COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type.

BACKGROUND: COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known. METHODS: Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR+)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components. RESULTS: The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P<0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51-4.24]; P<0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08-1.37]; P<0.005). A significant genetic interaction was observed between the ABO locus and hospitalization for COVID-19 (Pinteraction=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29-2.09]; P=4.8×10-5) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66-1.39]; P=0.82). CONCLUSIONS: Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post-acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.

The relationship between changes in inflammation and locomotor function in sensory phenotypes of central neuropathic pain after spinal cord injury.

Introduction: Central neuropathic pain (CNP) commonly develops in patients after spinal cord injury (SCI), causing debilitating symptoms and sensory abnormalities to mechanical and thermal stimuli. The biological variability of pain phenotypes in individuals has limited the number of positive outcomes. Thus, it is necessary to investigate the physiological processes contributing to sensory changes that develop over time. Objective: To investigate the physiological processes contributing to neuropathic pain sensory changes and locomotor impairments with sensory phenotypes that develop over time. Methods: Using the tail flick and von Frey tests, we performed hierarchical clustering to determine the subpopulation of rats that developed thermal and mechanical sensory abnormalities. To measure inflammation as a potential mediator of CNP phenotypes, we used flow cytometry and immunohistochemistry. Finally, to assess the secondary effects on locomotor recovery, up to 8 weeks after injury, we used the CatWalk test to assess multiple parameters of gait. Results: The von Frey test showed a subpopulation of SCI rats that were hyposensitive to mechanical stimuli from 6 to 8 weeks after injury. The tail flick test showed a subpopulation of SCI rats that were hypersensitive to thermal stimuli at 1 week and 3 to 8 weeks after injury. Although there were no differences in inflammatory cells between subpopulations, we did see significant changes in locomotor recovery between rats with and without sensory abnormalities. Conclusion: The myeloid cell population at large is not affected by mechanical or thermal phenotypes of pain in this model; however, locomotor recovery is impaired depending on the pain phenotype present. Further investigation into acute inflammatory cells may be insightful for predicting the development of pain phenotypes.

Association of SNP-SNP interactions of surfactant protein genes with severity of respiratory syncytial virus infection in children.

The severity of respiratory syncytial virus (RSV) may be linked to host genetic susceptibility. Surfactant protein (SP) genetic variants have been associated with RSV severity, but the impact of single-nucleotide polymorphism (SNP)-SNP interactions remains unexplored. Therefore, we used a novel statistical model to investigate the association of SNP-SNP interactions of SFTP genes with RSV severity in two- and three-interaction models. We analyzed available genotype and clinical data from prospectively enrolled 405 children diagnosed with RSV, categorizing them into moderate or severe RSV groups. Using Wang's statistical model, we studied significant associations of SNP-SNP interactions with RSV severity in a case-control design. We observed, first, association of three interactions with increased risk of severe RSV in a two-SNP model. One intragenic interaction was between SNPs of SFTPA2, and the other two were intergenic, involving SNPs of hydrophilic and hydrophobic SPs alone. We also observed, second, association of 22 interactions with RSV severity in a three-SNP model. Among these, 20 were unique, with 12 and 10 interactions associated with increased or decreased risk of RSV severity, respectively, and included at least one SNP of either SFTPA1 or SFTPA2. All interactions were intergenic except one, among SNPs of SFTPA1. The remaining interactions were either among SNPs of hydrophilic SPs alone (n = 8) or among SNPs of both hydrophilic or hydrophobic SPs (n = 11). Our findings indicate that SNPs of all SFTPs may contribute to genetic susceptibility to RSV severity. However, the predominant involvement of SFTPA1 and/or SFTPA2 SNPs in these interactions underscores their significance in RSV severity.NEW & NOTEWORTHY Although surfactant protein (SP) genetic variants are associated with respiratory syncytial virus (RSV) severity, the impact of single-nucleotide polymorphism (SNP)-SNP interactions of SP genes remained unexplored. Using advanced statistical models, we uncovered 22 SNP-SNP interactions associated with RSV severity, with notable involvement of SFTPA1 and SFTPA2 SNPs. This highlights the comprehensive role of all SPs in genetic susceptibility to RSV severity, shedding light on potential avenues for targeted interventions.

A Pilot Study of Saliva MicroRNA Signatures in Children with Moderate-to-Severe Traumatic Brain Injury.

