Pharmacological Investigation of Hypoalbuminemia on the Prolonged and Potentiated Action of Midazolam in Rats.

Midazolam (MDZ) is clinically used for its sedative and anticonvulsant properties. However, its prolonged or potentiated effects are sometimes concerning. The main binding protein of MDZ is albumin, and reduced serum albumin levels could lead to MDZ accumulation, thereby potentiating or prolonging its effects. Previous investigations have not thoroughly examined these phenomena from a behavioral pharmacology standpoint. Consequently, this study aimed to evaluate both the prolonged and potentiated effects of MDZ, as well as the effects of serum albumin levels on the action of MDZ in low-albumin rats. Male Wistar rats were classified into control (20% protein diet), low-protein (5% protein), and non-protein groups (0% protein diet) and were fed the protein-controlled diets for 30 d to obtain low-albumin rats. The locomotor activity and muscle relaxant effects of MDZ were evaluated using the rotarod, grip strength, and open-field tests conducted 10, 60, and 120 min after MDZ administration. Serum albumin levels decreased significantly in the low-protein and non-protein diet groups compared with those in the control group. Compared with the control rats, low-albumin rats demonstrated a significantly shorter time to fall, decreased muscle strength, and a significant decrease in the distance traveled after MDZ administration in the rotarod, grip strength, and open-field tests, respectively. Decreased serum albumin levels potentiated and prolonged the effects of MDZ. Hence, serum albumin level is a critical parameter associated with MDZ administration, which should be monitored, and any side effects related to decreased albumin levels should be investigated.

Prostanoids Regulate Angiogenesis and Lymphangiogenesis in Pathological Conditions.

Angiogenesis, the formation of new blood vessels from the preexistent microvasculature, is an essential component of wound repair and tumor growth. Nonsteroidal anti-inflammatory drugs that suppress prostanoid biosynthesis are known to suppress the incidence and progression of malignancies including colorectal cancers, and also to delay the wound healing. However, the precise mechanisms are not fully elucidated. Accumulated results obtained from prostanoid receptor knockout mice indicate that a prostaglandin E-type receptor signaling EP3 in the host microenvironment is critical in tumor angiogenesis inducing vascular endothelial growth factor A (VEGF-A). Further, lymphangiogenesis was also enhanced by EP signaling via VEGF-C/D inductions in pathological settings. These indicate the importance of EP receptor to facilitate angiogenesis and lymphangiogenesis in vivo. Prostanoids act beyond their commonly understood activities in smooth muscle contraction and vasoactivity, both of which are quick responses elicited within several seconds on stimulations. Prostanoid receptor signaling will be a potential therapeutic target for disease conditions related to angiogenesis and lymphangiogenesis.

Dysphagia Rehabilitation in Dysphagic Patients with Acute or Critical Illness: A Systematic Review and Meta-Analysis.

Dysphagia or swallowing dysfunction is common in patients with acute or critical illness, and diverse methods of dysphagia rehabilitation are provided worldwide. We aimed to examine the efficacy of rehabilitation to treat dysphagia in patients with acute or critical illness. We searched PubMed, ICHUSHI, and Cochrane Central Register of Controlled Trials databases from inception to November 22, 2023 for relevant randomized controlled trials. We focused on dysphagic patients with acute or critical illness who were not orotracheally intubated. Our target intervention included conventional rehabilitation and nerve stimulation/neuromodulation techniques as dysphagia rehabilitation. Comparators were conventional or standard care or no dysphagia interventions. Primary outcomes included mortality, incidence of pneumonia during the study period, and health-related quality of life (HRQoL) scores within 90 days of hospital discharge. We pooled the data using a random-effects model, and classified the certainty of evidence based on the Grading of Recommendations, Assessment, Development, and Evaluation system. Nineteen randomized controlled trials involving 1,096 participants were included. Dysphagia rehabilitation was associated with a reduced incidence of pneumonia (risk ratio [RR], 0.66; 95% confidence interval [CI], 0.54-0.81; moderate certainty), but not with reduced mortality (RR, 0.92; 95% CI, 0.61-1.39; very low certainty) or improved HRQoL scores (mean difference, -0.20; 95% CI, -20.34 to 19.94; very low certainty). Based on the available moderate- or very low- quality evidence, while dysphagia rehabilitation had no impact on mortality or HRQoL, they might reduce the incidence of pneumonia in dysphagic patients with acute or critical illness.

