Distinguishing two distinct types of salivary extracellular vesicles: a potential tool for understanding their pathophysiological roles.

Extracellular vesicles (EVs), which are found in almost all cells and human body fluids, are currently being studied as a source of pathophysiological information. Previously, we demonstrated that at least two types of EVs can be isolated from human whole saliva (WS) using enzymatic activity of dipeptidyl peptidase IV (DPP IV) as a marker for differentiating the EV subsets. In the present study, EV fractions, termed EV-I 20 k-ppt and EV-II 100 k-ppt, were prepared by a combination of size-exclusion chromatography of improved condition and sequential centrifugation. The EV-I 20 k-ppt fraction contained medium/large EVs with a diameter of 100-1,000 nm, including aminopeptidase N (APN), mucin 1, ezrin, and Annexin A1. EV-II 100 k-ppt contained small EVs with a diameter of 20-70 nm, with DPP IV and CD9, programmed cell death 6-interacting protein, and tumor susceptibility gene 101 as characteristic proteins. Proteomic analyses also revealed distinctive repertoires of constituent proteins. Immunoprecipitation of several membrane proteins of the EVs with respective antibodies suggested their differential local membrane environment between the two types of salivary vesicles. Thus, we identified two distinctive types of EVs, one is APN/MUC1- rich EVs (EV-I, large/medium EVs) and the other is DPP IV/CD9-rich EVs (EV-II, small EVs). Furthermore, analysis of the binding of the EVs to coronavirus spike proteins showed that EV-II 100 k-ppt, but not EV-I 20 k-ppt, significantly bound to the spike protein of Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we developed a simple method to prepare two distinctive EVs from only 1 mL of human WS using sequential immunoprecipitation. Elucidating the features and functions of these two types of salivary EVs may help us understand their pathophysiological roles in the oral cavity and gastrointestinal tract.

X-irradiated umbilical cord blood cells retain their regenerative effect in experimental stroke.

Although regenerative therapy with stem cells is believed to be affected by their proliferation and differentiation potential, there is insufficient evidence regarding the molecular and cellular mechanisms underlying this regenerative effect. We recently found that gap junction-mediated cell-cell transfer of small metabolites occurred very rapidly after stem cell treatment in a mouse model of experimental stroke. This study aimed to investigate whether the tissue repair ability of umbilical cord blood cells is affected by X-irradiation at 15 Gy or more, which suppresses their proliferative ability. In this study, X-irradiated mononuclear (XR) cells were prepared from umbilical cord blood. Even though hematopoietic stem/progenitor cell activity was diminished in the XR cells, the regenerative activity was surprisingly conserved and promoted recovery from experimental stroke in mice. Thus, our study provides evidence regarding the possible therapeutic mechanism by which damaged cerebrovascular endothelial cells or perivascular astrocytes may be rescued by low-molecular-weight metabolites supplied by injected XR cells in 10 min as energy sources, resulting in improved blood flow and neurogenesis in the infarction area. Thus, XR cells may exert their tissue repair capabilities by triggering neo-neuro-angiogenesis, rather than via cell-autonomous effects.

Preliminary Effectiveness of an In-Hospital Peer Support Program, Adolescent and Young Adult Hiroba, on Anxiety in Adolescent and Young Adult Patients with Cancer.

Purpose: Adolescent and young adult (AYA) patients with cancer have few opportunities to connect with patients of the same generation while hospitalized. Although anxiety is frequently reported by them, there are no reports on the psychological effectiveness of an in-hospital patient support program based on peer support. This study aimed to evaluate the effectiveness of a program, termed Adolescent and Young Adult Hiroba (AYA Hiroba), for anxiety in AYA patients with cancer. Methods: This single-center, prospective, observational study in 24 AYA patients with cancer was conducted at the National Cancer Center Hospital in Japan. The Hospital Anxiety and Depression Scale-Anxiety (HADS-A) was used to evaluate the primary outcome, anxiety. The Distress Thermometer (DT) was used to evaluate the secondary outcome, distress. The two outcomes were assessed before and after participation in AYA Hiroba. The Net Promoter Score (NPS) was used to evaluate satisfaction after participation in AYA Hiroba. Participants' free-text descriptions of the program were categorized according to similarities and differences. Results: The HADS-A and DT scores were significantly lower after the program than before (p < 0.001), as was the percentage of AYA patients with cancer with high distress (p = 0.04). The NPS was 27, which was lower than the value of 52 obtained in our previous study. Requests and suggestions to improve the program were grouped into three categories: content, facilitation, and online connection environment. Conclusion: This study suggests the preliminary effectiveness of the in-hospital peer support program for anxiety in AYA patients with cancer. The Clinical Trial Registration number: UMIN000045779.

