) is still controversial. This study is being conducted to investigate whether a higher PEEP setting (15 cmH2O) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting.Methods and analysis The study is an investigator-initiated, multicentre, open-label, two-arm, randomised controlled trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The subjects of the study are patients with severe ARDS who require V-V ECMO support. Eligible patients will be randomised equally to the high PEEP group or low PEEP group. Recruitment to the study will continue until a total of 210 patients with ARDS requiring V-V ECMO support have been randomised. In the high PEEP group, PEEP will be set at 15 cmH2O from the start of V-V ECMO until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmH2O. Other treatments will be the same in the two groups. The primary endpoint of the study is the number of ECMO-free days until day 28, defined as the length of time (in days) from successful libration from V-V ECMO to day 28. The secondary endpoints are mortality on day 28, in-hospital mortality on day 60, ventilator-free days during the first 60 days and length of ICU stay.Ethics and dissemination Ethics approval for the trial at all the participating hospitals was obtained on 27 September 2022, by central ethics approval (IRB at Hiroshima University Hospital, C2022-0006). The results of this study will be presented at domestic and international medical congresses, and also published in scientific journals.Trial registration number The Japan Registry of Clinical Trials jRCT1062220062. Registered on 28 September 2022.Protocol version 28 March 2023, version 4.0.

Objectives: Our aims were to clarify the actual situation regarding preoperative fasting and determine whether multidisciplinary interventions in a perioperative management center shorten the duration of preoperative fasting. Methods: The cohort of this before-and-after study comprised patients undergoing elective surgery aged 18 years or older who underwent general anesthesia at one of three stages: after starting a short preoperative fasting protocol (Group A), after the anesthesiologist started explaining the protocol (Group B), and after the start of the perioperative management center (Group C). Instructions on drinking clear fluids were given up to 2 h and 4 h before the start of elective surgery to the first patient on the list (on-time) and to the second and subsequent patients (on-call), respectively. Data were collected retrospectively in Groups A and B and prospectively in Group C. Results: The study cohort comprised 89 patients in Group A (50 on-time, 39 on-call), 108 in Group B (65 on-time, 43 on-call), and 284 in Group C (182 on-time, 102 on-call). The difference between the instructed and last drinking time was significantly shorter in Group C than Group A (30 [10, 140] vs. 30 [10, 60] vs. 20 [0, 50] min, p=0.003). The duration of fasting was significantly shorter in Group C than Group B (243 [150, 395] vs. 213 [151, 323] vs. 180 [146, 280] min, p=0.01). Conclusions: Multidisciplinary interventions at the perioperative management center tended to reduce the duration of fasting, suggesting that this approach may contribute to improved compliance.

Abstract Lysyl hydroxylase 2 (LH2) is a member of LH family that catalyzes the hydroxylation of lysine (Lys) residues on collagen, and this particular isozyme has been implicated in various diseases. While its function as a telopeptidyl LH is generally accepted, several fundamental questions remain unanswered: 1. Does LH2 catalyze the hydroxylation of all telopeptidyl Lys residues of collagen? 2. Is LH2 involved in the helical Lys hydroxylation? 3. What are the functional consequences when LH2 is completely absent? To answer these questions, we generated LH2-null MC3T3 cells (LH2KO), and extensively characterized the type I collagen phenotypes in comparison with controls. Cross-link analysis demonstrated that the hydroxylysine-aldehyde (Hylald)-derived cross-links were completely absent from LH2KO collagen with concomitant increases in the Lysald-derived cross-links. Mass spectrometric analysis revealed that, in LH2KO type I collagen, telopeptidyl Lys hydroxylation was completely abolished at all sites while helical Lys hydroxylation was slightly diminished in a site-specific manner. Moreover, di-glycosylated Hyl was diminished at the expense of mono-glycosylated Hyl. LH2KO collagen was highly soluble and digestible, fibril diameters were diminished, and mineralization impaired when compared to controls. Together, these data underscore the critical role of LH2-catalyzed collagen modifications in collagen stability, organization and mineralization in MC3T3 cells.