Background/Objectives: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Currently, no biological test can predict outcomes in pediatric TBI, complicating medical management. This study sought to identify brain-related micro-ribosomal nucleic acids (miRNAs) in saliva associated with moderate-to-severe TBI in children, offering a potential non-invasive, prognostic tool. Methods: A case-control design was used, enrolling participants ≤ 18 years old from three pediatric trauma centers. Participants were divided into moderate-to-severe TBI and non-TBI trauma control groups. Saliva samples were collected within 24 h of injury, with additional samples at 24-48 h and >48 h post-injury from the TBI group. miRNA profiles were visualized with partial least squares discriminant analysis (PLSDA) and hierarchical clustering. Mann-Whitney testing was used to compare miRNAs between groups, and mixed models were used to assess longitudinal expression patterns. DIANA miRPath v3.0 was used to interrogate the physiological functions of miRNAs. Results: Twenty-three participants were enrolled (14 TBI, nine controls). TBI and control groups displayed complete separation of miRNA profiles on PLSDA. Three miRNAs were elevated (adj. p < 0.05) in TBI (miR-1255b-5p, miR-3142, and miR-4320), and two were lower (miR-326 and miR-4646-5p). Three miRNAs (miR-3907, miR-4254, and miR-1273g-5p) showed temporal changes post-injury. Brain-related targets of these miRNAs included the glutamatergic synapse and GRIN2B. Conclusions: This study shows that saliva miRNA profiles in children with moderate-to-severe TBI may differ from those with non-TBI trauma and exhibit temporal changes post-injury. These miRNAs could serve as non-invasive biomarkers for prognosticating pediatric TBI outcomes. Further studies are needed to confirm these findings.

An evolving roadmap: using mitochondrial physiology to help guide conservation efforts.

The crucial role of aerobic energy production in sustaining eukaryotic life positions mitochondrial processes as key determinants of an animal's ability to withstand unpredictable environments. The advent of new techniques facilitating the measurement of mitochondrial function offers an increasingly promising tool for conservation approaches. Herein, we synthesize the current knowledge on the links between mitochondrial bioenergetics, ecophysiology and local adaptation, expanding them to the wider conservation physiology field. We discuss recent findings linking cellular bioenergetics to whole-animal fitness, in the current context of climate change. We summarize topics, questions, methods, pitfalls and caveats to help provide a comprehensive roadmap for studying mitochondria from a conservation perspective. Our overall aim is to help guide conservation in natural populations, outlining the methods and techniques that could be most useful to assess mitochondrial function in the field.

Streamlining the Conduct of Cancer Clinical Trials: New Standard Data Collection Practices for National Cancer Institute Late Phase Clinical Studies.

The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late phase trials which enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the impact of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress towards implementation, and the development of new streamlined standard practices for data collection for late phase NCTN trials effective January 1, 2025.

A Multi-Center Retrospective Database Evaluation of Pediatric Subjects Diagnosed With Methemoglobinemia.

Background: Methemoglobinemia requires early identification and treatment, but limited knowledge exists regarding the current therapeutic approach taken by clinicians as well as the outcomes that occur in children. Objectives: To determine the current prevalence of this rare disease in the pediatric population, evaluate the impact of methemoglobin and functional hemoglobin levels, and assess how this disease is approached by clinicians. We hypothesize that methemoglobinemia prevalence is low and more methylene blue use would be observed in subjects with functional hemoglobin levels less than 7 g/dL. Design: This was a retrospective observational cohort study utilizing deidentified TriNetX® electronic health record (EHR) data. Methods: Using a multicenter EHR database, we evaluated subjective characteristics, diagnostic, laboratory results, medication, and procedural codes. Results: Ninety-eight children (mean age 5.3 ± 5.3 years) from 53 healthcare organizations were included. Methemoglobinemia prevalence was 0.0015% with an overall 30-day mortality of 6.1%. Subjects with methemoglobin percentages greater than 20% had a higher frequency of methylene blue administration (70.6% versus 24.7%, P = .0005). Critical care service requirements and methylene blue administration were similar in the subjects with functional hemoglobin less than 7 g/dL and more than 7 g/dL groups. Overall, 13 (13.2%) subjects underwent glucose-6-phosphate dehydrogenase deficiency (G6PD) testing. Conclusion: In our study, we found methemoglobinemia prevalence in children is low, there is a low frequency of G6PD testing despite methylene blue hemolysis risk, and subjects appeared to be treated similarly despite a low functional hemoglobin. These findings highlight the continued critical nature of this disease and may highlight opportunities for education aimed at improving care in children diagnosed with methemoglobinemia, particularly related to G6PD testing.

Supraventricular tachycardia diagnosis in asthma patients is associated with adverse health outcomes.