Feasibility and Preliminary Effectiveness of Behavioral Activation for Patients with Cancer and Depression in Japan.

Background: Though the effectiveness of behavioral activation (BA) for patients with cancer and depression were reported, there is no evidence in Japan. Objectives: This study aimed at examining the feasibility and preliminary effectiveness of BA for patients with cancer and depression in Japan. Methods: This pre-post study without a control group was conducted in patients with cancer and depression in Japan. The program completion rate was compared with those of previous studies to examine feasibility. To examine the preliminary effectiveness, outcomes were evaluated four times: before and immediately after the program, and two weeks and three months after the program ended. The primary outcome was the remission rate of depression using the 17-item version of the GRID Hamilton Rating Scale for Depression (HAMD17). Secondary outcomes were self-reported depression, anxiety, quality of life, changes in behavior, values, and perceived reward of activity and environmental factors. Pre- and post-program data were compared using paired-samples t-tests, and data obtained at four time points were analyzed using one-way repeated-measures analysis of variance. Results: Of the 68 patients recruited from February 2018 to January 2022, 32 were registered. The completion rate was 75% (24/32), which was similar to previous studies. The total HAMD17 score significantly improved after the program. The remission rate of depression was 62.5% (20/32), which was above the defined threshold value (30%). All but two secondary outcomes significantly improved after the program (p < 0.05). Conclusions: The feasibility and preliminary effectiveness of BA for patients with cancer and depression in Japan were suggested.The Clinical Trial Registration number: UMIN 000036104.

A multi-centre, double-blind, randomized, placebo-controlled trial to evaluate the effectiveness and safety of ramelteon for the prevention of postoperative delirium in elderly cancer patients: a study protocol for JORTC-PON2/J-SUPPORT2103/NCCH2103.

Postoperative delirium is an important issue in cancer patients, affecting surgical outcomes and the quality of life. Ramelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors. Clinical trials and observational studies in Japan, including in surgical cancer patients, have shown efficacy of ramelteon in delirium prevention, with no serious safety concerns. However, clinical trials from the USA have reported conflicting results. A Japanese phase II study investigated the efficacy and safety of ramelteon for delirium prevention following gastrectomy in patients aged ≥75 years, with findings suggesting the feasibility of a phase III trial. The aim of this multi-centre, double-blind, randomized placebo-controlled phase III trial is to evaluate the effectiveness and safety of oral ramelteon for postoperative delirium prevention in cancer patients aged ≥65 years as advanced medical care. The trial protocol is described here.

Behavioral activation for depression in patients with advanced cancer: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Though behavioral activation (BA) has been shown to be effective for depression, evidence in patients with advanced cancer has not been established. This study aimed to examine the effectiveness of a BA program on depression in this population. METHODS: A randomized controlled trial with a wait-list control group (waiting group) of 38 patients with advanced cancer and depression will be conducted at three sites in Japan. The BA program consists of seven sessions. Outcome measures will be evaluated at three times in the intervention group; at the entry, at the end of the intervention and 4 months after the end of the intervention and four times in the waiting group: at the entry, before the intervention, at the end of the intervention, and 4 months after the end of the intervention. Primary outcome is Beck Depression Inventory-II (BDI-II) score. To examine the main effect of the intervention, two-way repeated measures analysis of variance (ANOVA) will be conducted, with timing and intervention status as the independent variables and BDI-II score as the dependent variable. One-way repeated measures ANOVA will be conducted to combine data from the intervention and control groups and examine changes in BDI-II scores by timing in both groups. Secondary endpoints (anxiety, quality of life, spirituality, degree of behavioral activation, value, and pain) will be evaluated with rating scales. Two-way repeated measures ANOVA will be conducted to examine whether there are differences between the groups before and after the intervention, with timing and intervention status as the independent variables and scores on each rating scale as the dependent variables. DISCUSSION: This multicenter randomized controlled trial is the first study to assess the effectiveness of BA on depression in patients with advanced cancer. Our findings will provide evidence about the effectiveness of BA on depression and provide an intervention option that is acceptable and feasible for the treatment of depression in this population. The results of this study will lead to improved mood and rebuilding to regain life purpose and value in this vulnerable population. TRIAL REGISTRATION NUMBER: jRCT, jRCT1030210687, Registered 22 March 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT1030210687 .