Physical symptoms such as fatigue and muscle weakness, and psychiatric symptoms like depression and anxiety are considered as complications and sequelae of COVID-19. This epidemiological study investigated the actual status of psychiatric symptoms and disorders caused by COVID-19, from four major university hospitals and five general hospitals in Fukuoka Prefecture, Japan, having a population of 5 million. We conducted a survey of psychiatric disorders associated with COVID-19 using Diagnosis Procedure Combination (DPC) data and the psychiatric records of the hospitals. In the study period from January 2019 to September 2021, 2743 COVID-19 admissions were determined from DPC data across the nine sites. These subjects had significantly more anxiety, depression, and insomnia, and were receiving higher rates of various psychotropic medications than controls influenza and respiratory infections. A review of psychiatric records revealed that the frequency of organic mental illness with insomnia and confusion was proportional to the severity of COVID-19 infection and that anxiety symptoms appeared independent of infection severity. These results indicate that COVID-19 is more likely to produce psychiatric symptoms such as anxiety and insomnia than conventional infections.

PurposeUpregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature.MethodsThe type I IFN signature was measured in patients’ whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature.ResultsA total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling.ConclusionsHalf of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.

Abstract Aim Approximately one‐third of patients with major depressive disorder develop treatment‐resistant depression. One‐third of patients with treatment‐resistant depression demonstrate resistance to ketamine, which is a novel antidepressant effective for this disorder. The objective of this study was to examine the utility of resting‐state functional magnetic resonance imaging for the prediction of treatment response to ketamine in treatment‐resistant depression. Methods An exploratory seed‐based resting‐state functional magnetic resonance imaging analysis was performed to examine baseline resting‐state functional connectivity differences between ketamine responders and nonresponders before treatment with multiple intravenous ketamine infusions. Results Fifteen patients with treatment‐resistant depression received multiple intravenous subanesthetic (0.5 mg/kg/40 minutes) ketamine infusions, and nine were identified as responders. The exploratory resting‐state functional magnetic resonance imaging analysis identified a cluster of significant baseline resting‐state functional connectivity differences associating ketamine response between the amygdala and subgenual anterior cingulate gyrus in the right hemisphere. Using anatomical region of interest analysis of the resting‐state functional connectivity, ketamine response was predicted with 88.9% sensitivity and 100% specificity. The resting‐state functional connectivity of significant group differences between responders and nonresponders retained throughout the treatment were considered a trait‐like feature of heterogeneity in treatment‐resistant depression. Conclusion This study suggests the possible clinical utility of resting‐state functional magnetic resonance imaging for predicting the antidepressant effects of ketamine in treatment‐resistant depression patients and implicated resting‐state functional connectivity alterations to determine the trait‐like pathophysiology underlying treatment response heterogeneity in treatment‐resistant depression.

Abstract Since the start of the coronavirus disease 2019 (COVID-19) pandemic, it has remained unknown whether conventional risk prediction tools used in intensive care units are applicable to patients with COVID-19. Therefore, we assessed the performance of established risk prediction models using the Japanese Intensive Care database. Discrimination and calibration of the models were poor. Revised risk prediction models are needed to assess the clinical severity of COVID-19 patients and monitor healthcare quality in ICUs overwhelmed by patients with COVID-19.

Abstract Background The Acute Physiology and Chronic Health Evaluation (APACHE) III-j model is widely used to predict mortality in Japanese intensive care units (ICUs). Although the model’s discrimination is excellent, its calibration is poor. APACHE III-j overestimates the risk of death, making its evaluation of healthcare quality inaccurate. This study aimed to improve the calibration of the model and develop a Japan Risk of Death (JROD) model for benchmarking purposes. Methods A retrospective analysis was conducted using a national clinical registry of ICU patients in Japan. Adult patients admitted to an ICU between April 1, 2018, and March 31, 2019, were included. The APACHE III-j model was recalibrated with the following models: Model 1, predicting mortality with an offset variable for the linear predictor of the APACHE III-j model using a generalized linear model; model 2, predicting mortality with the linear predictor of the APACHE III-j model using a generalized linear model; and model 3, predicting mortality with the linear predictor of the APACHE III-j model using a hierarchical generalized additive model. Model performance was assessed with the area under the receiver operating characteristic curve (AUROC), the Brier score, and the modified Hosmer–Lemeshow test. To confirm model applicability to evaluating quality of care, funnel plots of the standardized mortality ratio and exponentially weighted moving average (EWMA) charts for mortality were drawn. Results In total, 33,557 patients from 44 ICUs were included in the study population. ICU mortality was 3.8%, and hospital mortality was 8.1%. The AUROC, Brier score, and modified Hosmer–Lemeshow p value of the original model and models 1, 2, and 3 were 0.915, 0.062, and < .001; 0.915, 0.047, and < .001; 0.915, 0.047, and .002; and 0.917, 0.047, and .84, respectively. Except for model 3, the funnel plots showed overdispersion. The validity of the EWMA charts for the recalibrated models was determined by visual inspection. Conclusions Model 3 showed good performance and can be adopted as the JROD model for monitoring quality of care in an ICU, although further investigation of the clinical validity of outlier detection is required. This update method may also be useful in other settings.