The inter-laboratory validation study of EpiSensA for predicting skin sensitization potential.

The Epidermal Sensitization Assay (EpiSensA) is a reconstructed human epidermis (RhE)-based gene expression assay for predicting the skin sensitization potential of chemicals. Since the RhE model is covered by a stratified stratum corneum, various kinds of test chemicals, including lipophilic ones and pre-/pro-haptens, can be tested with a route of exposure akin to an in vivo assay and human exposure. This article presents the results of a formally managed validation study of the EpiSensA that was carried out by three participating laboratories. The purpose of this validation study was to assess transferability of the EpiSensA to new laboratories along with its within- (WLR) and between-laboratory reproducibility (BLR). The validation study was organized into two independent stages. As demonstrated during the first stage, where three sensitizers and one non-sensitizer were correctly predicted by all participating laboratories, the EpiSensA was successfully transferred to all three participating laboratories. For Phase I of the second stage, each participating laboratory performed three experiments with an identical set of 15 coded test chemicals resulting in WLR of 93.3%, 93.3%, and 86.7%, respectively. Furthermore, when the results from the 15 test chemicals were combined with those of the additional 12 chemicals tested in Phase II of the second stage, the BLR for 27 test chemicals was 88.9%. Moreover, the predictive capacity among the three laboratories showed 92.6% sensitivity, 63.0% specificity, 82.7% accuracy, and 77.8% balanced accuracy based on murine local lymph node assay (LLNA) results. Overall, this validation study concluded that EpiSensA is easily transferable and sufficiently robust for assessing the skin sensitization potential of chemicals.

Association Between Mobilization Level And Activity of Daily Living Independence in Critically Ill Patients.

OBJECTIVE: To examine the association between the mobilization level during intensive care unit (ICU) admission and independence in activity of daily living (ADL), defined as Barthel Index (BI)≥70. METHODS: This was a post-hoc analysis of the EMPICS study involving nine hospitals. Consecutive patients who spend >48 hours in the ICU were eligible for inclusion. Mobilization was performed at each hospital according to the shared protocol and the highest ICU mobility score (IMS) during the ICU stay, baseline characteristics, and BI at hospital discharge. Multiple logistic regression analysis, adjusted for baseline characteristics, was used to deter-mine the association between the highest IMS (using the receiver operating characteristic [ROC]) and ADL. RESULTS: Of the 203 patients, 143 were assigned to the ADL independence group and 60 to the ADL dependence group. The highest IMS score was significantly higher in the ADL independence group than in the dependence group and was a predictor of ADL independence at hospital discharge (odds ratio, 1.22; 95% confidence interval, 1.07-1.38; adjusted p=0.002). The ROC cutoff value for the highest IMS was 6 (specificity, 0.67; sensitivity, 0.70; area under the curve, 0.69). CONCLUSION: These results indicate that, in patients who were in the ICU for more than 48 hours, that patients with good function in the ICU also exhibit good function upon discharge. However, prospective, multicenter trials are needed to confirm this conclusion.

Rehabilitation contributes to lower readmission rates for individuals with peripheral arterial disease: A retrospective observational study.