An Attempt to Identify the Medaka Receptor for Somatolactin Alpha Using a Reverse Genetics Approach.

Somatolactin alpha (SLα) is a fish-specific hormone involved in body color regulation. The growth hormone (GH) is another hormone that is expressed in all vertebrates and promotes growth. These peptide hormones act by binding to receptors (SLα receptor (SLR) and GH receptor (GHR)); however, the relationships between these ligands and their receptors vary among species. Here, we first performed phylogenetic tree reconstruction by collecting the amino-acid sequences classified as SLR, GHR, or GHR-like from bony fish. Second, we impaired SLR or GHR functions in medaka (Oryzias sakaizumii) using CRISPR/Cas9. Lastly, we analyzed SLR and GHR mutants for phenotypes to deduce their functions. Phylogenetic tree reconstruction was performed using a total of 222 amino-acid sequences from 136 species, which revealed that many GHRa and GHRb are vaguely termed as GHR or GHR-like, while showing no orthologous/paralogous relationships. SLR and GHR mutants were successfully established for phenotyping. SLR mutants exhibited premature lethality after hatching, indicating an essential role for SLR in normal growth. GHR mutations did not affect viability, body length, or body color. These results provide no evidence that either SLR or GHR functions as a receptor for SLα; rather, phylogenetically and functionally, they seem to be receptors for GH, although their (subfunctionalized) roles warrant further investigation.

Gap Junction-Mediated Transport of Metabolites Between Stem Cells and Vascular Endothelial Cells.

We have previously demonstrated that small molecular transfer, such as glucose, between hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs) and vascular endothelial cells via gap junctions constitutes an important mechanism of stem cell therapy. Cell metabolites are high-potential small-molecule candidates that can be transferred to small molecules between stem cells and vascular endothelial cells. Here, we investigated the differences in metabolite levels between stem cells (HSCs and MSCs), vascular endothelial cells, and the levels of circulating non-hematopoietic white blood cells (WBCs). The results showed remarkable differences in metabolite concentrations between cells. Significantly higher concentrations of adenosine triphosphate (ATP), guanosine triphosphate (GTP), total adenylate or guanylate levels, glycolytic intermediates, and amino acids were found in HSCs compared with vascular endothelial cells. In contrast, there was no significant difference in the metabolism of MSCs and vascular endothelial cells. From the results of this study, it became clear that HSCs and MSCs differ in their metabolites. That is, metabolites that transfer between stem cells and vascular endothelial cells differ between HSCs and MSCs. HSCs may donate various metabolites, several glycolytic and tricarboxylic acid cycle metabolites, and amino acids to damaged vascular endothelial cells as energy sources and activate the energy metabolism of vascular endothelial cells. In contrast, MSCs and vascular endothelial cells regulate each other under normal conditions. As the existing MSCs cannot ameliorate the dysregulation during insult, exogenous MSCs administered by cell therapy may help restore normal metabolic function in the vascular endothelial cells by taking up excess energy sources from the lumens of blood vessels. Results of this study suggested that the appropriate timing of cell therapy is different between HSCs and MSCs.

Effect of Surface Pre-Reacted Glass Ionomer Containing Dental Sealant on the Inhibition of Enamel Demineralization.

The effect of a surface pre-reacted glass ionomer (S-PRG)-containing sealant on the demineralization inhibition and remineralization of intact enamel adjacent to the sealant material was investigated. BeautiSealant (BTS, S-PRG sealant, Shofu), Teeth Mate F-12.0 (TMF, fluoride-releasing sealant, Kuraray Noritake Dental), and an experimental silica-filler sealant were investigated. After pH cycling for 10 days, the enamel surface adjacent to the sealant material was observed using confocal laser microscopy and scanning electron microscopy. The polymerized sealant disks were immersed in a demineralized solution (pH: 4.3) to measure pH change. The enamel specimens with polymerized sealant disks were additionally immersed in demineralized solution, followed by energy-dispersive X-ray spectroscopy. The demineralized area of BTS was significantly smaller than that of TMF and SS (p < 0.05). The surfaces adjacent to the sealant of TMF and SS were demineralized, while the surface of BTS was comparatively intact. An increase in pH values were observed in the BTS and TMF groups. Enamel surfaces presented an inhibition of demineralization for BTS and TMF, but not for SS. Fluoride uptake from the polymerized sealant was greater for BTS than for TMF. The S-PRG-containing sealant showed a buffering ability, demineralization inhibition, promotion of remineralization, and it can be advised for clinical applications.