Abstract Secondary fungal infections are a critical problem that accompany immunosuppressive therapy for severe coronavirus disease 2019 (COVID‐19). We report a fatal case of COVID‐19 with disseminated mucormycosis diagnosed during autopsy. A 58‐year‐old man with diabetes was hospitalized for severe COVID‐19 and treated with remdesivir, systemic steroids and tocilizumab. Following treatment, he was provided extracorporeal membrane oxygenation support. However, he died of multiple organ failure accompanied by pulmonary and kidney infarction, as revealed by computed tomography. Autopsy revealed that the infarction was caused by thromboangiitis due to mucormycosis in the brain, lungs, heart, liver and kidneys. Therefore, the diagnosis of disseminated mucormycosis was established. Disseminated mucormycosis is a rare complication of COVID‐19. Although its early diagnosis is difficult, the disease progresses rapidly. Hence, we propose that immunosuppressive treatment for COVID‐19 should be administered with caution considering the risk of developing severe opportunistic infections, such as mucormycosis.

Objectives: Hepatectomy is used to treat several liver diseases, although perioperative mortality and postoperative complication rates remain high. Given the lack of relevant studies to date, the present study aimed to investigate potential predictive factors for postoperative complications in patients undergoing hepatectomies lasting 12 or more hours (termed “extremely long hepatectomies”). Methods: Adult patients undergoing treatment in the intensive care unit (ICU) after extremely long hepatectomies at Fujita Health University Hospital between 2014 and 2017 were enrolled in the study. Postoperative complications were classified as “major complications” and “non-major complications” according to the Clavien–Dindo Classification grading system. We also divided our study population into “simple hepatectomy” and “non-simple hepatectomy” subgroups for further analysis. Statistical analyses were performed using the Mann–Whitney U test, chi-squared test, and multiple logistic regression analysis. Results: In total, 114 patients (Major Complications Group, n=44; Non-Major Complications Group, n=70) were enrolled. In the Simple Hepatectomy Group, there were no significant variables. In the Non-Simple Hepatectomy Group, female sex (odds ratio [OR], 13.4; 95% confidence interval [CI], 1.00–1.81×102; p=0.04) and lactate levels at ICU admission (OR, 1.6; 95% CI, 0.99–2.59; p=0.05) were independent factors associated with major postoperative complications. Conclusions: In the Simple Hepatectomy Group, there were no significant variables. In the Non-Simple Hepatectomy Group, female sex and lactate levels at ICU admission of patients who underwent extremely long hepatectomies may be independent factors associated with major postoperative complications.

Abstract Gynaecological diagnoses were carried in three adult female orangutans (Pongo spp.) using ultrasound, and their estrous states were estimated by measuring urinary sex steroid hormone concentrations using enzyme immunoassay. Ultrasound diagnosis revealed that the endometrial thickness and follicle size were correlated with the oestrogen‐3‐glucuronide concentrations in the follicular phase. In addition, administration of the ovulation inducer human chorionic gonadotropin (hCG) had the strongest effect on the pregnanediol‐3‐glucuronide (PdG) concentration when the follicle size was 22.3 mm, suggesting that the follicle reaches this size before ovulation. The similarity between this and the maximum ovarian follicle size in humans (approximately 20 mm) indicates that the ancestral reproductive characteristics may have been retained in these species.

