Search

Summary: Background & Aims: Branched-chain amino acids (BCAAs), and the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent physical decline in older people. However, their combined effect on physical function in heart failure (HF) is unclear. This study aimed to investigate the association of BCAAs and EPA/DHA with exercise tolerance in people with HF. Methods: In total, 124 patients with HF were prospectively enrolled, and their serum BCAA and EPA/DHA levels, dietary pattern, and 6-minute walking distance (6-MWD) were assessed. Results: Lower 6-MWD quantiles contained more female patients than higher 6-MWD quantiles. Patients with a shorter 6-MWD were older and had a smaller leg circumference, higher B-type natriuretic peptide concentrations, and lower BCAA and EPA/DHA levels than those with longer 6-MWD (all P < 0.05). Patients with a shorter 6-MWD had an imbalanced dietary pattern with low intakes of oily fish, soy products, and vegetables. Meanwhile, their estimated nutrient intakes were high in saturated fatty acids and sucrose and low in polyunsaturated fatty acids and dietary fiber (all P < 0.05). According to multivariate analysis, low EPA/DHA concentrations (per 50 μg/mL decrease) [odds ratio, 95% confidence interval: 1.479 (1.025–2.137)], low dietary fiber intake (per 1 g/1000kcal decrease) [1.524 (1.098–2.119)], and high sucrose intake (per 1 g/1000kcal increase) [1.170 (1.040–1.310)] were independently associated with short 6-MWD (the lowest quantile of 6-MWD,

Summary: Background and aims: Muscle mass is an important component of nutritional status. At intensive care unit (ICU) admission, ultrasound is an important tool to assess the muscle mass, but there are currently no established cut-off values. Therefore, we retrospectively analyzed cut-off values for an ultrasound-based muscle mass assessment at ICU admission. Methods: We retrospectively analyzed data collected in an observational study. These data included a muscle mass assessment of lower limb thickness and cross-sectional area (CSA), upper limb thickness and CSA, and diaphragm thickness at ICU admission. Skeletal muscle mass was calculated from computed tomography (CT) imaging of the third lumbar vertebra for comparison. Cut-off values were estimated from the relationship between the ultrasound-based muscle mass assessment and CT-derived skeletal muscle index at 7.0 kg/m2 in males and 5.4 kg/m2 in females. Results: Lower limb, upper limb, and diaphragm assessments included 89, 52, and 79 patients, respectively. The age was 70 ± 13 years and body mass index was 22.2 ± 4.4 kg/m2. Cut-off values were 22.5 mm (male) and 19.0 mm (female) for femoral thickness and 5.0 cm2 (male) and 4.5 cm2 (female) for rectus femoris CSA. Cut-off values were 26.9mm (male) and 20.6 mm (female) for upper limb thickness and 6.5 cm2 (male) and 4.0 cm2 (female) for biceps brachii CSA. Cut-off values were 1.8 mm (male) and 1.5 mm (female) for diaphragm. Conclusion: We proposed cut-off values for ultrasound-based muscle mass assessment at ICU admission. Further studies are needed to validate these cut-off values.

Abstract Background X‐linked dystrophin‐deficient muscular dystrophy (MD) is a form of MD caused by variants in the DMD gene. It is a fatal disease characterized by progressive weakness and degeneration of skeletal muscles. Hypothesis/Objectives Identify deleterious genetic variants in DMD by whole‐genome sequencing (WGS) using a next‐generation sequencer. Animals One MD‐affected cat, its parents, and 354 cats from a breeding colony. Methods We compared the WGS data of the affected cat with data available in the National Center for Biotechnology Information database and searched for candidate high‐impact variants by in silico analyses. Next, we confirmed the candidate variants by Sanger sequencing using samples from the parents and cats from the breeding colony. We used 2 genome assemblies, the standard felCat9 (from an Abyssinian cat) and the novel AnAms1.0 (from an American Shorthair cat), to evaluate genome assembly differences. Results We found 2 novel high‐impact variants: a 1‐bp deletion in felCat9 and an identical nonsense variant in felCat9 and AnAms1.0. Whole genome and Sanger sequencing validation showed that the deletion in felCat9 was a false positive because of misassembly. Among the 357 cats, the nonsense variant was only found in the affected cat, which indicated it was a de novo variant. Conclusion and Clinical Importance We identified a de novo variant in the affected cat and next‐generation sequencing‐based genotyping of the whole DMD gene was determined to be necessary for affected cats because the parents of the affected cat did not have the risk variant.

Abstract Background As advancements in critical care medicine continue to improve Intensive Care Unit (ICU) survival rates, clinical and research attention is urgently shifting toward improving the quality of survival. Post-Intensive Care Syndrome (PICS) is a complex constellation of physical, cognitive, and mental dysfunctions that severely impact patients’ lives after hospital discharge. This review provides a comprehensive and multi-dimensional summary of the current evidence and practice of exercise therapy (ET) during and after an ICU admission to prevent and manage the various domains of PICS. The review aims to elucidate the evidence of the mechanisms and effects of ET in ICU rehabilitation and highlight that suboptimal clinical and functional outcomes of ICU patients is a growing public health concern that needs to be urgently addressed. Main body This review commences with a brief overview of the current relationship between PICS and ET, describing the latest research on this topic. It subsequently summarises the use of ET in ICU, hospital wards, and post-hospital discharge, illuminating the problematic transition between these settings. The following chapters focus on the effects of ET on physical, cognitive, and mental function, detailing the multi-faceted biological and pathophysiological mechanisms of dysfunctions and the benefits of ET in all three domains. This is followed by a chapter focusing on co-interventions and how to maximise and enhance the effect of ET, outlining practical strategies for how to optimise the effectiveness of ET. The review next describes several emerging technologies that have been introduced/suggested to augment and support the provision of ET during and after ICU admission. Lastly, the review discusses future research directions. Conclusion PICS is a growing global healthcare concern. This review aims to guide clinicians, researchers, policymakers, and healthcare providers in utilising ET as a therapeutic and preventive measure for patients during and after an ICU admission to address this problem. An improved understanding of the effectiveness of ET and the clinical and research gaps that needs to be urgently addressed will greatly assist clinicians in their efforts to rehabilitate ICU survivors, improving patients’ quality of survival and helping them return to their normal lives after hospital discharge.

