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Background Determine if apneic oxygenation (AO) delivered via nasal cannula during the apneic phase of tracheal intubation (TI), reduces adverse TI-associated events (TIAEs) in children. Methods AO was implemented across 14 pediatric intensive care units as a quality improvement intervention during 2016–2020. Implementation consisted of an intubation safety checklist, leadership endorsement, local champion, and data feedback to frontline clinicians. Standardized oxygen flow via nasal cannula for AO was as follows: 5 L/min for infants (< 1 year), 10 L/min for young children (1–7 years), and 15 L/min for older children (≥ 8 years). Outcomes were the occurrence of adverse TIAEs (primary) and hypoxemia (SpO 2  < 80%, secondary). Results Of 6549 TIs during the study period, 2554 (39.0%) occurred during the pre-implementation phase and 3995 (61.0%) during post-implementation phase. AO utilization increased from 23 to 68%, p  < 0.001. AO was utilized less often when intubating infants, those with a primary cardiac diagnosis or difficult airway features, and patient intubated due to respiratory or neurological failure or shock. Conversely, AO was used more often in TIs done for procedures and those assisted by video laryngoscopy. AO utilization was associated with a lower incidence of adverse TIAEs (AO 10.5% vs. without AO 13.5%, p  < 0.001), aOR 0.75 (95% CI 0.58–0.98, p  = 0.03) after adjusting for site clustering (primary analysis). However, after further adjusting for patient and provider characteristics (secondary analysis), AO utilization was not independently associated with the occurrence of adverse TIAEs: aOR 0.90, 95% CI 0.72–1.12, p  = 0.33 and the occurrence of hypoxemia was not different: AO 14.2% versus without AO 15.2%, p  = 0.43. Conclusion While AO use was associated with a lower occurrence of adverse TIAEs in children who required TI in the pediatric ICU after accounting for site-level clustering, this result may be explained by differences in patient, provider, and practice factors. Trial Registration Trial not registered.

Pediatric intensive care unit (PICU)-associated delirium contributes to a decline in postdischarge quality of life, with worse outcomes for individuals with delayed identification. As delirium screening rates remain low within PICUs, caregivers may be able to assist with early detection, for which they need more education, as awareness of pediatric delirium among caregivers remains limited. This study aimed to develop an educational tool for caregivers to identify potential delirium symptoms during their child's PICU stay, educate them on how to best support their child if they experience delirium, and guide them to relevant family resources. Web-based focus groups were conducted at a tertiary pediatric hospital with expected end users of the tool (ie, PICU health care professionals and caregivers of children with an expected PICU length of stay of over 48 h) to identify potential educational information for inclusion in a family resource guide and to identify strategies for effective implementation. Data were analyzed thematically to generate requirements to inform prototype development. Participants then provided critical feedback on the initial prototype, which guided the final design. In all, 24 participants (18 health care professionals and 6 caregivers) attended 7 focus groups. Participants identified five informational sections for inclusion: (1) delirium definition, (2) key features of delirium (signs and symptoms), (3) postdischarge outcomes associated with delirium, (4) tips to inform family-centered care, and (5) education or supportive resources. Participants identified seven design requirements: information should (1) be presented in an order that resembles the structure of the clinical discussion around delirium; (2) increase accessibility, recall, and preparedness by providing multiple formats; (3) aim to reduce stress by implementing positive framing; (4) minimize cognitive load to ensure adequate information processing; (5) provide supplemental electronic resources via QR codes; (6) emphasize collaboration between caregivers and the health care team; and (7) use prompting questions to act as a call to action for caregivers. Key design requirements derived from end-user feedback were established and guided the development of a novel pediatric delirium education tool. Implementing this tool into regular practice has the potential to reduce distress and assist in the early recognition and treatment of delirium in the PICU domain. Future evaluation of its clinical utility is necessary.

