Japanese Clinical Practice Guidelines for Rehabilitation in Critically Ill Patients 2023 (J-ReCIP 2023).

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.

Efficacy of Higher Positive End-Expiratory Pressure Ventilation Strategy in Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

Previous systematic reviews and meta-analyses assessing the pooled effects of higher positive end-expiratory pressure (PEEP) failed to show significantly reduced mortality in patients with acute respiratory distress syndrome (ARDS). Some new randomized controlled trials (RCTs) have been reported and an updated systematic review is needed to evaluate the use of higher PEEP in patients with ARDS. We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Igaku-Chuo-Zasshi, ICTRP, the National Institute of Health Clinical Trials Register, and the reference list of recent guidelines. We included RCTs to compare the higher PEEP ventilation strategy with the lower strategy in patients with ARDS. Two authors independently assessed the eligibility of the studies and extracted the data. The primary outcomes were 28-day mortality. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) methodology was used to evaluate the certainty of the evidence. Among the 6530 screened records, 16 randomized trials involving 4150 patients were included in our meta-analysis. When comparing higher PEEP versus lower PEEP, the pooled risk ratio (RR) for 28-day mortality was 0.85 (15 studies, n=4108, 95% CI 0.72 to 1.00, I2=58%, low certainty of evidence). Subgroup analysis by study participants with a low tidal volume (LTV) strategy showed an interaction (P for interaction, 0.001). Our study showed that in patients with ARDS, the use of higher PEEP did not significantly reduce 28-day mortality compared to the use of lower PEEP.

Loss of tolerance to multiple environmental stresses due to limitation of structural diversity of complex sphingolipids.

Structural diversity of complex sphingolipids is important for maintenance of various cellular functions; however, the overall picture of the significance of this structural diversity remains largely unknown. To investigate the physiological importance of the structural diversity of complex sphingolipids, we here constructed a complex sphingolipid structural diversity disruption library in budding yeast, which comprises 11 mutants including with combinations of deletions of sphingolipid-metabolizing enzyme genes. The sensitivity of the mutants to various environmental stresses revealed that the more the structural variation of complex sphingolipids is limited, the more stress sensitivity tends to increase. Moreover, it was found that in mutant cells with only one subtype of complex sphingolipid, Slt2 MAP kinase and Msn2/4 transcriptional factors are essential for maintenance of a normal growth and compensation for reduced tolerance of multiple stresses caused by loss of complex sphingolipid diversity. Slt2 and Msn2/4 are involved in compensation for impaired integrity of cell walls and plasma membranes caused by loss of complex sphingolipid diversity, respectively. From these findings, it was suggested that loss of structural diversity of complex sphingolipids affects the environment of the cell surface, including both plasma membranes and cell walls, which could cause multiple environmental stress hypersensitivity.

Involvement of the mitochondrial retrograde pathway in dihydrosphingosine-induced cytotoxicity in budding yeast.

Sphingoid long-chain bases are essential intermediates of ceramides and complex sphingolipids, and function in the regulation of various signal transduction systems. Previously, we found that, in budding yeast, intracellularly accumulated dihydrosphingosine (DHS) causes mitochondrial reactive-oxygen species (ROS)-mediated cytotoxicity, which is much stronger than phytosphingosine. In this study, we screened for suppressor mutations that confer resistance to DHS, and identified RTG2, which encodes upregulation of the mitochondrial retrograde signaling pathway (RTG pathway). Deletion of RTG3 encoding transcriptional factor for the RTG pathway suppressed the cytotoxicity of DHS, whereas deletion of MKS1 or point mutation of LST8, both of which cause increased activity of the RTG pathway, enhanced the cytotoxicity. Moreover, the deletion of RTG3 also suppressed the DHS-induced increases in ROS levels. Finally, it was found that the RTG pathway is activated on DHS treatment. These results suggested that the cytotoxicity of DHS is partially mediated through activation of the RTG pathway.

ROS-mediated synthetic growth defect caused by impaired metabolism of sphingolipids and phosphatidylserine in budding yeast.

Previously, we found that yeast exhibits a strong growth defect with the combination of a lack of gene involved in structural modification of sphingolipids and repression of the phosphatidylserine synthase gene. Here we found that the double gene mutation causes reactive oxygen species-mediated cell growth defect, which is suppressed by deletion of LEM3 encoding the subunit of phospholipid flippase.

Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response.

BACKGROUND: Dendritic cells (DCs), as antigen-presenting cells, play a key role in the induction and regulation of adaptive immune response. Midazolam is reported to have immunomodulatory properties that affect immune cells. However, the effect of midazolam on DCs has not been characterized. We examined the immunomodulatory properties of midazolam on DC-mediated immune response. METHODS: After allowing murine bone marrow-derived DCs induced by granulocyte macrophage colony stimulating factor to mature, we analyzed their expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class II molecules, and the secretion of interleukin-12 p40. In vitro, we evaluated the effect of midazolam on maturing DCs in mixed cell cultures containing DCs and T cells. In vivo, we investigated the contact-hypersensitivity response. RESULTS: Midazolam suppressed the expression of CD80, CD86, and major histocompatibility complex class II molecules from murine DCs. Treated with midazolam, DCs also secreted less interleukin-12 p40. In mixed cell cultures with CD3-positive T cells, midazolam-treated DCs showed less propensity to stimulate the proliferation of CD3-positive T cells and the secretion of interferon-γ from CD4-positive T cells. Midazolam-treated DCs impaired the induction of contact-hypersensitivity response. Treatment with ligands for peripheral benzodiazepine receptor inhibited the up-regulation of CD80 during DC maturation. CONCLUSION: Midazolam inhibits the functional maturation of murine DCs and interferes with DC induction of T helper 1 immunity in the whole mouse. In addition, it appears that the immunomodulatory effect of midazolam is mediated via the action of midazolam on the peripheral benzodiazepine receptor.