Abstract Background Post-intensive care syndrome (PICS) is the long-lasting impairment of physical functions, cognitive functions, and mental health after intensive care. Although a long-term follow-up is essential for the successful management of PICS, few reviews have summarized evidence for the efficacy and management of the PICS follow-up system. Main text The PICS follow-up system includes a PICS follow-up clinic, home visitations, telephone or mail follow-ups, and telemedicine. The first PICS follow-up clinic was established in the U.K. in 1993 and its use spread thereafter. There are currently no consistent findings on the efficacy of PICS follow-up clinics. Under recent evidence and recommendations, attendance at a PICS follow-up clinic needs to start within three months after hospital discharge. A multidisciplinary team approach is important for the treatment of PICS from various aspects of impairments, including the nutritional status. We classified face-to-face and telephone-based assessments for a PICS follow-up from recent recommendations. Recent findings on medications, rehabilitation, and nutrition for the treatment of PICS were summarized. Conclusions This narrative review aimed to summarize the PICS follow-up system after hospital discharge and provide a comprehensive approach for the prevention and treatment of PICS.

Deep learning has achieved efficient success in the field of machine learning, made possible by the emergence of efficient optimization methods such as Stochastic Gradient Descent (SGD) and its variants. Simultaneously, the Information Bottleneck theory (IB) has been studied to train neural networks, aiming to enhance the performance of optimization methods. However, previous works have focused on their specific tasks, and the effect of the IB theory on general deep learning tasks is still unclear. In this study, we introduce a new method inspired by the proximal operator, which sequentially updates the neural network parameters based on the defined bottleneck features between the forward and backward networks. Unlike the conventional proximal-based methods, we consider the second-order gradients of the objective function to achieve better updates for the forward networks. In contrast to SGD-based methods, our approach involves accessing the network’s black box, and incorporating the bottleneck feature update process into the parameter update process. This way, from the perspective of the IB theory, the data is well compressed up to the bottleneck feature, ensuring that the compressed information maintains sufficient mutual information up to the final output. To demonstrate the performance of the proposed approach, we applied the method to various optimizers with several tasks and analyzed the results by training on both the MNIST dataset and CIFAR-10 dataset. We also conducted several ablation studies by modifying the components of the proposed algorithm to further validate its performance.

Echinococcus multilocularis is a cestode that causes human alveolar echinococcosis, a lethal zoonotic disease distributed in the northern hemisphere. The life cycle of this parasite is maintained in nature by voles as intermediate hosts and foxes as definitive hosts in Hokkaido, Japan. Although dogs are also susceptible to the parasite, the infection has been considered typically asymptomatic. We report the detection of E. multilocularis eggs in the diarrheal feces of a dog with chronic gastrointestinal signs, which disappeared after anthelmintic treatment. The mitochondrial genome sequence constructed by sequencing of the overlapping PCRs using DNA from the eggs was identical to the most predominant haplotype previously reported in red foxes in Hokkaido. This case highlights that Echinococcus infection should be considered as a differential diagnosis for diarrheal dogs in the disease endemic areas. Further efforts are needed to accumulate parasite genotypes in domestic dogs as well as humans to assess the risk of human infection from dogs.

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

BackgroundMechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention.MethodsA randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors.ResultsForty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25).ConclusionIn ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.

Abstract Background Canine hepatocellular tumours (HCTs) are common primary liver tumours. However, the exact mechanisms of tumourigenesis remain unclear. Although some genetic mutations have been reported, DNA methylation alterations in canine HCT have not been well studied. Objectives In this study, we aimed to analyse the DNA methylation status of canine HCT. Methods Tissues from 33 hepatocellular carcinomas, 3 hepatocellular adenomas, 1 nodular hyperplasia, 21 non‐tumour livers from the patients and normal livers from 5 healthy dogs were used. We analysed the DNA methylation levels of 72,367 cytosine–guanine dinucleotides (CpG sites) in all 63 samples. Results and conclusions Although a large fraction of CpG sites that were highly methylated in the normal liver became hypomethylated in tumours from most patients, we also found some patients with less remarkable change or no change in DNA methylation. Hierarchical clustering analysis revealed that 32 of 37 tumour samples differed from normal livers, although the remaining 5 tumour livers fell into the same cluster as normal livers. In addition, the number of hypermethylated genes in tumour livers varied among tumour cases, suggesting various DNA methylation patterns in different tumour groups. However, patient and clinical parameters, such as age, were not associated with DNA methylation status. In conclusion, we found that HCTs undergo aberrant and diverse patterns of genome‐wide DNA methylation compared with normal liver tissue, suggesting a complex epigenetic mechanism in canine HCT.

Abstract Background Vasopressin is a second-line vasoactive agent for refractory septic shock. Vasopressin loading is not generally performed because of the lack of evidence for its effects and safety. However, based on our previous findings, we hypothesized it can predict the responsibility to vasopressin infusion with safety, and prospectively examined it in the present study. Methods Vasopressin loading was performed via the intravenous administration of a bolus of 1 U, followed by its continuous infusion at 1U/h in patients with septic shock treated with ≥ 0.2 μg/kg/min noradrenaline. An arterial pressure wave analysis was conducted, and endocrinological tests were performed immediately prior to vasopressin loading. We classified patients into responders/non-responders based on mean arterial pressure (MAP) changes after vasopressin loading. Based on our previous findings, the lower tertile of MAP changes was selected as the cut-off. The change in the catecholamine index (CAI) after 6 h was assigned as the primary outcome. Digital ischemia, mesenteric ischemia, and myocardial ischemia during the admission period were prospectively and systematically recorded as adverse events. Results Ninety-two patients were registered during the study period and examined. Sixty-two patients with a MAP change > 22 mmHg were assigned as responders and the others as non-responders. Blood adrenocorticotropic hormone levels were significantly higher in non-responders. Stroke volume variations were higher in responders before loading, while stroke volume and dP/dtmax were higher in responders after loading. Median CAI changes were − 10 in responders and 0 in non-responders, which was significantly lower in the former (p