Pre-Clinical Proof of Concept: Intra-Carotid Injection of Autologous CD34-Positive Cells for Chronic Ischemic Stroke.

This study was conducted to evaluate the safety and efficacy of human peripheral blood CD34 positive (CD34+) cells transplanted into a murine chronic stroke model to obtain pre-clinical proof of concept, prior to clinical testing. Granulocyte colony stimulating factor (G-CSF) mobilized human CD34+ cells [1 × 104 cells in 50 µl phosphate-buffered saline (PBS)] were intravenously (iv) or intra-carotid arterially (ia) transplanted 4 weeks after the induction of stroke (chronic stage), and neurological function was evaluated. In this study, severe combined immune deficiency (SCID) mice were used to prevent excessive immune response after cell therapy. Two weeks post cell therapy, the ia CD34+ cells group demonstrated a significant improvement in neurological functions compared to the PBS control. The therapeutic effect was maintained 8 weeks after the treatment. Even after a single administration, ia transplantation of CD34+ cells had a significant therapeutic effect on chronic stroke. Based on the result of this pre-clinical proof of concept study, a future clinical trial of autologous peripheral blood CD34+ cells administration in the intra-carotid artery for chronic stroke patients is planned.

Increased RNA Transcription of Energy Source Transporters in Circulating White Blood Cells of Aged Mice.

Circulating white blood cells (WBC) contribute toward maintenance of cerebral metabolism and brain function. Recently, we showed that during aging, transcription of metabolism related genes, including energy source transports, in the brain significantly decreased at the hippocampus resulting in impaired neurological functions. In this article, we investigated the changes in RNA transcription of metabolism related genes (glucose transporter 1 [Glut1], Glut3, monocarboxylate transporter 4 [MCT4], hypoxia inducible factor 1-α [Hif1-α], prolyl hydroxylase 3 [PHD3] and pyruvate dehydrogenase kinase 1 [PDK1]) in circulating WBC and correlated these with brain function in mice. Contrary to our expectations, most of these metabolism related genes in circulating WBC significantly increased in aged mice, and correlation between their increased RNA transcription and impaired neurological functions was observed. Bone marrow mononuclear transplantation into aged mice decreased metabolism related genes in WBC with accelerated neurogenesis in the hippocampus. In vitro analysis revealed that cell-cell interaction between WBC and endothelial cells via gap junction is impaired with aging, and blockade of the interaction increased their transcription in WBC. Our findings indicate that gross analysis of RNA transcription of metabolism related genes in circulating WBC has the potential to provide significant information relating to impaired cell-cell interaction between WBC and endothelial cells of aged mice. Additionally, this can serve as a tool to evaluate the change of the cell-cell interaction caused by various treatments or diseases.

A Hospital-Based Online Patients Support Program, Online Adolescent and Young Adult Hiroba, for Adolescent and Young Adult Cancer Patients at a Designated Cancer Center in Japan.

Adolescent and young adult (AYA) patients with cancer have few opportunities to interact with peers in their lives. To meet peers safely during the coronavirus disease 2019 (COVID-19) pandemic, a hospital-based online patients support program called Online AYA Hiroba was launched for AYA patients with cancer and held regularly by the National Cancer Center Hospital in Japan. This retrospective study suggested the degree of satisfaction with this program and issues about facilitating the sessions that are unique to the online environment. Our findings potentially contribute to the establishment of a hospital-based online patients support program for AYA patients with cancer at other hospitals.

A Questionnaire Survey on Adolescent and Young Adult Hiroba, a Peer Support System for Adolescent and Young Adult Cancer Patients at a Designated Cancer Center in Japan.

Adolescent and young adult (AYA) cancer patients have few opportunities to interact with peers in the hospital. AYA Hiroba, a peer support system for AYA cancer patients, was launched and held regularly at the National Cancer Center Hospital in Japan. This questionnaire survey was conducted to investigate the degree of satisfaction and opinions of AYA cancer patients regarding this program. Participants reported that the content was satisfying and useful. Their impressions suggested that AYA Hiroba is potentially effective for promoting interaction with the same generation, change in mood, and acquisition of information.

Effects of transdiagnostic group treatment for sleep disturbances in adult attention-deficit/hyperactivity disorders and autistic spectrum disorder: a pilot study.

