Early prediction of delirium upon intensive care unit admission: Model development, validation, and deployment.

STUDY OBJECTIVE: To develop, validate, and deploy models for predicting delirium in critically ill adult patients as early as upon intensive care unit (ICU) admission. DESIGN: Retrospective cohort study. SETTING: Single university teaching hospital in Taipei, Taiwan. PATIENTS: 6238 critically ill patients from August 2020 to August 2021. MEASUREMENTS: Data were extracted, pre-processed, and split into training and testing datasets based on the time period. Eligible variables included demographic characteristics, Glasgow Coma Scale, vital signs parameters, treatments, and laboratory data. The predicted outcome was delirium, defined as any positive result (a score ≥ 4) of the Intensive Care Delirium Screening Checklist that was assessed by primary care nurses in each 8-h shift within 48 h after ICU admission. We trained models to predict delirium upon ICU admission (ADM) and at 24 h (24H) after ICU admission by using logistic regression (LR), gradient boosted trees (GBT), and deep learning (DL) algorithms and compared the models' performance. MAIN RESULTS: Eight features were extracted from the eligible features to train the ADM models, including age, body mass index, medical history of dementia, postoperative intensive monitoring, elective surgery, pre-ICU hospital stays, and GCS score and initial respiratory rate upon ICU admission. In the ADM testing dataset, the incidence of ICU delirium occurred within 24 h and 48 h was 32.9% and 36.2%, respectively. The area under the receiver operating characteristic curve (AUROC) (0.858, 95% CI 0.835-0.879) and area under the precision-recall curve (AUPRC) (0.814, 95% CI 0.780-0.844) for the ADM GBT model were the highest. The Brier scores of the ADM LR, GBT, and DL models were 0.149, 0.140, and 0.145, respectively. The AUROC (0.931, 95% CI 0.911-0.949) was the highest for the 24H DL model and the AUPRC (0.842, 95% CI 0.792-0.886) was the highest for the 24H LR model. CONCLUSION: Our early prediction models based on data obtained upon ICU admission could achieve good performance in predicting delirium occurred within 48 h after ICU admission. Our 24-h models can improve delirium prediction for patients discharged >1 day after ICU admission.

αvß1 integrin is enriched in extracellular vesicles of metastatic breast cancer cells: A mechanism mediated by galectin-3.

Breast cancer cells release a large quantity of biocargo-bearing extracellular vesicles (EVs), which mediate intercellular communication within the tumour microenvironment and promote metastasis. To identify EV-bound proteins related to metastasis, we used mass spectrometry to profile EVs from highly and poorly metastatic breast cancer lines of human and mouse origins. Comparative mass spectrometry indicated that integrins, including αv and ß1 subunits, are preferentially enriched in EVs of highly metastatic origin over those of poorly metastatic origin. These results are consistent with our histopathological findings, which show that integrin αv is associated with disease progression in breast cancer patients. Integrin αv colocalizes with the multivesicular-body marker CD63 at a higher frequency in the tumour and is enriched in circulating EVs of breast cancer patients at late stages when compared with circulating EVs from early-stage patients. With a magnetic bead-based flow cytometry assay, we confirmed that integrins αv and ß1 are enriched in the CD63+ subsets of EVs from both human and mouse highly metastatic cells. By analysing the level of integrin αv on circulating EVs, this assay could predict the metastatic potential of a xenografted mouse model. To explore the export mechanism of integrins into EVs, we performed immunoprecipitation mass spectrometry and identified members of the galectin family as potential shuttlers of integrin αvß1 into EVs. In particular, knockdown of galectin-3, but not galectin-1, causes a reduction in the levels of cell surface integrins ß1 and αv, and decreases the colocalization of these integrins with CD63. Importantly, knockdown of galectin-3 leads to a decrease of integrin αvß1 export into the EVs concomitant with a decrease in the metastatic potential of breast cancer cells. Moreover, inhibition of the integrin αvß1 complex leads to a reduction in the binding of EVs to fibronectin, suggesting that integrin αvß1 is important for EV retention in the extracellular matrix. EVs retained in the extracellular matrix are taken up by fibroblasts, which differentiate into cancer associated fibroblasts. In summary, our data indicate an important link between EV-bound integrin αvß1 with breast cancer metastasis and provide additional insights into the export of integrin αvß1 into EVs in the context of metastasis.