Objective: Sivelestat sodium hydrate (Siv) is expected to be an effective therapy for acute respiratory distress syndrome, although its mechanism of action is not understood. In this study, we investigated which myeloid cells-derived cytokines were suppressed by Siv. Methods: Continuous hemofiltration was performed by circulating fresh porcine blood through a semi-closed circuit. To ensure that leukocytes survived for 360 min, 5% glucose, heparin, and air were continuously injected. The control group received continuous administration of lipopolysaccharide (LPS) only, whereas the Siv group received LPS and Siv. Complete blood count, levels of various cytokines, and other variables were compared between the groups. Results: Interleukin (IL)-1β level was significantly suppressed in the Siv group compared with that in the control group (p

Blood purification is performed to control cytokines in critically ill patients. The relationship between the clearance (CL) and the membrane area during adsorption is not clear. We hypothesized that the CL increases with the hydrophobic area when hydrophobic binding contributes to cytokine adsorption. We investigated the relationship between the hemofilter membrane area and the CL of the high mobility group box 1 protein (HMGB-1) and interleukin-6 (IL-6). We performed experimental hemofiltration in vitro using polymethyl methacrylate membranes CH-1.8W (1.8 m2) and CH-1.0N (1.0 m2), as well as polysulfone membrane NV-18X (1.8 m2). After adding 100 mg of HMGB1 or 10 μg of IL-6 into the test solution, experimental hemofiltration was conducted for 360 min in a closed-loop circulation system, and the same amount of HMGB1 and IL-6 was added after 180 min. With CH-1.8W and CH-1.0N, both HMGB-1 and IL-6 showed a rapid concentration decrease of more than 70% at 180 min and 360 min after the re-addition. At 15 min, the CL of HMGB-1 was CH-1.8W: 28.4 and CH-1.0N: 19.8, and that of IL-6 was CH-1.8W: 41.1 and CH-1.0N: 25.4. CH-1.8W and CH-1.0N removed HMGB1 and IL-6 by adsorption and CH-1.8W was superior in CL, which increased with a greater membrane area.

Mitochondrial dysfunction has been implicated in the pathogenesis of inflammation and multi-organ dysfunction in major trauma, including burn injury. Coenzyme Q10 (CoQ10) is a metabolite of the mevalonate pathway and an essential cofactor for the electron transport in the mitochondria. In addition, its reduced form (ubiquinol) functions as an antioxidant. Little is known as to whether oral CoQ10 supplementation effectively increases intracellular CoQ10 levels in humans. To study the bioavailability of CoQ10 supplementation, we conducted a randomized, double-blind, placebo-controlled study of reduced CoQ10 (ubiquinol-10) (1800 mg/day, t.i.d.) in burn patients at a single, tertiary-care hospital. Baseline plasma CoQ10 levels were significantly lower in burn patients than in healthy volunteers, although plasma CoQ10/cholesterol ratio did not differ between the groups. CoQ10 supplementation increased plasma concentrations of total and reduced CoQ10 and total CoQ10 content in peripheral blood mononuclear cells (PBMCs) in burn patients compared with the placebo group. CoQ10 supplementation did not significantly change circulating levels of mitochondrial DNA, inflammatory markers (e.g., interleukins, TNF-α, IFN-γ), or Sequential Organ Failure Assessment (SOFA) scores compared with the placebo group. This study showed that a relatively high dose of reduced CoQ10 supplementation increased the intracellular CoQ10 content in PBMCs as well as plasma concentrations in burn patients.

This report describes clinical and radiographic characteristics of two pediatric patients with a presumptive diagnosis of subchondral fracture of the femoral head made based on their clinical course and imaging findings. An 8-year-old boy and an 8-year-old girl had subchondral fracture in the femoral head without osteonecrosis, which was verified by contrast-enhanced magnetic resonance imaging. Although complete disappearance of the fracture line was confirmed in the boy, the girl had a residual femoral head deformity after conservative treatment. Subchondral fracture of the femoral head should be included in the differential diagnosis of pediatric hip pain.