BackgroundViral respiratory tract infections (vRTIs) are a leading cause of paediatric hospitalisation and healthcare utilisation. Existing syndromic surveillance tools, including the WHO Severe Acute Respiratory Infection definition, demonstrate limited diagnostic accuracy in children whose symptom profiles vary widely. This study aimed to develop a machine learning (ML) model to predict microbiologically confirmed vRTIs in hospitalised children and to evaluate performance across age groups and viral pathogens.MethodsWe conducted a retrospective cross-sectional study of 2050 paediatric patients (<18 years) admitted with acute respiratory infections to two tertiary paediatric hospitals in Canada. Predictors included age, sex, hospital transfer status, chronic comorbidity status and 22 presenting symptoms. The primary outcome was microbiologically confirmed vRTI, determined by multiplex PCR or rapid antigen testing. Six ML algorithms were trained and the best-performing model, identified by area under the receiver operating characteristic curve (auROC), was tested on age subgroups, viral pathogens and sites.ResultsAmong 2050 patients (median (IQR) age 2.4 (0.8–5.2) years), 1831 (89.3%) tested positive, most commonly for respiratory syncytial virus (RSV) (38.7%) and enterovirus/rhinovirus (32.8%). Logistic regression with L2 regularisation demonstrated the best performance (auROC, 0.754; 95% CI 0.697 to 0.808; sensitivity, 69.2%; specificity, 69.9%), with greatest performance among children <1 year (auROC, 0.763) and RSV cases (auROC, 0.727).ConclusionsAn ML-based logistic regression model using admission data accurately predicted paediatric vRTIs, outperforming traditional syndromic surveillance definitions, especially among infants <1 year. By integrating ML models into hospital electronic medical records, healthcare systems can achieve enhanced respiratory virus surveillance, faster outbreak detection, greater diagnostic efficiency and improved pandemic preparedness.

Regional citrate anticoagulation has become a common alternative to systemic heparinization in adult continuous venovenous hemofiltration (CVVH) practice. We report our experience with the technique in critically ill children. We carried out a retrospective chart review of a 22-bed pediatric intensive care unit. CVVH with pre-filter citrate and systemic calcium replacement infusions was performed according to a strict protocol in nine consecutive critically ill children. All charts were reviewed for patient characteristics and CVVH circuit parameters, including filter survival. All complications were noted. Nurse specialists were interviewed about the practical management of citrate anticoagulation. All patient measurements of blood urea nitrogen, creatinine, sodium, ionized calcium (iCa), potassium, and bicarbonate were collected over the CVVH period. In seven patients, 12 simultaneous citrate measurements were taken from patient blood, pre-filter blood, and hemofiltrate fluid. Nine patients (mean age 8.8+/-6.8 years) were treated with CVVH and regional citrate anticoagulation for 1-14 days (mean 5.2+/-4.0 days). Of 19 filters used, 15 were replaced non-electively (mean filter survival 55.6+/-22.0 h). Control of azotemia and hyperkalemia was good. Sodium and iCa levels were well maintained. Bicarbonate levels were elevated in four patients without adverse effects. The mean systemic citrate level at equilibrium was 1.6+/-0.23 mmol/l. No systemic bleeding complications were observed. In children, regional citrate anticoagulation provides equivalent filter survival to heparin without bleeding complications. With good staff preparation, it is simple to perform and safe with respect to metabolic side effects.

Objective: The objectives of our study were to determine the incidence of catheter-associated blood stream infection (CA-BSI) pre- and postintroduction of our CA-BSI bundle. Design: Retrospective chart review for 2004 and prospective descriptive study for 2005. Setting: A tertiary referral, university affiliated, medical-surgical pediatric intensive care unit with 22 beds and approximately 1100 admissions per year. Patients: All patients who were admitted to our unit who had any documented CA-BSI according to the Centre for Disease Control criteria between January 2004 and December 2005. Interventions: Education and institution of a bundle for decreasing CA-BSI. The CA-BSI bundle was adapted for pediatrics and included components for catheter insertion and ongoing catheter maintenance. Measurements and Main Results: Cases of CA-BSI were collected and rates per 1000 line days and per 1000 admissions were calculated pre institution of bundle (January to September 2004), during institution (October 2004 to May 2005) and postinstitution (June 2005 to December 2005). Infection rates per 1000 line days decreased from pre 8.8 (17/1934; 95% confidence interval [CI], 5.2–14) to during 1.8 (3/1665; 95% CI, 0.4–5.3) and post 2.2 (3/1367; 55% CI, 0.4–6.4). Decreases per 1000 admissions were also seen: pre 18.3 (17/928; 95% CI, 10.7–29), during 4.3 (3/691; 95% CI, 0.9–12.3) and post 5.1 (3/583; 95% CI, 1–15). Conclusion: Strategies aimed at reducing CA-BSI appear to be effective.

Due to the poor prognosis of advanced metastatic melanoma, it is crucial to find early biomarkers that help identify which melanomas will metastasize. By comparing the gene expression data from primary and cutaneous melanoma samples from The Cancer Genome Atlas (TCGA), we identified GPC6 among a set of genes whose expression levels can distinguish between primary melanoma and regional cutaneous/subcutaneous metastases. Glypicans are thought to play a role in tumor growth by regulating the signaling pathways of Wnt, Hedgehogs, fibroblast growth factors (FGFs), and bone morphogenetic proteins (BMPs). We showed that GPC6 expression was up-regulated in a melanoma cell line compared to normal melanocytes and in metastatic melanoma compared to primary melanoma. Furthermore, GPC6 expression was positively correlated with genes largely involved in cell adhesion and migration in both melanoma samples and in RNA-seq samples from other TCGA tumors. Our results suggest that GPC6 may play a role in tumor metastatic progression. In TCGA melanoma samples, we also showed that GPC6 expression was negatively correlated with miR-509-3p, which has previously been shown to function as a tumor suppressor in various cancer cell lines. We overexpressed miR-509-3p in A375 melanoma cells and showed that GPC6 expression was significantly suppressed. This result suggested that GPC6 was a putative target of miR-509-3p in melanoma. Together, our findings identified GPC6 as an early biomarker for melanoma metastatic progression, one that can be regulated by miR-509-3p.