BACKGROUND: Non-pharmacological interventions, such as rehabilitation, are crucial for the treatment of people with peripheral arterial disease (PAD). Although several studies have shown rehabilitation is effective in improving the functional prognosis of PAD, there is currently insufficient evidence regarding its effect on readmission rates. OBJECTIVES: To examine the impact of rehabilitation on readmission rates for people with PAD. METHODS: A retrospective analysis of the JMDC hospital database was performed on data from two groups of people aged ≥20 years who were hospitalized between 2014 and 2020 with PAD, as based on a previous diagnosis. Participants were divided according to whether they did, or did not, receive any form of rehabilitation as part of their treatment in hospital. The primary outcome was readmission rates at 30, 60, 90, and 180 days after initial admission. A one-to-one propensity score matching was used to compare readmission rates between rehabilitation and non-rehabilitation groups. RESULTS: We included 13,453 people with PAD, of whom 2701 pairs (5402 subjects) were selected after being matched in the rehabilitation and non-rehabilitation groups. The rehabilitation group participants had significantly lower mortality and readmission rates at 30, 60, 90, and 180 days. The odds ratios (95% confidence interval) for both groups were 0.79 (0.69-0.91; 30 days), 0.81 (0.71-0.91; 60 days), 0.78 (0.69-0.88; 90 days), and 0.79 (0.71-0.88; 180 days). CONCLUSIONS: This large, nationwide study found that rehabilitation treatment during hospitalization was associated with lower readmission rates and mortality for people following hospitalization with PAD and supports its inclusion as a standard PAD treatment.

Effects of Mobilization within 72 h of ICU Admission in Critically Ill Patients: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Previous systematic review and meta-analysis indicates that rehabilitation within a week of intensive care unit (ICU) admission benefits physical function in critically ill patients. This updated systematic review and meta-analysis aim to clarify effects of initiating rehabilitation within 72 h of ICU admission on long-term physical, cognitive, and mental health. We systematically searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for randomized controlled trials (RCTs) between April 2019 and November 2022 to add to the previous review. Two investigators independently selected and extracted data. Pooled effect estimates for muscle strength, cognitive function, mental health after discharge, and adverse events were calculated. Evidence certainty was assessed via Grading of Recommendations, Assessment, Development, and Evaluations. Eleven RCTs were included in the meta-analysis. Early rehabilitation may improve muscle strength (three trials; standard mean difference [SMD], 0.16; 95% confidence interval [CI], -0.04-0.36) and cognitive function (two trials; SMD, 0.54; 95% CI, -0.13-1.20). Contrastingly, early mobilization showed limited impact on mental health or adverse events. In summary, initiating rehabilitation for critically ill patients within 72 h may improve physical and cognitive function to prevent post-intensive care syndrome without increasing adverse events. The effect on mental function remains uncertain.

Reliability and Effectiveness of the Japanese Version of the Mobilization Quantification Score.

Background The mobilization quantification score (MQS) provides an opportunity to quantify the duration and intensity of mobilization therapy in the intensive care unit (ICU) and predict functional outcomes in ICU patients after surgery and stroke. MQS is a numerical measurement of early mobilization dose in the ICU, and its relationship with activities of daily living (ADL) dependence has been shown. We created and validated the Japanese version of the MQS using the endpoint ADL in a mixed population of patients in the ICU. Materials and methods In this prospective study, consecutive patients who were admitted to one of three ICUs of a tertiary care hospital in Japan, aged ≥18 years, and who received mechanical ventilation for >48 hours were enrolled. The Japanese version of the MQS was applied twice daily by an ICU physiotherapist and data recorded for analysis. The primary outcome was ADL dependence at hospital discharge, defined as a Barthel index (BI) of <70 or in-hospital death. The reliability among assessors was verified by calculating the interclass correlation coefficient (ICC) (2.1) for the average daily MQS. We performed a multiple logistic regression analysis to examine and identify a binary cutoff point for high-/low-dose rehabilitation. Results Of the 340 target patients, eight were aged <18 years, 109 had neurological complications, 11 had a BI <70 before admission, 79 had a lack of communication skills, 16 were terminally ill, eight did not complete the assessment during their ICU stay, 18 died in the ICU, and 53 denied consent. After 302 patients were excluded, 38 were included in the study. Six assessors, two at each hospital, measured the MQS in 38 patients. The ICC (2.1) for the MQS mean value was 0.98 (0.96-0.99) during the ICU stay. Logistic regression analysis using the mean MQS on admission to ICUs as an explanatory variable showed a significant association between increased MQS and decreased ADL dependence at discharge (odds ratio (OR): 0.76, confidence interval (CI): 0.61-0.96, adjusted p = 0.009). Logistic regression analysis using a high MQS on admission to ICUs as an explanatory variable showed a significant association between increased MQS and decreased ADL dependence at hospital discharge (OR: 0.14, CI: 0.03-0.66, adjusted p = 0.013). Conclusions We present a validated version of the Japanese MQS with a high inter-rater reliability that predicts ADL dependence at hospital discharge. The instrument can be used in future clinical trials in the ICU to control for the mobilization level in the ICU. The increased utilization of mobilization acutely in the ICU setting as quantified by the MQS may improve patient outcomes.