INTRODUCTION: Supraventricular tachycardia (SVT) can occur during treatment of an acute asthma exacerbation. There are, however, no data on the long-term outcomes of children who are diagnosed with both asthma and SVT. This study aims to analyze the impact of SVT in asthmatic children on mortality and/or cardiac arrest, hypothesizing asthmatic subjects with SVT have increased mortality and/or cardiac arrest compared to asthmatic subject with no-SVT. METHODS: This was a retrospective cohort study, utilizing the TriNetX© electronic health record (EHR) database that included asthmatic subjects 2-18 years of age. The study population was divided into two groups (subjects with SVT diagnosis and no-SVT diagnosis). Data related to demographics, diagnostic, procedural, and medication codes were collected. The primary outcome was any death and/or cardiac arrest in a patient after the first asthma diagnosis date. RESULTS: This study included 91,066 asthmatic subjects (244 [0.27%] with SVT and 90,822 [99.73%] with no-SVT). Multivariable logistic regression analysis demonstrated that after controlling for demographic and clinical features, the odds of all-cause death and/or cardiac arrest after the first reported asthma exacerbation was significantly higher in asthmatic children with SVT compared to no-SVT (odds ratio [OR]: 4.30, confidence interval [CI]: 2.50-7.39, p < .001). CONCLUSIONS: Our large nationwide EHR study suggests that asthmatic pediatric patients with documented SVT diagnosis at any point in their EHR may be at increased risk of adverse health outcomes compared to no-SVT. Further studies are needed to determine the factors contributing to the increased risk of mortality and/or cardiac arrest in children with asthma and SVT.

Diagnostic Validation of the Updated Pediatric Sepsis Biomarker Risk II for Acute Kidney Injury Prediction Model in Pediatric Septic Shock.

OBJECTIVES: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed. DESIGN: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022. SETTING: Ten PICUs in the United States. PATIENTS: Children with septic shock 1 week to 18 years old admitted to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69). CONCLUSIONS: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations.

Re-Envisioning Electronic Health Records to Optimize Patient-Centered Cancer Care, Quality, Surveillance, and Research.

Electronic health records (EHRs) are a significant advancement over paper records. However, the full potential of EHRs for improving care quality, patient outcomes, surveillance, and research in cancer care is yet to be realized. The organic evolution of EHRs has resulted in a number of unanticipated consequences including increased time spent by clinicians interfacing with the EHR for daily workflows. Patient access to clinicians and their records has been an important advancement in patient-centered care; however, this has brought to light additional gaps and challenges in EHRs meeting these needs. A significant challenge for EHR design and physician workflows is how best to meet the complex goals and priorities of various stakeholders including providers, researchers, patients, health systems, payors, and regulatory agencies. The National Cancer Policy Forum convened a 2022 workshop, "Innovations in Electronic Health Records for Oncology Care, Research and Surveillance," to address these challenges and to facilitate collaboration across all user groups with the goal of re-envisioning EHRs that will better support shared goals of improving patient outcomes and advancing cancer care and research without overburdening clinicians with administrative tasks. Here, we summarize the current EHR ecosystem as discussed at the workshop and highlight opportunities to improve EHR contributions to oncology evidence and care.

Are community oncology practices with or without clinical research programs different? A comparison of patient and practice characteristics.

BACKGROUND: Expanding access to clinical trials in community settings is a potential approach to addressing disparities in accrual of historically underrepresented populations. However, little is known about the characteristics of practices that do not participate in research. We investigated differences in patient and practice characteristics of US community oncology practices with high vs low engagement in clinical research. METHODS: We included patients from a real-world, nationwide electronic health record-derived, de-identified database who received active treatment for cancer at community oncology practices between November 1, 2017, and October 31, 2022. We assessed patient and practice characteristics and their associations with high vs low research engagement using descriptive analyses and logistic regression models. RESULTS: Of the 178 practices, 70 (39.3%) events had high research engagement, treated 57.8% of the overall 568 540 patient cohort, and enrolled 3.25% of their patients on cancer treatment trials during the 5-year observation period (vs 0.27% enrollment among low engagement practices). Practices with low vs high research engagement treated higher proportions of the following patient groups: ages 75 years and older (24.2% vs 21.8%), non-Latinx Black (12.6% vs 10.3%) or Latinx (11.6% vs 6.1%), were within the lowest socioeconomic status quintile (21.9% vs16.5%), and were uninsured or had no documented insurance (22.2% vs 13.6%). CONCLUSIONS: Patient groups historically underrepresented in oncology clinical trials are more likely to be treated at community practices with limited or no access to trials. These results suggest that investments to expand the clinical research footprint among practices with low research engagement could help address persistent inequities in trial representation.