Nsp15, a uridine specific endoribonuclease conserved across coronaviruses, processes viral RNA to evade detection by host defense systems. Crystal structures of Nsp15 from different coronaviruses have shown a common hexameric assembly, yet how the enzyme recognizes and processes RNA remains poorly understood. Here we report a series of cryo-EM reconstructions of SARS-CoV-2 Nsp15, in both apo and UTP-bound states. The cryo-EM reconstructions, combined with biochemistry, mass spectrometry, and molecular dynamics, expose molecular details of how critical active site residues recognize uridine and facilitate catalysis of the phosphodiester bond. Mass spectrometry revealed the accumulation of cyclic phosphate cleavage products, while analysis of the apo and UTP-bound datasets revealed conformational dynamics not observed by crystal structures that are likely important to facilitate substrate recognition and regulate nuclease activity. Collectively, these findings advance understanding of how Nsp15 processes viral RNA and provide a structural framework for the development of new therapeutics. Nsp15 is a uridine specific endoribonuclease present in all coronaviruses. Here, the authors determine the cryo-EM structures of SARS-CoV-2 Nsp15 in the apo and UTP-bound states, which together with biochemical experiments, mass spectrometry and molecular dynamics simulations provide insights into the catalytic mechanism of Nsp15 and its conformational dynamics.

PELP1 (Proline-, Glutamic acid-, Leucine-rich protein 1) is a large scaffolding protein that functions in many cellular pathways including steroid receptor (SR) coactivation, heterochromatin maintenance, and ribosome biogenesis. PELP1 is a proto-oncogene whose expression is upregulated in many human cancers, but how the PELP1 scaffold coordinates its diverse cellular functions is poorly understood. Here we show that PELP1 serves as the central scaffold for the human Rix1 complex whose members include WDR18, TEX10, and SENP3. We reconstitute the mammalian Rix1 complex and identified a stable sub-complex comprised of the conserved PELP1 Rix1 domain and WDR18. We determine a 2.7 Å cryo-EM structure of the subcomplex revealing an interconnected tetrameric assembly and the architecture of PELP1’s signaling motifs, including eleven LxxLL motifs previously implicated in SR signaling and coactivation of Estrogen Receptor alpha (ERα) mediated transcription. However, the structure shows that none of these motifs is in a conformation that would support SR binding. Together this work establishes that PELP1 scaffolds the Rix1 complex, and association with WDR18 may direct PELP1’s activity away from SR coactivation. PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.

The COVID-19 pandemic has had wide reaching effects especially for people with disabilities. Drawing on Sen’s Capability approach, we explored experiences of people with disabilities and older adults using semi-structured interviews that were conducted three to four months after the pandemic was declared. We recruited 71 adults from British Columbia, Canada: adults with spinal cord injuries (n = 22), adults who have experienced a stroke (n = 26), adults with general disabilities (n = 13), and older adults (over the age of 65) without reported disabilities (n = 10). Our analysis identified one overarching theme: “navigating the new normal: the societal reconfiguration of functionings and capabilities” described the challenges and successes participants experienced during pandemic-related restrictions and regulations. This theme encapsulated three sub-themes: 1) “Trying to stay connected: resuming functionings via alternative means,” 2) “Worrying about future capability opportunities,” and 3) “Wanting to exert control in the face of constrained capabilities.” The pandemic created unique challenges for people with disabilities. The capability approach appears to be a helpful lens to interpret pandemic restrictions among people with disabilities, which could inform future policy.

Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death syndrome and sudden unexplained death in infancy, which includes genetic testing, are provided as these topics were not covered in the previous consensus statement. The most obvious difference encountered for inherited diseases is that randomized and/or blinded studies do not exist in this field. [...]most of the available data derive from registries that have followed patients and recorded outcome information. The final judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all relevant circumstances. The following lifestyle changes are recommended in all patients with a diagnosis of LQTS: (a) Avoidance of QT-prolonging drugs (www.qtdrugs.org) (b) Identification and correction of electrolyte abnormalities that may occur during diarrhea, vomiting, metabolic conditions or imbalanced diets for weight loss. 2.