Impact of Extra-Corporeal Membrane Oxygenation and Blood Purification Therapy on Early Mobilization in the Intensive Care Unit: Retrospective Cohort Study.

OBJECTIVE: To investigate the effect on early mobilization in patients undergoing extra-corporeal membrane oxygenation (ECMO) and acute blood purification therapy in the intensive care unit (ICU). METHODS: We conducted this multicenter retrospective cohort study by collecting data from six ICUs in Japan. Consecutive patients who were admitted to the ICU, aged ≥18 years, and received mechanical ventilation for >48 hours were eligible. The analyzed were divided into two groups: ECMO/blood purification or control group. Clinical outcomes; time to first mobilization, number of total ICU rehabilitations, mean and highest ICU mobility scale (IMS); and daily barrier changes were also investigated. RESULTS: A total of 204 patients were included in the analysis, 43 in the ECMO/blood purification group and 161 in the control group. In comparison of clinical outcome, the ECMO/blood purification group had a significantly longer time to first mobilization: ECMO/blood purification group 6 vs. control group 4 (p=0.003), higher number of total ICU rehabilitations: 6 vs. 5 (p=0.042), lower mean: 0 vs. 1 (p=0.043) and highest IMS: 2 vs. 3 (p=0.039) during ICU stay. Circulatory factor were most frequently described as barriers to early mobilization on days 1 (51%), 2 (47%), and 3 (26%). On days 4 to 7, the most frequently described barrier was consciousness factors (21%, 16%, 19%, and 21%, respectively). CONCLUSION: The results of this study comparing the ECMO/blood purification group and the untreated group in the ICU showed that the ECMO/blood purification group had significantly longer days to mobilization and significantly lower mean and highest IMS.

Current Practice and Barriers to the Implementation of Mobilization in ICUs in Japan: A Multicenter Prospective Cohort Study.

Background: Limited information is currently available on the barriers to implementing mobilization at the bedside for critically ill patients. Therefore, we investigated the current practice of and barriers to the implementation of mobilization in intensive care units (ICU). Methods: A multicenter prospective observational study was conducted at nine hospitals between June 2019 and December 2019. Consecutive patients admitted to the ICU for more than 48 h were enrolled. Quantitative data were analyzed descriptively, and qualitative data were analyzed thematically. Results: The 203 patients enrolled in the present study were divided into 69 elective surgical patients and 134 unplanned admission patients. The mean periods of time until the initiation of rehabilitation programs after ICU admission were 2.9 ± 7.7 and 1.7 ± 2.0 days, respectively. Median ICU mobility scales were five (Interquartile range: three and eight) and six (Interquartile range: three and nine), respectively. The most common barriers to mobilization in the ICU were circulatory instability (29.9%) and a physician's order for postoperative bed rest (23.4%) in the unplanned admission and elective surgery groups, respectively. Conclusions: Rehabilitation programs were initiated later for unplanned admission patients and were less intense than those for elective surgical patients, irrespective of the time after ICU admission.

Association of early oral intake after extubation and independent activities of daily living at discharge among intensive care unit patients: A single centre retrospective cohort study.

PURPOSE: We investigated the association between the time to first post-extubation oral intake, barriers to oral intake, and the rate of activities of daily living (ADL) independence at discharge (Barthel Index score <70). METHOD: Consecutive patients admitted to the intensive care unit, aged ≥18 years, and mechanically ventilated for ≥48 hr were retrospectively enrolled. The time to first oral intake, barriers to oral intake, daily changes, and clinical outcomes were assessed. Multiple logistic regression analysis adjusted for baseline characteristics was used to determine the association between time to first post-extubation oral intake and ADL independence. RESULT: Among the 136 patients, 74 were assigned to the ADL independence group and 62 to the dependence group. The time to first post-extubation oral intake was significantly associated with ADL independence (adjusted p = < 0.001) and was a predictor of ADL independence at discharge. Respiratory and dysphagia-related factors (odds ratio [OR] 0.35; 95% confidence interval [CI] 0.15-0.82, p = 0.015 and OR 0.07; CI 0.01-0.68, p = 0.021, respectively) were significantly associated with the ADL independence at discharge. CONCLUSION: Respiratory and dysphagia-related factors, as barriers to the initiation of oral intake after extubation, were significantly associated with ADL independence at discharge.