Internal water channel formation in CXCR4 is crucial for Gi-protein coupling upon activation by CXCL12.

Chemokine receptor CXCR4 is a major drug target for numerous diseases because of its involvement in the regulation of cell migration and the developmental process. In this study, atomic-level molecular dynamics simulations were used to determine the activation mechanism and internal water formation of CXCR4 in complex with chemokine CXCL12 and Gi-protein. The results indicated that CXCL12-bound CXCR4 underwent transmembrane 6 (TM6) outward movement and a decrease in tyrosine toggle switch by eliciting the breakage of hydrophobic layer to form a continuous internal water channel. In the GDP-bound Gαi-protein state, the rotation and translation of the α5-helix of Gαi-protein toward the cytoplasmic pocket of CXCR4 induced an increase in interdomain distance for GDP leaving. Finally, an internal water channel formation model was proposed based on our simulations for CXCL12-bound CXCR4 in complex with Gαi-protein upon activation for downstream signaling. This model could be useful in anticancer drug development.

Diverse presentations in pediatric Meckel's diverticulum: a review of 100 cases.

BACKGROUND: Our objective was to analyze demographics and characteristics of Meckel's diverticulum with different manifestations in pediatric patients. METHODS: This is a retrospective study in children with symptomatic Meckel's diverticulum who underwent resection between September 1998 and October 2010. The diagnosis was confirmed by surgery and pathology. Demographic characteristics, manifestations, Meckel's scan results, surgical and histological findings were analyzed. RESULTS: One hundred symptomatic Meckel's diverticula were identified in 74 boys and 26 girls aged from one day to 18 years old over 13 years. Depending on whether or not obstruction occurred, the patients were classified into two categories. Each category was further subdivided into two diagnostic groups: 17 intussusception and 24 non-intussusception bowel obstruction in the obstructive category and 44 gastrointestinal bleeding and 15 diverticulitis and/or perforation in the non-obstructive category. The sex discrepancy was higher in the non-obstructive category than in the obstructive category (male-to-female, 4.36 vs. 1.73, p < 0.05). Forty-one of 44 patients with gastrointestinal bleeding underwent a Meckel's scan with a high positive rate (92.7%). The ectopic tissues were identified in 73 patients and included 61 gastric type, two pancreatic type and 10 mixed type. Ectopic tissues were more prevalent in non-obstructive category (p < 0.05) with ectopic gastric tissue even more pronounced (p < 0.01). Ectopic pancreatic tissue was significantly more prevalent in intussusception (p < 0.01). Laparoscopic surgery was performed more frequently in Meckel's diverticulum with non-obstructive symptoms (p < 0.001). CONCLUSION: Diverse presentations in pediatric Meckel's diverticulum are affected by different ectopic tissue types and male sex. Laparoscopic surgery is widely used for children with non-obstructive symptoms.

Clinical and economic evidence for intravenous acetaminophen.

Intravenous acetaminophen received United States Food and Drug Administration approval in November 2010 for the management of mild-to-moderate pain, management of moderate-to-severe pain with adjunctive opioid analgesics, and reduction of fever. Although intravenous acetaminophen generally improved pain relief and demonstrated opioid-sparing effects compared with placebo, it did not consistently reduce the frequency of opioid-related adverse events (e.g., postoperative nausea and vomiting). The safety and efficacy of intravenous acetaminophen as an antipyretic agent have been documented in adults and children; however, its cost is several-fold higher than that of the oral and rectal formulations. Although use of intravenous acetaminophen has reduced other postoperative resource utilization (e.g., hospital length of stay) in some studies outside the United States in patients undergoing abdominal surgery, a full economic evaluation in the United States has yet to be undertaken. In addition, its administration time (15-min infusion) and packaging (glass, single-use vial) have the potential to adversely affect patient flow in the postanesthesia care unit, create burden on patient care units, and lead to drug waste. Furthermore, 1 g of intravenous acetaminophen is formulated in 100 ml of solution, which may be an issue for patients with fluid restrictions. Given the clinical and economic evidence currently available, intravenous acetaminophen should not replace oral or rectal acetaminophen, but its use may be considered in a limited number of patients who cannot receive drugs orally and rectally and who cannot tolerate other parenteral nonopioid analgesic or antipyretic agents.