Background: The utility of using indirect calorimetry (IC) to estimate energy needs and methods for its application to this purpose remain unclear. This systematic review investigated whether using IC to estimate energy expenditure in critically ill patients is more meaningful for improving survival than other estimation methods. Methods: Comprehensive searches were conducted in MEDLINE using PubMed, Cochrane Central Register of Controlled Trials, and Igaku-Chuo-Zasshi up to March 2023. Results: Nine RCTs involving 1178 patients were included in the meta-analysis. The evidence obtained suggested that energy delivery by IC improved short-term mortality (risk ratio, 0.86; 95% confidence interval [CI], 0.70 to 1.06). However, the use of IC did not appear to affect the length of ICU stay (mean difference [MD], 0.86; 95% CI, −0.98 to 2.70) or the duration of mechanical ventilation (MD, 0.66; 95% CI, −0.39 to 1.72). Post hoc analyses using short-term mortality as the outcome found no significant difference by target calories in resting energy expenditure, whereas more frequent IC estimates were associated with lower short-term mortality and were more effective in mechanically ventilated patients. Conclusions: This updated meta-analysis revealed that the use of IC may improve short-term mortality in patients with critical illness and did not increase adverse events.

Abstract Mutations in activin receptor-like kinase 2 (ALK2) can cause the pathological osteogenic signaling seen in some patients with fibrodysplasia ossificans progressiva and other conditions such as diffuse intrinsic pontine glioma. Here, we report that intracellular domain of wild-type ALK2 readily dimerizes in response to BMP7 binding to drive osteogenic signaling. This osteogenic signaling is pathologically triggered by heterotetramers of type II receptor kinases and ALK2 mutant forms, which form intracellular domain dimers in response to activin A binding. We develop a blocking monoclonal antibody, Rm0443, that can suppress ALK2 signaling. We solve the crystal structure of the ALK2 extracellular domain complex with a Fab fragment of Rm0443 and show that Rm0443 induces dimerization of ALK2 extracellular domains in a back-to-back orientation on the cell membrane by binding the residues H64 and F63 on opposite faces of the ligand-binding site. Rm0443 could prevent heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva that carries the human R206H pathogenic mutant.

Case summary An 8-year-old neutered male domestic shorthair indoor cat was presented with an 8-week history of intermittent vomiting, anorexia and weight loss that had been unresponsive to supportive treatment. Abdominal ultrasound revealed plication of the small intestine and fluid accumulation proximal to the lesion, and a linear foreign body was suspected. An exploratory celiotomy showed cocoon-like encapsulation of the entire intestine. Surgical adhesiolysis and full-thickness biopsy were performed, and histopathologic examination revealed mild thickening of the visceral peritoneum with fibrin deposition, as well as mild neutrophil and lymphocyte infiltration. These findings were compatible with sclerosing encapsulating peritonitis (SEP). The cat recovered well postoperatively and was discharged the next day. Prednisolone was administered for 7 weeks to prevent recurrence of SEP. Five months after surgery, the cat was re-presented with anorexia and chronic vomiting. Based on the clinical examination findings, recurrent SEP was suspected. At the second surgery, surgical adhesiolysis was repeated and a bioresorbable hyaluronate-carboxymethylcellulose membrane was used to cover the serosal surface and thus prevent adhesion formation. Histopathologic findings of the peritoneal biopsy specimen confirmed SEP. Long-term prednisolone treatment (1 mg/kg for the first dose and 0.5 mg/kg every 48 h for maintenance) was administered postoperatively. The cat survived for more than 1239 days without recurrence. Relevance and novel information To our knowledge, this is the first report of SEP in a cat with long-term survival. The use of a bioresorbable hyaluronate-carboxymethylcellulose membrane and long-term prednisolone treatment may have prevented short-term and long-term recurrence, respectively, in this case.

Continual learning aims to enable neural networks to learn new tasks without catastrophic forgetting of previously learned knowledge. Orthogonal Gradient Descent algorithms have been proposed as an effective solution to mitigate catastrophic forgetting. However, these algorithms often rely on the Neural Tangent Kernel regime, which imposes limitations on network architecture. In this study, we propose a novel method to construct an orthonormal basis set for orthogonal projection by leveraging Catastrophic Forgetting Loss. In contrast to the conventional gradient-based basis that reflects an update of model within an infinitesimal range, our loss-based basis can account for the variance within two distinct points in the model parameter space, thus overcoming the limitations of the Neural Tangent Kernel regime. We provide both quantitative and qualitative analysis of the proposed method, discussing its advantages over conventional gradient-based baselines. Our approach is extensively evaluated on various model architectures and datasets, demonstrating a significant performance advantage, especially for deep or narrow networks where the Neural Tangent Kernel regime is violated. Furthermore, we offer a mathematical analysis based on higher-order Taylor series to provide theoretical justification. This study introduces a novel theoretical framework and a practical algorithm, potentially inspiring further research in areas such as continual learning, network debugging, and one-pass learning.

Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. In vitro experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of TG suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that TG expression together with two NF-κB targets, IL6 and CCL2, was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP.

Abstract Aims The aim of this study was to compare the diagnostic performance of the nutritional indicators, the mini nutritional assessment‐short form (MNA‐SF), the geriatric nutritional risk index (GNRI), and the controlling nutritional status (CONUT), in heart failure (HF) patients. Methods and results Nutritional status was prospectively assessed by the aforementioned three nutritional indicators in 150 outpatients with HF who were then followed for 1 year. The prevalence of patients with the nutritional risk as assessed by the MNA‐SF, GNRI, and CONUT scores was 50.0%, 13.3%, and 54.0%, respectively. There was slight agreement of nutritional risk assessment between the MNA‐SF and GNRI scores (κ coefficient = 0.16), as well as the GNRI and CONUT scores (κ = 0.11), but poor agreement between the MNA‐SF and CONUT scores (κ = −0.09). The CONUT score had the lowest area under the curve (AUC) for the identification of low body weight, low muscle mass, and low physical function among the three indicators (all P