Objectives: Nasal high-flow (NHF) therapy provides continuous positive airway pressure (CPAP), flushes the anatomical dead space, and improves mucociliary clearance. CPAP is usually applied at a flow rate at or above an established threshold value with the mouth closed because it is hard to maintain it with an open mouth. We conducted a prospective study to validate our hypothesis that CPAP can be applied with the mouth open through a surgical face mask. Methods: We inserted 12-Fr nasogastric tubes through the noses of 18 healthy individuals and fixed each tube within the pharynx to monitor the intrapharyngeal pressure. We monitored the pressure during the following two conditions: NHF oxygen with the mouth open (condition O) and NHF oxygen with the mouth open and wearing a surgical face mask (condition OM). We set the NHF rate at 40 L/min and the oxygen concentration at 21%, under all conditions. We measured the intrapharyngeal pressure five times during each inspiration and expiration, and calculated mean values. Results: The mean expiratory intrapharyngeal pressure (median [interquartile range]) increased significantly from the baseline during conditions O (2.08 [1.58–4.02] cm H2O) and OM (3.35 [2.72–3.79] cm H2O). In addition, there was a significant difference in pressure between conditions O and OM (p=0.0263, Wilcoxon signed-rank test). Conclusions: In our healthy volunteers, the intrapharyngeal pressures increased during expiration with an open mouth while wearing a surgical face mask.

Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) is increasingly used in a broad range of research due to its ability to visualize the spatial distribution of metabolites in vivo. Here, we have developed a method, named thoracic Mass Spectrometry Imaging (tMSI), as a standard protocol of molecular imaging of whole-animal sectioning in various settings of mice in vivo. Further application of the strategy that involved the systemic administration of dexamethasone (DEX) in mice, enabled a dynamic shift in the energy status of multiple thoracic organs to be visualized, based on tMSI data of purine and pyrimidine metabolites. Furthermore, with the introduction of uniform manifold approximation and projection (UMAP) for tMSI data, metabolic profiles normally localized in the cortex and cortico-medullary junction (CMJ) of the thymus were drastically shifted as minor profiles into the medulla of DEX-treated thymus. As a massive apoptotic cell death in the thymic cortex was noticeable, a single molecule, which was upregulated in the cortex of the thymus, enabled us to predict ongoing immunosuppression by in vivo DEX-administration.

Abstract Metabolic derangements are a clinically significant complication of major trauma (e.g., burn injury) and include various aspects of metabolism, such as insulin resistance, muscle wasting, mitochondrial dysfunction and hyperlactatemia. Nonetheless, the molecular pathogenesis and the relation between these diverse metabolic alterations are poorly understood. We have previously shown that burn increases farnesyltransferase (FTase) expression and protein farnesylation and that FTase inhibitor (FTI) prevents burn-induced hyperlactatemia, insulin resistance, and increased proteolysis in mouse skeletal muscle. In this study, we found that burn injury activated mTORC1 and hypoxia-inducible factor (HIF)-1α, which paralleled dysfunction, morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of respiratory supercomplex assembly of the mitochondria, and ER stress. FTI reversed or ameliorated all of these alterations in burned mice. These findings indicate that these burn-induced changes, which encompass various aspects of metabolism, may be linked to one another and require protein farnesylation. Our results provide evidence of involvement of the mTORC1-HIF-1α pathway in burn-induced metabolic derangements. Our study identifies protein farnesylation as a potential hub of the signaling network affecting multiple aspects of metabolic alterations after burn injury and as a novel potential molecular target to improve the clinical outcome of severely burned patients.

Abstract Background Extubation is a more challenging medical practice than intubation, and countermeasures against it are similar to those described in the Difficult Intubation Guidelines, but problems cannot be overcome by completely the same methods. We predicted difficult extubation in a pediatric patient with left recurrent laryngeal nerve paralysis and devised an extubation method. Case presentation The patient was a 2-year-and-8-month-old boy scheduled for cleft palate repair. Concomitant cardiac anomaly and first and second branchial arch syndrome-associated facial malformations, such as mandibular micrognathia and auricular malformation, were observed. He had a past medical history of difficult intubation and respiratory arrest on a catheter test under intravenous sedation at 4 months old. Left recurrent laryngeal nerve paralysis was discovered on preoperative examination of the cleft palate, based on which difficulty in postoperative extubation was predicted. A catheter for tracheal tube exchange proposed by the extubation guidelines of the Difficult Airway Society (DAS) was placed, endoscopic examination was performed while inducing spontaneous breathing and swallowing reflex by an otolaryngologist, and the tube was removed while movement of the tissue around the glottis was visually evaluated. The patient was managed in an ICU after extubation, and both the systemic and respiratory conditions were favorable. Conclusions Extubation and airway management could be safely performed by devising extubation while conforming to the DAS guidelines.