Comparison of healthcare resource use between patients receiving ondansetron or palonosetron as prophylaxis for chemotherapy-induced nausea and vomiting.

OBJECTIVE: To analyze the differences between ondansetron and palonosetron in healthcare resource use (i.e., inpatient/ outpatient encounters) among patients receiving intraperitoneal cisplatin. METHOD: A medical record review was performed. Intraperitoneal cisplatin administrations for gynecological cancers from January through June 2006 and from October 2007 through June 2008 were divided into two groups based on the serotonin-receptor antagonist used. The occurrence of chemotherapy-induced nausea and vomiting (CINV)-related hospital readmissions, emergency department visits, and outpatient encounters occurring within 7 days after cisplatin administration was compared. CINV-related resource use was defined as events associated with dehydration, hypovolemia, nausea/vomiting, hypokalemia, constipation, shortness of breath, or syncope/collapse. RESULTS: Ondansetron or palonosetron was used in 39 and 89 cisplatin administrations, respectively. The baseline characteristics were similar between the groups with mean age of 59 years and ovarian cancer being the most common cancer. Length of stay was approximately 2 days. Palonosetron was always administered as a single-day therapy while one- or multi-day ondansetron therapy was administered in 27% and 73% of cycles, respectively. A trend towards more CINV-related hospitalizations with ondansetron versus palonosetron was observed (5.1% vs. 0%, p = 0.09) with no significant difference in other CINV-related encounters. CONCLUSION: Palonosetron was associated with a trend to a lower risk of CINV-related hospital readmission than ondansetron in patients receiving intraperitoneal cisplatin for gynecological cancers, although not statistically significant. The duration of ondansetron therapy might be suboptimal with 27% of patients receiving only 1 day of therapy during hospital stay. These findings need to be confirmed in future studies.

Use of injectable nicardipine for neurovascular indications.

Injectable nicardipine is increasingly being used to manage neurovascular conditions. To better understand its place in therapy, we conducted an evidenced-based literature review. Two-hundred twenty-three article abstracts were identified; after independent review by two individuals and a supplemental manual search, 29 were deemed relevant and were included in this review. Nicardipine has been studied or recommended for management of hypertension in many neurovascular settings (ischemic stroke, intracerebral hemorrhage, craniotomy, and spinal surgery), for vasospasm in aneurysmal subarachnoid hemorrhage, and in acute traumatic brain injury. In the management of hypertension in acute stroke, nicardipine is one of several recommended options available; expert opinion forms the basis of these recommendations in clinical guidelines, with limited randomized controlled trial evidence to support its use. Among the various antihypertensive agents, nicardipine has the highest drug acquisition cost. In two meta-analyses, intravenous nicardipine had no impact on patient outcomes (death, disability) in patients with acute traumatic brain injury (relative risk [RR] 0.25, 95% confidence interval [CI] 0.05-1.27) or in patients with aneursymal subarachnoid hemorrhage (RR 0.97, 95% CI 0.78-1.20). Intraarterial nicardipine reduced angiographic diameter (p value not reported) and peak systolic velocities on transcranial Doppler images (p<0.001) in published case series. Given nicardipine's high cost relative to that of other agents and the limited evidence to support its use in patients with neurovascular conditions, this drug should be considered only in patients who have failed or have contraindications to alternative agents in the management of hypertension. Although intraarterial nicardipine appears to be promising in aneurysmal subarachnoid hemorrhage, well-designed studies are needed in this setting before its use can be routinely recommended.