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

Abstract Aims Increased left ventricular mass index (LVMI) disproportionate to electrocardiographic QRS voltage has been reported to be associated with cardiac fibrosis and amyloid infiltration to myocardium. This study aimed to assess whether the LVMI‐to‐QRS‐voltage ratio predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF). Methods and results The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of Japanese patients hospitalized with HFpEF (EF ≥ 50%). LVMI was assessed by echocardiography using the cube formula. QRS voltage was assessed by Sokolow–Lyon voltage criteria. We divided 290 patients in the registry who met inclusion criteria into five groups according to the quintile values of their LVMI‐to‐QRS‐voltage ratio. In the highest quintile group (≥71.8 g/m2/mV), approximately 50% of the patients had concentric hypertrophy and 30% had eccentric hypertrophy. These patients had the highest proportion of atrial fibrillation (61.4%) and history of pacemaker implantation (12.1%) among the five groups (P

Abstract Aim To investigate the association between comorbid mental illness and preceding emergency department (ED) visits in patients with unplanned admission. Methods This is a retrospective observational study using data from the EDs of three large tertiary medical facilities in Japan. We included adult patients who were admitted to these hospitals via the ED from 2017 to 2020. To investigate whether patients with mental illness were more likely to have preceding ED visits within 30 days prior to unplanned admissions compared with those without, we used univariate and multivariable logistic regression models. In the multivariable model, we adjusted for age category, gender, facility, year, and ambulance use. Results Out of 15,429 total admissions, 766 (5.0%) cases had documented comorbid mental illness and 14,663 (95.0%) did not. The prevalence of preceding ED visits among patients with mental illness was significantly higher than in those without (17.1% vs 8.8%; unadjusted odds ratio 2.15, 95% confidence interval [CI] 1.76–2.61; P

Precursor-targeted immune-mediated anemia (PIMA) in dogs is characterized by persistent non-regenerative anemia and ineffective erythropoiesis, and it is suspected to be an immune-mediated disease. Most affected dogs respond to immunosuppressive therapies; however, some are resistant. In this study, we carried out splenectomy as an alternative therapy for refractory PIMA in dogs, and analyzed gene expression levels in the spleen of dogs with or without PIMA and in serum before and after splenectomy. A total of 1,385 genes were found to express differentially in the spleens from dogs with PIMA compared with healthy dogs by transcriptome analysis, of which 707 genes were up-regulated, including S100A12, S100A8, and S100A9 that are linked directly to the innate immune system and have been characterized as endogenous damage-associated molecular patterns. Furthermore, immunohistochemistry confirmed that S100A8/A9 protein expression levels were significantly higher in dogs with PIMA compared with those in healthy dogs. A total of 22 proteins were found to express differentially between the serum samples collected before and after splenectomy by proteome analysis, of which 12 proteins were up-regulated in the samples before. The lectin pathway of complement activation was identified by pathway analysis in pre-splenectomy samples. We speculated that S100A8/9 expression may be increased in the spleen of dogs with PIMA, resulting in activation of the lectin pathway before splenectomy. These findings further our understanding of the pathology and mechanisms of splenectomy for PIMA.

BackgroundThe quick sequential organ failure assessment (qSOFA) was widely used to estimate the risks of sepsis in patients with suspected infection in the prehospital and emergency department (ED) settings. Due to the insufficient sensitivity of qSOFA on arrival at the ED (ED qSOFA), the Surviving Sepsis Campaign 2021 recommended against using qSOFA as a single screening tool for sepsis. However, it remains unclear whether the combined use of prehospital and ED qSOFA improves its sensitivity for identifying patients at a higher risk of sepsis at the ED.MethodsWe retrospectively analyzed the data from the ED of a tertiary medical center in Japan from April 2018 through March 2021. Among all adult patients (aged ≥18 years) transported by ambulance to the ED with suspected infection, we identified patients who were subsequently diagnosed with sepsis based on the Sepsis-3 criteria. We compared the predictive abilities of prehospital qSOFA, ED qSOFA, and the sum of prehospital and ED qSOFA (combined qSOFA) for sepsis in patients with suspected infection at the ED.ResultsAmong 2,407 patients with suspected infection transported to the ED by ambulance, 369 (15%) patients were subsequently diagnosed with sepsis, and 217 (9%) died during hospitalization. The sensitivity of prehospital qSOFA ≥2 and ED qSOFA ≥2 were comparable (c-statistics for sepsis [95%CI], 0.57 [0.52-0.62] vs. 0.55 [0.50-0.60]). However, combined qSOFA (cutoff, ≥3 [max 6]) was more sensitive than ED qSOFA (cutoff, ≥2) for identifying sepsis (0.67 [95%CI, 0.62-0.72] vs. 0.55 [95%CI, 0.50-0.60]). Using combined qSOFA, we identified 44 (12%) out of 369 patients who were subsequently diagnosed with sepsis, which would have been missed using ED qSOFA alone.ConclusionsUsing both prehospital and ED qSOFA could improve the screening ability of sepsis among patients with suspected infection at the ED.

Regularization is essential for avoiding over-fitting to training data in network optimization, leading to better generalization of the trained networks. The label noise provides a strong implicit regularization by replacing the target ground truth labels of training examples by uniform random labels. However, it can cause undesirable misleading gradients due to the large loss associated with incorrect labels. We propose a first-order optimization method (Label-Noised Trim-SGD) that uses the label noise with the example trimming in order to remove the outliers based on the loss. The proposed algorithm is simple yet enables us to impose a large label-noise and obtain a better regularization effect than the original methods. The quantitative analysis is performed by comparing the behavior of the label noise, the example trimming, and the proposed algorithm. We also present empirical results that demonstrate the effectiveness of our algorithm using the major benchmarks and the fundamental networks, where our method has successfully outperformed the state-of-the-art optimization methods.

Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PIICS) is known as a prolonged immunodeficiency that occurs after severe infection. Few studies have demonstrated a direct relationship between PIICS and physical dysfunction in post-intensive care syndrome (PICS). We herein investigated how each component of PICS was affected by the diagnosis of PIICS during hospitalization and examined the relationship between PIICS and PICS using PICS assessments performed at the Hitachi General Hospital PICS Clinic. Methods: The 273 patients who visited the PICS clinic at one month after discharge from the ICU at Hitachi General Hospital were included in the study. We used the diagnostic criteria for PIICS described in previous studies. At least two of the following blood test values on day 14 of hospitalization had to be met for a diagnosis of PIICS: C-reactive protein (CRP) > 2.0 mg/dL, albumin (Alb) < 3.0 g/dL, and lymphocytes (Lym) < 800/μL. Blood test values closest to day 14 out of 11–17 days of hospitalization were used. The primary outcome was a Barthel Index (BI) < 90, while secondary outcomes were the results of various PICS assessments, including mental and cognitive impairments, performed at the PICS clinic. We supplemented missing data with multiple imputations by chained equations. We performed a nominal logistic regression analysis with age, sex, BMI, SOFA, and the presence of PIICS as variables for BI < 90. Results: Forty-three out of two hundred seventy-three PICS outpatients met the diagnostic criteria for PIICS during hospitalization. In comparisons with non-PIICS patients, significantly higher severity scores for APACHE II and SOFA and a longer hospital stay were observed in PIICS patients, suggesting a higher clinical severity. The primary outcome, BI, was lower in the PIICS group (97.5 (58.5, 100) vs. 100 (95, 100), p = 0.008), as were the secondary outcomes (FSS-ICU: 35 (31, 35) vs. 35 (35, 35), MRC score: 55 (50.25, 58) vs. 58 (53, 60), grip strength: 16.45 (9.2, 25.47) vs. 20.4 (15.3, 27.7)). No significant differences were noted in mental or cognitive function assessments, such as HADS, IES-R, and SMQ. A multivariable analysis supplemented with missing data revealed that PIICS (odds ratio: 1.23 (1.08–1.40 p = 0.001) and age (odds ratio: 1.007 (1.004–1.01), p < 0.001) correlated with BI < 90, independent of clinical severity such as sequential organ failure assessment (SOFA). Similar results were obtained in the sensitivity analysis excluding missing data. Conclusions: The present study revealed a strong relationship between PIICS and post-discharge PICS physical dysfunction in patients requiring intensive care.

Abstract Background Although the combination of rehabilitation and nutrition may be important for the prevention of intensive care unit (ICU)-acquired weakness, a protocolized intervention of this combination has not yet been reported. We herein developed an original combined protocol and evaluated its efficacy. Methods In this single-center historical control study, we enrolled adult patients admitted to the ICU. Patients in the control group received standard care, while those in the intervention group received the protocol-based intervention. The ICU mobility scale was used to set goals for early mobilization and a neuromuscular electrical stimulation was employed when patients were unable to stand. The nutritional status was assessed for nutritional therapy, and target calorie delivery was set at 20 or 30 kcal/kg/day and target protein delivery at 1.8 g/kg/day in the intervention group. The primary endpoint was a decrease in femoral muscle volume in 10 days assessed by computed tomography. Results Forty-five patients in the control group and 56 in the intervention group were included in the analysis. Femoral muscle volume loss was significantly lower in the intervention group (11.6 vs 14.5%, p = 0.03). The absolute risk difference was 2.9% (95% CI 0.1–5.6%). Early mobilization to a sitting position by day 10 was achieved earlier (p = 0.03), and mean calorie delivery (20.1 vs. 16.8 kcal/kg/day, p = 0.01) and mean protein delivery (1.4 vs. 0.8 g/kg/day, p

Abstract The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Abstract Background Understanding heterogeneity of the respiratory rate (RR) as a risk stratification marker across chief complaints is important to reduce misinterpretation of the risk posed by outcome events and to build accurate risk stratification tools. This study was conducted to investigate the associations between RR and clinical outcomes according to the five most frequent chief complaints in an emergency department (ED): fever, shortness of breath, altered mental status, chest pain, and abdominal pain. Methods This retrospective cohort study examined ED data of all adult patients who visited the ED of a tertiary medical center during April 2018‐September 2019. The primary exposure was RR at the ED visit. Outcome measures were hospitalization and mechanical ventilation use. We used restrictive cubic spline and logistic regression models to assess the association of interest. Results Of 16 956 eligible ED patients, 4926 (29%) required hospitalization; 448 (3%) required mechanical ventilation. Overall, U‐shaped associations were found between RR and the risk of hospitalization (eg, using RR = 16 as the reference, the odds ratio [OR] of RR = 32, 6.57 [95% CI 5.87‐7.37]) and between RR and the risk of mechanical ventilation. This U‐shaped association was driven by patients' association with altered mental status (eg, OR of RR = 12, 2.63 [95% CI 1.25‐5.53]). For patients who have fever or shortness of breath, the risk of hospitalization increased monotonously with increased RR. Conclusions U‐shaped associations of RR with the risk of overall clinical outcomes were found. These associations varied across chief complaints.

Abstract Background In human medicine, congenital maljunction of the common bile duct (CBD) and main pancreatic duct (MPD), or pancreatobiliary maljunction (PBM), is a known cause of cholecystitis. Objective Pancreatic enzyme activity in the bile (a diagnostic marker for PBM) of healthy cats was measured to determine normal values and evaluate its relationship with biliary morphology. Animals Fifty‐two healthy cats. Methods Cross‐sectional study of the biliary tracts of healthy cats during laparoscopic ovariohysterectomy and measurement of pancreatic enzyme activity in bile. The cats were divided into groups A and B based on the ratio of the diameter of the cystic duct (CD) to the CBD. The normal ratio was 3.4. Pancreatic enzyme activity in bile was compared between the groups. Results The CBDs were straight in all cases, whereas the CDs were variably tortuous or dilated. Amylase activity in the bile (median, 3.4, had significantly higher amylase activity (median, 109 U/L; range,

BackgroundHepatocellular carcinoma (HCC) is one of the most common primary liver tumors in humans and dogs. Excessive adrenocortical hormone exposure may cause steroid hepatopathy, which may develop into HCC. In our previous study, hyperadrenocorticism (HAC) was a highly concurrent disease in dogs with HCC. Therefore, this study hypothesized that adrenal steroid alterations might be involved in hepatocarcinogenesis and aimed to specify the relationship between HAC and HCC in dogs.Materials and methodsThis study included 46 dogs brought to the Hokkaido University Veterinary Teaching Hospital between March 2019 and December 2020. Owners gave their signed consent for blood collection on their first visit. A total of 19 steroids (14 steroids and 5 metabolites) in the baseline serum of 15 dogs with HCC, 15 dogs with HAC, and 10 dogs with both diseases were quantitatively measured using the developed liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) method.ResultsIn each group, 11 steroids were detected higher than 50%. The detection rate of steroid hormones did not significantly differ between the groups (p > 0.05). Principle component analysis (PCA) showed that the steroid profiles of the three groups were comparable. Median steroid hormone concentrations were not significantly different between the study diseases (p > 0.05).ConclusionThe developed LC/MS/MS was useful for measuring steroid hormones. Although it was clear that HAC was concurrent in dogs with HCC, none of the serum steroids was suggested to be involved in HCC.