Although adult patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often have sleep problems, few studies have verified the effect of a psychological approach specific to sleep-wake rhythms on these sleep disturbances. Therefore, the aim of this pilot study was to develop a trans-diagnostic approach with sleep scheduling and regularity of sleep duration as core modules, and to examine the effect of the intervention in adult ADHD and/or ASD subjects with sleep disturbances. This was a within-group pilot study. Ten patients with adult ADHD and/or ASD with sleep disturbances (10 males, age: 27.4 ± 5.6 years) took part in a 90-min weekly group intervention for 5 weeks. All participants were assessed on scales for sleep complaints, anxiety, depression, and symptoms of ADHD and ASD before and after the intervention, and at 3-month follow-up. The results showed that the intervention significantly improved sleep disturbances at post-intervention (p = 0.003, d = 1.30, 95% CI 0.31-2.28) and at the 3-month follow-up (p = 0.035, d = 0.41, 95% CI - 0.48 to 1.30). In addition, attention switching for ASD symptoms was significantly reduced post-intervention (p = 0.031, d = 1.16, 95% CI 0.19-2.13). This is the first pilot study of a trans-diagnostic group approach for adult ADHD and/or ASD with sleep disturbances. The intervention primarily led to an improvement of sleep disturbances, followed by improvement of disease-specific symptoms in adult subjects with ADHD and ASD.

Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers.

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

Stability of human salivary extracellular vesicles containing dipeptidyl peptidase IV under simulated gastrointestinal tract conditions.

BACKGROUND: Extracellular vesicles (EVs) have been isolated from various sources, including primary and cultured cell lines and body fluids. Previous studies, including those conducted in our laboratory, have reported the stability of EVs under various storage conditions. METHODS: EVs from human whole saliva were separated via size-exclusion chromatography. To simulate the effects of gastric or intestinal fluids on the stability of EVs, pepsin or pancreatin was added to the samples. Additionally, to determine the effect of bile acids, sodium cholate was added. The samples were then subjected to western blotting, dynamic light scattering, and transmission electron microscopy analyses. In addition, the activity of dipeptidyl peptidase (DPP) IV retained in the samples was examined to monitor the stability of EVs. RESULTS: Under acidic conditions, with pepsin mimicking the milieu of the stomach, the EVs remained stable. However, they partially lost their membrane integrity in the presence of pancreatin and sodium cholate, indicating that they may be destabilized after passing through the duodenum. Although several associated proteins, such as mucin 5B and CD9 were degraded, DPP IV was stable, and its activity was retained under the simulated gastrointestinal conditions. CONCLUSION: Our data indicate that although EVs can pass through the stomach without undergoing significant damage, they may be disrupted in the intestine to release their contents. The consistent delivery of active components such as DPP IV from EVs into the intestine might play a role in the efficient modulation of homeostasis of the signal transduction pathways occurring in the gastrointestinal tract.

Bone Marrow Mononuclear Cells Transplantation and Training Increased Transplantation of Energy Source Transporters in Chronic Stroke.

OBJECTIVES: Bone marrow mononuclear cells (BM-MNC) show a significant therapeutic effect in combination with training even in the chronic phase of stroke. However, the mechanism of this combination therapy has not been investigated. Here, we examined its effects on brain metabolism in chronic stroke mice. MATERIALS AND METHODS: BM-MNC (1x105 cells in 100 µL of phosphate-buffered saline) were intravenously transplanted at 4 weeks (chronic stage) after the middle cerebral artery occlusion. At 3 h and 10 weeks after the administration of BM-MNC, we evaluated transcription changes of the metabolism-related genes, hypoxia inducible factor 1-α (Hif-1α), prolyl hydroxylase 3 (Phd3), pyruvate dehydrogenase kinase 1 (Pdk1), Na+/K+-ATPase (Atp1α1‒3), connexins, glucose transporters, and monocarboxylate transporters, in the brain during chronic phase of stroke using quantitative polymerase chain reaction. RESULTS: The results showed transcriptional activation of the metabolism-related genes in the contralateral cortex at 3 h after BM-MNC transplantation. Behavioral tests were performed after cell therapy, and the brain metabolism of mice with improved motor function was examined at 10 weeks after cell therapy. The therapeutic efficacy of the combination therapy with BM-MNC transplantation and training was evident in the form of transcriptional activation of ipsilateral anterior cerebral artery (ACA) cortex. CONCLUSIONS: BM-MNC transplantation combined with training for chronic stroke activated gene expression in both the ipsilateral and the contralateral side.

Gap junction-mediated cell-cell interaction between transplanted mesenchymal stem cells and vascular endothelium in stroke.