A biologically active lipid, thromboxane, as a regulator of angiogenesis and lymphangiogenesis.

Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target.

Effect of Neuromuscular Electrical Stimulation in Patients With Critical Illness: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Neuromuscular electrical stimulation (NMES) is used in the rehabilitation of patients with critical illness. However, it is unclear whether NMES prevents ICU-acquired weakness (ICU-AW). For this purpose, we conducted an updated systematic review and meta-analysis. DATA SOURCES: We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases from April 2019 to November 2022 to identify new randomized controlled trials to the previous meta-analysis. STUDY SELECTION: We systematically searched the literature for all randomized controlled trials on the effect of NMES in patients with critical illness. DATA EXTRACTION: Two authors independently selected the studies and extracted data. They calculated the pooled effect estimates associated with the occurrence of ICU-AW and adverse events as primary outcomes and muscle mass change, muscle strength, length of ICU stay, mortality, and quality of life as secondary outcomes. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: Overall, eight studies were added to the previous 10 studies. Evidence suggests that the use of NMES reduces the occurrence of ICU-AW (six trials; risk ratio [RR], 0.48; 95% CI, 0.32-0.72); however, NMES may have little to no effect on pricking sensation in patients (eight trials; RR, 6.87; 95% CI, 0.84-56.50). NMES is likely to reduce the change in muscle mass (four trials; mean difference, -10.01; 95% CI, -15.54 to -4.48) and may increase muscle strength (six trials; standardized mean difference, 0.43; 95% CI, 0.19-0.68). Further, NMES may result in little to no difference in the length of ICU stay, and the evidence is uncertain about the effect on mortality and quality of life. CONCLUSIONS: This updated meta-analysis revealed that the use of NMES may result in a lower occurrence of ICU-AW in patients with critical illness, but its use may have little to no effect on pricking sensation in patients.

Hospital pharmacist interventions for the management of oral mucositis in patients with head and neck cancer receiving chemoradiotherapy: a multicenter, prospective cohort study.

PURPOSE: Oral mucositis is a severe adverse event in patients with head and neck cancer (HNC) receiving chemotherapy and radiotherapy that may cause the termination of cancer treatment. In this study, we aimed to reveal the benefits of pharmacist interventions in oral health care for patients with HNC receiving concurrent chemoradiotherapy (CCRT). METHODS: We conducted a multicenter, prospective cohort study on 173 patients from September 2019 to August 2022. We evaluated the association between the occurrence of oral mucositis during CCRT and various factors in the absence or presence of direct medication instructions from hospital pharmacists. RESULTS: Sixty-eight patients received medication instructions from pharmacists (the pharmacist intervention group), whereas 105 patients did not receive instructions (the control group). Logistic regression analysis showed that grade 2 (Gr 2) oral mucositis was significantly lower in patients receiving pharmacist interventions than in patients in the control group (adjusted odds ratio [aOR], 0.42; 95% confidence interval [CI], 0.18-0.96; P = 0.04). The time to onset of Gr 2 oral mucositis was significantly longer in the pharmacist intervention group than in the control group (hazard ratio, 0.53; 95% CI, 0.29-0.97; P = 0.04). CONCLUSION: Direct intervention, especially when provided by hospital pharmacists, can have a real effect in supporting patients with HNC experiencing severe side effects of treatments. Moreover, the integration of pharmacists into the oral healthcare team is becoming even more essential to reduce the severity of side effects.

Relationship between grip strength during hospitalisation and mental disorders after discharge in critically ill patients: a post-hoc analysis of a prospective observational study.