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.

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) is a serious condition after critical care. We examined the efficacy of antithrombin, which may attenuate coagulopathy with the control of inflammation, for PICS among patients with sepsis-induced disseminated intravascular coagulation (DIC). The present study used the inpatient claims database with laboratory findings to identify patients admitted to intensive care units and diagnosed with sepsis and DIC. A composite of the incidence of PICS on day 14 or 14-day mortality as the primary outcome was compared between the antithrombin and control groups using a propensity-score-matched analysis. Secondary outcomes were the incidence of PICS on day 28, 28-day mortality, and in-hospital mortality. A total of 324 well-balanced matched pairs were generated from 1622 patients. The primary outcome did not differ between the antithrombin and control groups (63.9% vs. 68.2%, respectively, p = 0.245). However, the incidences of 28-day and in-hospital mortality were significantly lower in the antithrombin group (16.0% vs. 23.5% and 24.4% vs. 35.8%, respectively). Similar results were obtained in a sensitivity analysis using overlap weighting. Antithrombin did not reduce the occurrence of PICS on day 14 in patients with sepsis-induced DIC; however, it was associated with a better mid-term (day 28) prognosis.

Abstract Aims Trimethylamine N‐oxide (TMAO) is a metabolite derived from the gut microbiota. Elevated TMAO levels are associated with a poor prognosis in patients with heart failure with reduced ejection fraction. However, the prognostic effect of elevated TMAO levels on heart failure with preserved ejection fraction (HFpEF) remains unclear. Methods and results We consecutively enrolled 146 patients who were hospitalized and discharged from Tottori University Hospital with the primary diagnosis of HFpEF (ejection fraction ≥ 50%). High TMAO levels were defined as those greater than the median value in the patients (20.37 μmol/L). Patients with high TMAO levels had a significantly higher prevalence of prior hospitalization for heart failure and severe renal dysfunction than those with low TMAO levels. They also had a significantly higher acylcarnitine to free carnitine ratio than those with low TMAO levels, which indicated abnormal fatty acid metabolism and relative carnitine deficiency. After adjustment for differences in the patients' background in multivariate analysis, high TMAO levels remained independently associated with a high incidence of the composite endpoints of death due to cardiac causes and hospitalization for heart failure (adjusted hazard ratio, 1.91; 95% confidence interval, 1.01 to 3.62; P

Abstract Background Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE. Methods This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is “continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance.” In both groups, diazepam is initially administered at 1–20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000–3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes. Discussion The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application. Trial registration Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019

Masaki Odahara and Kensuke Nakamura et al. use deep paired-end sequencing to examine organellar genome recombination when homologous recombination repair genes are individually knocked out in the moss, Physcomitrella patens. Their results suggest that chloroplasts and mitochondria share a common mechanism for replication-related rearrangements.

BackgroundDespite the increasing availability of clinical decision support systems (CDSSs) and rising expectation for CDSSs based on artificial intelligence (AI), little is known about the acceptance of AI-based CDSS by physicians and its barriers and facilitators in emergency care settings. ObjectiveWe aimed to evaluate the acceptance, barriers, and facilitators to implementing AI-based CDSSs in the emergency care setting through the opinions of physicians on our newly developed, real-time AI-based CDSS, which alerts ED physicians by predicting aortic dissection based on numeric and text information from medical charts, by using the Unified Theory of Acceptance and Use of Technology (UTAUT; for quantitative evaluation) and the Consolidated Framework for Implementation Research (CFIR; for qualitative evaluation) frameworks. MethodsThis mixed methods study was performed from March to April 2021. Transitional year residents (n=6), emergency medicine residents (n=5), and emergency physicians (n=3) from two community, tertiary care hospitals in Japan were included. We first developed a real-time CDSS for predicting aortic dissection based on numeric and text information from medical charts (eg, chief complaints, medical history, vital signs) with natural language processing. This system was deployed on the internet, and the participants used the system with clinical vignettes of model cases. Participants were then involved in a mixed methods evaluation consisting of a UTAUT-based questionnaire with a 5-point Likert scale (quantitative) and a CFIR-based semistructured interview (qualitative). Cronbach α was calculated as a reliability estimate for UTAUT subconstructs. Interviews were sampled, transcribed, and analyzed using the MaxQDA software. The framework analysis approach was used during the study to determine the relevance of the CFIR constructs. ResultsAll 14 participants completed the questionnaires and interviews. Quantitative analysis revealed generally positive responses for user acceptance with all scores above the neutral score of 3.0. In addition, the mixed methods analysis identified two significant barriers (System Performance, Compatibility) and two major facilitators (Evidence Strength, Design Quality) for implementation of AI-based CDSSs in emergency care settings. ConclusionsOur mixed methods evaluation based on theoretically grounded frameworks revealed the acceptance, barriers, and facilitators of implementation of AI-based CDSS. Although the concern of system failure and overtrusting of the system could be barriers to implementation, the locality of the system and designing an intuitive user interface could likely facilitate the use of optimal AI-based CDSS. Alleviating and resolving these factors should be key to achieving good user acceptance of AI-based CDSS.