We have shown previously that transplanted bone marrow mononuclear cells (BM-MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction-mediated cell-cell interaction. In the present study, we investigated such cell-cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM-MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction-mediated cell-cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction-mediated cell-cell interaction is one of the major pathways for MSC-mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood-brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID-19 (coronavirus disease 2019).

Quality Assessment of the Literature on Quality Improvement in PICUs: A Systematic Review.

OBJECTIVES: To synthesize the literature describing quality improvement in PICUs and to appraise the quality of extant research. DATA SOURCES: We searched the PubMed, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Central Register of Controlled Trials databases between May and June 2020. STUDY SELECTION: Peer-reviewed articles in English that report quality improvement interventions in PICUs were included. Titles and abstracts were screened, and articles were reviewed to determine whether they met quality improvement criteria. DATA EXTRACTION: Data were abstracted using a structured template. The quality of the included articles was assessed using the Quality Improvement Minimum Quality Criteria Set and scored on a scale of 0-16. DATA SYNTHESIS: Of the 2,449 articles identified, 158 were included in the analysis. The most common targets of quality improvement interventions were healthcare-associated infections (n = 17, 10.8%), handoffs (n = 15, 9.5%), rounds (n = 13, 8.2%), sedation/pain/delirium (n = 13, 8.2%), medication safety (n = 11, 7.0%), and unplanned extubation (n = 9, 5.7%). Of the six domains of healthcare quality described by the Institute of Medicine, patient-centeredness and timeliness were infrequently addressed, and none of the studies addressed equity. The median quality score based on the Quality Improvement Minimum Quality Criteria Set was 11.0 (25-75th interquartile range, 9.0-13.0). Although the quantity and quality of articles have been increasing, only 17% of the studies were deemed "high quality," having a score between 14 and 16. Only eight articles (5%) cited Standards for QUality Improvement Reporting Excellence guidelines for reporting quality improvement works. CONCLUSIONS: The number of publications, including high-quality publications, on quality improvement interventions in PICUs has been increasing. However, low-quality articles continue to be published, even in recent years. Therefore, there is room for improvement in the quality of reporting.

Early dark cortical band sign on CT for differentiating clear cell renal cell carcinoma from fat poor angiomyolipoma and detecting peritumoral pseudocapsule.

OBJECTIVES: To retrospectively evaluate whether the early dark cortical band (EDCB) on CT can be a predictor to differentiate clear cell renal cell carcinoma (ccRCC) from fat poor angiomyolipoma (Fp-AML) and to detect peritumoral pseudocapsules in ccRCC. METHODS: The EDCBs, which are comprised of unenhanced thin lines at the tumor-renal cortex border in the corticomedullary phase, on the CT images of 342 patients who underwent partial nephrectomy were evaluated. Independent predictors among the clinical and CT findings for differentiating ccRCC from Fp-AML were identified using multivariate analyses. The diagnostic performance of the EDCB for diagnosing peritumoral pseudocapsule in ccRCC and differentiating ccRCC from Fp-AML was calculated. RESULTS: The EDCB was observed in 157 of 254 (61.8%) ccRCCs, 4 of 31 (12.9%) chromophobe RCCs, 1 of 21 (4.8%) papillary RCCs, 3 of 11 (27.3%) clear cell papillary RCCs, 3 of 8 (37.5%) oncocytomas, and 0 of 17 (0%) Fp-AMLs. There was substantial interobserver agreement for the EDCB (k = 0.719). The EDCB was a significant predictor for differentiating ccRCC from Fp-AML (p < 0.001). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value of the EDCB for differentiating ccRCC from Fp-AML were 61.8%, 100%, 100%, and 14.9%, respectively, and those for detecting pseudocapsule in 236 ccRCCs were 62.3%, 68.8%, 96.5%, and 11.7%, respectively. CONCLUSION: Although diagnostic accuracy of the EDCB for detecting peritumoral pseudocapsule in RCC is inadequate, it can be a predictor for differentiating ccRCC from Fp-AML with high specificity and PPV. KEY POINTS: • The early dark cortical band (EDCB) sign is observed in nearly two-thirds of clear cell renal cell carcinoma (ccRCC) that are treated by partial nephrectomy and have substantial interobserver agreement. • The EDCB is a significant predictor for differentiating ccRCCs from fat poor angiomyolipomas, with a high specificity and positive predictive value. • Diagnostic accuracy of the EDCB for detecting peritumoral pseudocapsule in ccRCC is inadequate, though better than those in the nephrographic and excretory-phase images.