OBJECTIVES: Post-intensive care syndrome (PICS) is a recognised sequela after critical care. The development of an index that predicts PICS mental disorders will be of significance for the selection of subsequent interventions. The purpose of this study was to find factors associated with PICS mental disorders. We hypothesised that grip strength during hospitalisation may be associated with the PICS mental status after discharge. DESIGN: A post-hoc analysis of a multicentre prospective observational study. SETTING: Nine hospitals in Japan. PARTICIPANTS: Patients who were newly admitted to intensive care unit and stayed for at least 48 hours were included. Exclusion criteria were patients younger than 18 years, those who required assistance with ambulation prior to admission, those with concomitant central nervous system disorders and those with terminal conditions. PRIMARY AND SECONDARY OUTCOME MEASURES: Psychiatric symptoms 3 months after discharge were assessed using the Hospital Anxiety and Depression Scale (HADS). The HADS total score (HADS-total) was assigned as the primary outcome. RESULTS: 98 patients were included into this study. Grip strength at discharge negatively correlated with HADS-total 3 months after discharge (r=-0.37, p<0.001, 95% CI -0.53 to -0.18). A multivariate analysis showed that grip strength was associated with anxiety (p=0.025, 95% CI -0.21 to -0.015). Area under the curve for HADS anxiety score with grip strength at discharge was higher than that with Medical Research Council scores and the Barthel Index (0.71, 0.60, 0.61). CONCLUSIONS: Grip strength at discharge correlated with mental disorders 3 months after discharge. Therefore, it may be useful for predicting postdischarge mental disorders. TRIAL REGISTRATION NUMBER: UMIN000036503.

Association Between Intensive Care Unit-Acquired Weakness and Early Nutrition and Rehabilitation Intensity in Mechanically Ventilated Patients: A Multicenter Retrospective Observational Study.

BACKGROUND: Muscle weakness in the intensive care unit (ICU), referred to as ICU-acquired weakness (ICUAW), is a common complication observed in patients receiving mechanical ventilation. This study aimed to investigate whether rehabilitation intensity and nutrition during ICU admission are associated with the incidence of ICUAW. MATERIALS AND METHODS: Consecutive patients aged ≥18 years who were admitted to the ICU between April 2019 and March 2020 and who received mechanical ventilation for >48 h were eligible. The included patients were divided into two groups: the ICUAW group and the non-ICUAW group. ICUAW was designated by a Medical Research Council score of less than 48 during discharge from the ICU. Patient characteristics, time to achieve ICU mobility scale (IMS) 1 and IMS 3, calorie and protein deliveries, and blood creatinine and creatine kinase levels were evaluated as study data. In this study, the target dose for the first week after admission to the ICU at each hospital was set at 60-70% of the energy requirement calculated by the Harris-Benedict formula. Univariate and multivariate analyses were used to determine the odds ratios (OR) for each factor and to explain the risk factors for the occurrence of ICUAW at ICU discharge. RESULTS: During the study period, 206 patients were enrolled; 62 of the 143 included patients (43%) had ICUAW. The results of multivariate regression analysis showed that low time to IMS 3 achievement (OR 1.19, 95% confidence interval (CI) 1.01-1.42, p=0.033), and high mean calorie (OR 0.83, 95% CI 0.75-0.93, p<0.001) and protein deliveries (OR 0.27, 95% CI 0.13-0.56, p<0.001) were independently associated with the occurrence of ICUAW. CONCLUSIONS: Increase in rehabilitation intensity and mean calorie and protein deliveries were associated with a decrease in the occurrence of ICUAW at ICU discharge. Further research is required to validate our results. Our observations, increasing the intensity of physical rehabilitation and the average calorie and protein delivery levels during ICU stay, appear to be the preferred strategies for achieving non-ICUAW.

Association between the early mobilization of mechanically ventilated patients and independence in activities of daily living at hospital discharge.