BackgroundThe diagnosis of acute pulmonary thromboembolism is challenging in dogs. Little has been reported on changes in echocardiographic indices in dogs with acute pulmonary thromboembolism. The objective of this study was to validate the relationship between echocardiographic indices and right heart catheterization variables in dogs with acute pulmonary embolism and to identify a useful echocardiographic index for diagnosing acute pulmonary embolism.Materials and MethodsSix healthy laboratory beagles were included in the study. Echocardiography and right heart catheterization were performed in a dog model of acute pulmonary embolism produced by microsphere injection. Echocardiographic indices, including the right ventricular (RV) Tei index, RV longitudinal strain, and the dyssynchrony index using speckle tracking echocardiography, transmitral flow, and eccentricity index, were measured.ResultsThe mean pulmonary arterial pressure increased (22.2 ± 1.2 mmHg) and the blood pressure decreased after microsphere injection. Although the mean pulmonary arterial pressure remained elevated, the blood pressure recovered 2 days after the microsphere injection. Most echocardiographic indices of RV function were significantly impaired following microsphere injection and recovered after 2 days. In contrast, the RV Tei index was significantly impaired after microsphere injection and the impairment persisted after 2 days. Multivariable analysis revealed that the RV Tei index was an independent echocardiographic predictor of pulmonary vascular resistance (β = 0.88, P < 0.001), and transmitral early diastolic wave was an independent predictor of the cardiac index (β = −0.86, P = 0.001).ConclusionsThe RV Tei index is a useful echocardiographic index for diagnosing acute pulmonary embolism. Ventricular interdependence may be an important factor causing low cardiac output in dogs with acute pulmonary embolism.

Overwhelming postsplenectomy infection (OPSI) is a life-threatening condition causing fulminant bacteremia in asplenic patients. Intravenous immunoglobulin (IVIG) therapy is theoretically effective for OPSI. Herein, we present a case of OPSI treated successfully with IVIG, along with results of a literature review. An asplenic 70-year-old male with acute ischemic stroke presented with rapid and fulminant septic shock from pneumococcus pneumonia and bacteremia. Resuscitation and antibiotics including IVIG therapy were instituted. The patient survived with favorable outcomes. We analyzed all case reports or case series of OPSI from 1971 through 2017. Cases with IVIG treatment showed a significantly higher survival rate than those without IVIG, even with multivariable regression analysis, suggesting IVIG as an independent predictive factor for survival. It suggests that IVIG is effective for OPSI and that it can be regarded as an adjunctive treatment option for OPSI.

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

Intravesical chemotherapy after transurethral resection is a treatment option in patients with non-muscle invasive bladder cancer. The efficacy of intravesical chemotherapy is determined by the cellular uptake of intravesical drugs. Therefore, drug delivery technologies in the urinary bladder are promising tools for enhancing the efficacy of intravesical chemotherapy. Ultrasound-triggered microbubble cavitation may enhance the permeability of the urothelium, and thus may have potential as a drug delivery technology in the urinary bladder. Meanwhile, the enhanced permeability may increase systemic absorption of intravesical drugs, which may increase the adverse effects of the drug. The aim of this preliminary safety study was to assess the systemic absorption of an intravesical drug that was delivered by ultrasound-triggered microbubble cavitation in the urinary bladder of normal dogs. Pirarubicin, a derivative of doxorubicin, and an ultrasound contrast agent (Sonazoid) microbubbles were administered in the urinary bladder. Ultrasound (transmitting frequency 5 MHz; pulse duration 0.44 μsec; pulse repetition frequency 7.7 kHz; peak negative pressure −1.2 MPa) was exposed to the bladder using a diagnostic ultrasound probe (PLT-704SBT). The combination of ultrasound and microbubbles did not increase the plasma concentration of intravesical pirarubicin. In addition, hematoxylin and eosin staining showed that the combination of ultrasound and microbubble did not cause observable damages to the urothelium. Tissue pirarubicin concentration in the sonicated region was higher than that of the non-sonicated region in two of three dogs. The results of this pilot study demonstrate the safety of the combination of intravesical pirarubicin and ultrasound-triggered microbubble cavitation, that is, ultrasound-assisted intravesical chemotherapy.

Aim Hip fracture is one of the most common fall‐related injuries in the elderly population. Although falls may cause multiple types of injuries, no study has investigated the details of fall‐related injuries accompanied by hip fractures. This study aimed to characterize the features of such injuries. Methods This is a cross‐sectional study using data from four tertiary emergency departments in Japan. We identified patients diagnosed with hip fracture including femoral neck fracture, trochanter fracture, or subtrochanteric fracture from May 12, 2014 to July 12, 2021. Among patients with hip fracture, we included those with fall‐related hip fracture. We excluded patients ages

In this paper, we investigate a quantitative evaluation method for symmetry in lower limb movements during the standing movement. In the standing movement, the foot is fixed to the floor and the two segments of shank and thigh are displaced. Therefore, we compared two methods: one is to measure the actual value of elevation angle of shank and thigh, and the other is to use the vector information of elevation angle of those. As a result, the two elevation angle plots of the left and right lower limbs of the healthy group were drawn near a specific straight line, and the patient group tended to be drawn relatively far from. It was shown that the method using the vector information of the elevation angle may provide more concise information to the analyst as a symmetry evaluation and be easier to interpret.

Background: Data regarding delivery of evidence-based care to critically ill patients in Intensive Care Units (ICU) during the COVID-19 pandemic is crucial but lacking. This study aimed to evaluate the implementation rate of the ABCDEF bundle, which is a collection of six evidence-based ICU care initiatives which are strongly recommended to be incorporated into clinical practice, and ICU diaries for patients with and without COVID-19 infections in ICUs, and to analyze the impact of COVID-19 on implementation of each element of the bundle and independent associated factors.Methods: A world-wide 1-day point prevalence study investigated the delivery of the ABCDEF bundle and ICU diary to patients without or with COVID-19 infections on 27 January 2021 via an online questionnaire. Multivariable logistic regression analysis with adjustment for patient demographics evaluated the impact of COVID-19 and identified factors in ICU administrative structures and policies independently associated with delivery.Results: From 54 countries and 135 ICUs, 1,229 patients were eligible, and 607 (49%) had COVID-19 infections. Implementation rates were: entire bundle (without COVID-19: 0% and with COVID-19: 1%), Element A (regular pain assessment: 64 and 55%), Element B (both spontaneous awakening and breathing trials: 17 and 10%), Element C (regular sedation assessment: 45 and 61%), Element D (regular delirium assessment: 39 and 35%), Element E (exercise: 22 and 25%), Element F (family engagement/empowerment: 16 and 30%), and ICU diary (17 and 21%). The presence of COVID-19 was not associated with failure to implement individual elements. Independently associated factors for each element in common between the two groups included presence of a specific written protocol, application of a target/goal, and tele-ICU management. A lower income status country and a 3:1 nurse-patient ratio were significantly associated with non-implementation of elements A, C, and D, while a lower income status country was also associated with implementation of element F.Conclusions: Regardless of COVID-19 infection status, implementation rates for the ABCDEF bundle, for each element individually and an ICU diary were extremely low for patients without and with COVID-19 infections during the pandemic. Strategies to facilitate implementation of and adherence to the complete ABCDEF bundle should be optimized and addressed based on unit-specific barriers and facilitators.