Consistent changes in muscle phenotype and mitochondrial abundance underlie dive performance across multiple lineages of diving ducks.

Diving animals must sustain high muscle activity with finite oxygen (O2) to forage underwater. Studies have shown that some diving mammals exhibit changes in the metabolic phenotype of locomotory muscles compared with non-divers, but the pervasiveness of such changes across diving animals is unclear, particularly among diving birds. Here, we examined whether changes in muscle phenotype and mitochondrial abundance are associated with dive capacity across 17 species of ducks from three distinct evolutionary clades (tribes) in the subfamily Anatinae: the longest diving sea ducks, the mid-tier diving pochards and the non-diving dabblers. In the gastrocnemius (the primary swimming and diving muscle), mitochondrial volume density in both oxidative and glycolytic fiber types was 70% and 30% higher in sea ducks compared with dabblers, respectively. These differences were associated with preferential proliferation of the subsarcolemmal subfraction, the mitochondria adjacent to the cell membrane and nearest to capillaries, relative to the intermyofibrillar subfraction. Capillary density and capillary-to-fiber ratio were positively correlated with mitochondrial volume density, with no variation in the density of oxidative fiber types across tribes. In the pectoralis, sea ducks had greater abundance of oxidative fiber types than dabblers, whereas pochards were intermediate between the two. These data suggest that skeletal muscles of sea ducks have a heightened capacity for aerobic metabolism and an enhanced ability to utilize O2 stores in the blood and muscle while diving.

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

Identification and transcriptomic assessment of latent profile pediatric septic shock phenotypes.

BACKGROUND: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches. METHODS: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme. RESULTS: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes. CONCLUSIONS: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill.

A Single-Center Retrospective Evaluation of Unplanned Pediatric Critical Care Upgrades.

Background Inappropriate triage of critically ill pediatric patients can lead to poor outcomes and suboptimal resource utilization. This study aimed to determine and describe the demographic characteristics, diagnostic categories, and timing of unplanned upgrades to the pediatric intensive care unit (PICU) that required short (< 24 hours of care) and extended (≥ 24 hours of care) stays. In this article, we hypothesized that we will identify demographic characteristics, diagnostic categories, and frequent upgrade timing periods in both of these groups that may justify more optimal triage strategies. Methods This was a single-institution retrospective study of unplanned PICU upgrades between 2012 and 2018. The cohort was divided into two groups (short and extended PICU stay). We reviewed the electronic health record and evaluated for: demographics, mortality scores, upgrade timing (7a-3p, 3p-11p, 11p-7a), lead-in time (time spent on clinical service before upgrade), patient origin, and diagnostic category. Results Four hundred and ninety-eight patients' unplanned PICU upgrades were included. One hundred and nine patients (21.9%) required a short and 389 (78.1%) required an extended PICU stay. Lead-in time (mean, standard deviation) was significantly lower in the short group (0.65 ± 0.66 vs. 0.91 ± 0.82) ( p = 0.0006). A higher proportion of short group patients (59, 46.1%) were upgraded during the 3p-11p shift ( p = 0.0077). Conclusion We found that approximately one-fifth of PICU upgrades required less than 24 hours of critical care services, were more likely to be transferred between 3p-11p, and had lower lead-in times. In institutions where ill pediatric patients can be admitted to either a PICU or a monitored step-down unit, this study highlights quality improvement opportunities, particularly in recognizing which pediatric patients truly need critical care.

Outcomes of critically ill children with pre-existing mental health conditions.

Importance: Critically ill children with pre-existing mental health conditions may have an increased risk of poor health outcomes. Objective: We aimed to evaluate if pre-existing mental health conditions in critically ill pediatric patients would be associated with worse clinical outcomes, compared to children with no documented mental health conditions. Methods: This retrospective observational cohort study utilized the TriNetX electronic health record database of critically ill subjects aged 12-18 years. Data were analyzed for demographics, pre-existing conditions, diagnostic, medication, procedural codes, and mortality. Results: From a dataset of 102 027 critically ill children, we analyzed 1999 subjects (284 [14.2%] with a pre-existing mental health condition and 1715 [85.8%] with no pre-existing mental health condition). Multivariable analysis demonstrated that death within one year was associated with the presence of pre-existing mental health conditions (odds ratio 8.97 [3.48-23.15], P < 0.001), even after controlling for the presence of a complex chronic condition. Interpretation: The present study demonstrates that the presence of pre-existing mental health conditions was associated with higher odds of death within 1 year after receiving critical care. However, the confidence interval was wide and hence, the findings are inconclusive. Future studies with a larger sample size may be necessary to evaluate the true long-term impact of children with pre-existing mental health conditions who require critical care services.