Physical dysfunction after discharge from the intensive care unit (ICU) is recognized as a common complication among ICU patients. Early mobilization (EM), defined as the ability to sit on the edge of the bed within 5 days, may help improve physical dysfunction. However, the barriers to, and achievement of, EM and their impact on physical dysfunction have not been fully investigated. This study aimed to investigate the achievement of EM and barriers to it and their impact on patient outcomes in mechanically ventilated ICU patients. We conducted this multicenter retrospective cohort study by collecting data from six ICUs in Japan. Consecutive patients who were admitted to the ICU between April 2019 and March 2020, were aged ≥ 18 years, and received mechanical ventilation for > 48 h were eligible. The primary outcome was the rate of independent activities of daily living (ADL), defined as a score ≥ 70 on the Barthel index at hospital discharge. Daily changes in barriers of mobilization, including consciousness, respiratory, circulatory, medical staff factors, and device factors (catheter, drain, and dialysis), along with the clinical outcomes were investigated. The association among barriers, mobilization, and Barthel index ≥ 70 was analyzed using multivariable logistic regression analysis. During the study period, 206 patients were enrolled. EM was achieved in 116 patients (68%) on the fifth ICU day. The primary outcome revealed that achieving EM was associated with a Barthel index ≥ 70 at hospital discharge [adjusted odds ratio (AOR), 3.44; 95% confidence interval (CI), 1.70-6.96]. Device factors (AOR, 0.31; 95% CI, 0.13-0.75, respectively) were significantly associated with EM achievement. EM was associated with independent ADL at hospital discharge. Time to first mobilization and barriers to achieving mobilization can be important parameters for achieving ADL independence at discharge. Further research is required to determine the most common barriers so that they can be identified and removed.

The effect of early irregular cell division of human embryos on blastocyst euploidy: considerations from the subsequent development of the blastomeres by direct or reverse cleavage.

OBJECTIVE: To investigate whether blastocysts that divide irregularly reduce subsequent blastocyst euploidy. DESIGN: Retrospective study. SETTING: Private clinic. PATIENT(S): A total of 122 blastocysts for which consent for disposal and research use was obtained. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Results of next-generation sequencing analysis of the blastocysts and whether blastomeres by normal or irregular divisions subsequently participated in blastocyst formation or not. RESULT(S): The embryos were classified according to their dynamics until the second cleavage. The blastocyst euploidy rates were 33.3% (19/57) in the normal cleavage (NC) group, 38.3% (18/47) in the direct cleavage (embryos with one cell dividing into 3 cells) (DC) group, and 72.2% (13/18) in the reverse cleavage (RC) (embryos with fused cells once divided) group. The rate of the RC group was significantly higher than that of the NC group. The blastocyst participation rate of the blastomeres were 95.6% in the NC group and 56.5% in that derived from DC of the first cleavage, and 91.7% in that of blastomeres derived from normal division of the second cleavage and 53.6% in that derived from DC of the second cleavage, both of which were significantly lower in the latter. In the RC group, the rates of fused and nonfused blastomeres were 62.1% and 87.5%, respectively, with no significant difference. CONCLUSION(S): The blastomeres generated by DC were often excluded from blastocyst formation, and we speculate that this is one reason why their division does not reduce blastocyst euploidy. The association between RC and euploidy of blastocysts merits further study.

Development of an oral mucosal irritation test using a three-dimensional human buccal oral mucosal model.

The oral mucosa can become irritated by oral care products and lip cosmetics. Therefore, it is important to determine the irritation potential of their ingredients and products during safety evaluations. We developed a method for oral mucosal irritation test using EpiOral, which is a three-dimensional cultured model. Exposure of sodium lauryl sulphate (SLS) to EpiOral showed a dose-dependent decrease in cell viability. Under 120 min exposure conditions, SLS irritation was detected when 60% cell viability was set as a criterion. Evaluation of the irritancy of SLS and four other raw materials used in oral products at three laboratories under the above conditions confirmed good transferability of the test. Focused on the similarity of the oral and eye mucous, 32 chemicals categorised by the UN-GHS eye-irritation classification were evaluated to ensure the reliability of our criteria at these laboratories. The concordance rate between the UN-GHS classification and our test results was 100% for irritants and 60% for non-irritants. The good intra-laboratory reproducibility of our test was confirmed from the evaluation results of negative and positive controls, and the good inter-laboratory reproducibility was confirmed from the results of 32 chemicals. These findings showed that oral mucosal irritation can be evaluated using EpiOral.