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

The structure and function of bacterial chromosomes are dynamically regulated by a wide variety of nucleoid-associated proteins (NAPs) and DNA superstructures, such as DNA supercoiling. In Escherichia coli, integration host factor (IHF), a NAP, binds to specific transcription promoters and regulatory DNA elements of DNA replication such as the replication origin oriC: binding to these elements depends on the cell cycle but underlying mechanisms are unknown. In this study, we combined GeF-seq (genome footprinting with high-throughput sequencing) with synchronization of the E. coli cell cycle to determine the genome-wide, cell cycle-dependent binding of IHF with base-pair resolution. The GeF-seq results in this study were qualified enough to analyze genomic IHF binding sites (e.g., oriC and the transcriptional promoters of ilvG and osmY) except some of the known sites. Unexpectedly, we found that before replication initiation, oriC was a predominant site for stable IHF binding, whereas all other loci exhibited reduced IHF binding. To reveal the specific mechanism of stable oriC–IHF binding, we inserted a truncated oriC sequence in the terC (replication terminus) locus of the genome. Before replication initiation, stable IHF binding was detected even at this additional oriC site, dependent on the specific DnaA-binding sequence DnaA box R1 within the site. DnaA oligomers formed on oriC might protect the oriC–IHF complex from IHF dissociation. After replication initiation, IHF rapidly dissociated from oriC, and IHF binding to other sites was sustained or stimulated. In addition, we identified a novel locus associated with cell cycle-dependent IHF binding. These findings provide mechanistic insight into IHF binding and dissociation in the genome.

In this paper, we propose a method that uses the femoral and tibial elevation angles to quantitatively evaluate the symmetry of lower limb movement during the transition from a sitting position to a standing position. In kinematic analysis of the transition from sitting to standing, the angles of the three joints of the lower limb are often measured. However, due to the large number of variables, it is difficult to evaluate the symmetry of the lower limb movement by comparing data from the six joints of the left and right lower limbs. In this study, therefore, we measured the femoral and tibial elevation angles of healthy participants and rehabilitation patients and visually and numerically evaluated the symmetry and asymmetry of the movement of the left and right lower limbs. We were able to identify the kinematically major lower limbs in the transition from sitting to standing and quantify the symmetry of the movement patterns of the left and right lower limbs. Furthermore, we examined the possibility that the method could be effectively used in the rehabilitation field to evaluate the motor co-ordination that constitutes the lower limb movement pattern in the transition from the sitting to standing position, such as the gait plane rule.

Introduction: Post-intensive care syndrome (PICS) is an emerging problem in critically ill patients and the prevalence and risk factors are unclear in patients with severe coronavirus disease 2019 (COVID-19). This multicenter prospective observational study aimed to investigate the prevalence and risk factors of PICS in ventilated patients with COVID-19 after ICU discharge. Methods: Questionnaires were administered twice in surviving patients with COVID-19 who had required mechanical ventilation, concerning Barthel Index, Short-Memory Questionnaire, and Hospital Anxiety and Depression Scale scores. The risk factors for PICS were examined using a multivariate logistic regression analysis. Results: The first and second PICS surveys were obtained at 5.5 and 13.5 months (mean) after ICU discharge, with 251 and 209 patients completing the questionnaires and with a prevalence of PICS of 58.6% and 60.8%, respectively, along with the highest percentages of cognitive impairment. Delirium (with an odds ratio of (OR) 2.34, 95% CI 1.1–4.9, and p = 0.03) and the duration of mechanical ventilation (with an OR of 1.29, 95% CI 1.05–1.58, and p = 0.02) were independently identified as the risk factors for PICS in the first PICS survey. Conclusion: Approximately 60% of the ventilated patients with COVID-19 experienced persistent PICS, especially delirium, and required longer mechanical ventilation.

Background: While clinical criteria have been proposed for persistent inflammation, immunosuppression, and catabolism syndrome (PICS) using C-reactive protein (CRP), albumin, and lymphocyte count, there is no substantial basis for their optimal cut-off values. We herein aimed to develop and externally validate clinical criteria for PICS by investigating the optimal cut-off values for these biomarkers using machine-learning approaches and confirmed it with external validation. Methods: To develop criteria, we included ICU patients treated at a tertiary care hospital in Japan between 2018 and 2021 (derivation cohort). We introduced CRP, albumin and lymphocyte counts at around day 14 into six machine-learning models to predict PICS, defined as the compound outcome of the Barthel index (BI) < 70 at hospital discharge and in-hospital death. We incorporated the results of these models to assess the optimal cut-off values for biomarkers. We then developed and externally validated criteria for PICS using a nationwide claims database in Japan (validation cohort). Results: In the derivation cohort, 291 out of 441 patients had BI < 70 or in-hospital death. Based on machine-learning models, the optimal cut-off values for biomarkers to predict them were a CRP of 2.0 mg/dL, albumin of 3.0 g/dL, and a lymphocyte count of 800/μL, with an AUROC of 0.67. In the external validation cohort, 4492 out of 15,302 patients had BI < 70 or in-hospital death. The AUROC of the criteria was 0.71, with sensitivity of 0.71 and specificity of 0.68 to predict PICS. Conclusions: We herein provide a fundamental basis for PICS clinical criteria with CRP >2.0 mg/dL, albumin

With the development of intensive care medicine and the standardization of various therapeutic guidelines and education systems, mortality rates in critically ill patients have improved markedly [...]