Background MicroRNA (miR)‐33 targets cholesterol transporter ATP‐binding cassette protein A1 and other antiatherogenic targets and contributes to atherogenic progression. Its inhibition or deletion is known to result in the amelioration of atherosclerosis in mice. However, mice lack the other member of the miR‐33 family, miR‐33b, which exists in humans and other large mammals. Thus, precise evaluation and comparison of the responsibilities of these 2 miRs during the progression of atherosclerosis has not been reported, although they are essential. Methods and Results In this study, we performed a comprehensive analysis of the difference between the function of miR‐33a and miR‐33b using genetically modified mice. We generated 4 strains with or without miR‐33a and miR‐33b. Comparison between mice with only miR‐33a (wild‐type mice) and mice with only miR‐33b (miR‐33a−/−/miR‐33b+/+) revealed the dominant expression of miR‐33b in the liver. To evaluate the whole body atherogenic potency of miR‐33a and miR‐33b, we developed apolipoprotein E–deficient/miR‐33a+/+/miR‐33b−/− mice and apolipoprotein E–deficient/miR‐33a−/−/miR‐33b+/+ mice. With a high‐fat and high‐cholesterol diet, the apolipoprotein E–deficient/miR‐33a−/−/miR‐33b+/+ mice developed increased atherosclerotic plaque versus apolipoprotein E–deficient/miR‐33a+/+/miR‐33b−/− mice, in line with the predominant expression of miR‐33b in the liver and worsened serum cholesterol profile. By contrast, a bone marrow transplantation study showed no significant difference, which was consistent with the relevant expression levels of miR‐33a and miR‐33b in bone marrow cells. Conclusions The miR‐33 family exhibits differences in distribution and regulation and particularly in the progression of atherosclerosis; miR‐33b would be more potent than miR‐33a.

Trps1 is considered as an important gene involved in the interactions between the epithelial and mesenchymal cells during hair follicle morphogenesis. The number of hair follicles in Trps1 Knockout (KO) newborn mouse skin was significantly lower than that in wild-type (WT) newborn skin. To gain insight into the functional role of Trps1 in hair development, we transplanted Trps1 KO newborn mouse skin on the backs of nude mice and examined hair growth at day 42 after transplantation. Surprisingly, transplanted skin from Trps1 KO newborn mice gave rise to substantial amount of hair, although the hair was softer than that of WT mice. Histological examination revealed that the diameter of both hair follicles and hair shafts were significantly lower, whereas the density of hair follicles showed no significant difference between the Trps1 KO and WT mice. We introduce mouse hair follicles as a fascinating model to study the functions of Trps1 in mouse hair growth and pathology. This model suggests that the function of Trps1 is unnecessary for the development of normal hair follicles and hair shafts, although the loss of Trps1 affects the diameters of hair follicles and hair shaft.

Neutrophil extracellular trap (NET) formation, an innate immune system response, is associated with thrombogenesis and vascular endothelial injury. Circulatory disorders due to microvascular thrombogenesis are one of the principal causes of organ damage. NET formation in organs contributes to the exacerbation of sepsis, which is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We have previously reported that recombinant human soluble thrombomodulin (rTM) reduces lipopolysaccharide (LPS)-induced NET formation in vitro. Here, we aimed to show that thrombomodulin (TM)-mediated suppression of NET formation protects against organ damage in sepsis. Mice were injected intraperitoneally (i.p.) with 10 mg/kg LPS. rTM (6 mg/kg/day) or saline was administered i.p. 1 h after LPS injection. In the LPS-induced murine septic shock model, extracellular histones, which are components of NETs, were observed in the liver and lungs. In addition, the serum cytokine (interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), macrophage chemotactic protein-1 (MCP-1), and interleukin-10 (IL-10)) levels were increased. The administration of rTM in this model prevented NET formation in the organs and suppressed the increase in the levels of all cytokines except IL-1β. Furthermore, the survival rate improved. We provide a novel role of TM in treating inflammation and NETs in organs during sepsis.