Climate change may shift metapopulations towards unstable source-sink dynamics in a fire-killed, serotinous shrub.

Climate change, with warming and drying weather conditions, is reducing the growth, seed production, and survival of fire-adapted plants in fire-prone regions such as Mediterranean-type ecosystems. These effects of climate change on local plant demographics have recently been shown to reduce the persistence time of local populations of the fire-killed shrub Banksia hookeriana dramatically. In principle, extinctions of local populations may be partly compensated by recolonization events through long-distance dispersal mechanisms of seeds, such as post-fire wind and bird-mediated dispersal, facilitating persistence in spatially structured metapopulations. However, to what degree and under which assumptions metapopulation dynamics might compensate for the drastically increased local extinction risk remains to be explored. Given the long timespans involved and the complexity of interwoven local and regional processes, mechanistic, process-based models are one of the most suitable approaches to systematically explore the potential role of metapopulation dynamics and its underlying ecological assumptions for fire-prone ecosystems. Here we extend a recent mechanistic, process-based, spatially implicit population model for the well-studied fire-killed and serotinous shrub species B. hookeriana to a spatially explicit metapopulation model. We systematically tested the effects of different ecological processes and assumptions on metapopulation dynamics under past (1988-2002) and current (2003-2017) climatic conditions, including (i) effects of different spatio-temporal fires, (ii) effects of (likely) reduced intraspecific plant competition under current conditions and (iii) effects of variation in plant performance among and within patches. In general, metapopulation dynamics had the potential to increase the overall regional persistence of B. hookeriana. However, increased population persistence only occurred under specific optimistic assumptions. In both climate scenarios, the highest persistence occurred with larger fires and intermediate to long inter-fire intervals. The assumption of lower intraspecific plant competition caused by lower densities under current conditions alone was not sufficient to increase persistence significantly. To achieve long-term persistence (defined as >400 years) it was necessary to additionally consider empirically observed variation in plant performance among and within patches, that is, improved habitat quality in some large habitat patches (≥7) that could function as source patches and a higher survival rate and seed production for a subset of plants, specifically the top 25% of flower producers based on current climate conditions monitoring data. Our model results demonstrate that the impacts of ongoing climate change on plant demographics are so severe that even under optimistic assumptions, the existing metapopulation dynamics shift to an unstable source-sink dynamic state. Based on our findings, we recommend increased research efforts to understand the consequences of intraspecific trait variation on plant demographics, emphasizing the variation of individual traits both among and within populations. From a conservation perspective, we encourage fire and land managers to revise their prescribed fire plans, which are typically short interval, small fires, as they conflict with the ecologically appropriate spatio-temporal fire regime for B. hookeriana, and likely as well for many other fire-killed species.

A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Helical twists and ß-turns in structures at serine-proline sequences: Stabilization of cis-proline and type VI ß-turns via C-H/O interactions.

Structures at serine-proline sites in proteins were analyzed using a combination of peptide synthesis with structural methods and bioinformatics analysis of the PDB. Dipeptides were synthesized with the proline derivative (2S,4S)-(4-iodophenyl)hydroxyproline [hyp(4-I-Ph)]. The crystal structure of Boc-Ser-hyp(4-I-Ph)-OMe had two molecules in the unit cell. One molecule exhibited cis-proline and a type VIa2 ß-turn (BcisD). The cis-proline conformation was stabilized by a C-H/O interaction between Pro C-Hα and the Ser side-chain oxygen. NMR data were consistent with stabilization of cis-proline by a C-H/O interaction in solution. The other crystallographically observed molecule had trans-Pro and both residues in the PPII conformation. Two conformations were observed in the crystal structure of Ac-Ser-hyp(4-I-Ph)-OMe, with Ser adopting PPII in one and the ß conformation in the other, each with Pro in the δ conformation and trans-Pro. Structures at Ser-Pro sequences were further examined via bioinformatics analysis of the PDB and via DFT calculations. Ser-Pro versus Ala-Pro sequences were compared to identify bases for Ser stabilization of local structures. C-H/O interactions between the Ser side-chain Oγ and Pro C-Hα were observed in 45% of structures with Ser-cis-Pro in the PDB, with nearly all Ser-cis-Pro structures adopting a type VI ß-turn. 53% of Ser-trans-Pro sequences exhibited main-chain COi•••HNi+3 or COi•••HNi+4 hydrogen bonds, with Ser as the i residue and Pro as the i + 1 residue. These structures were overwhelmingly either type I ß-turns or N-terminal capping motifs on α-helices or 310-helices. These results indicate that Ser-Pro sequences are particularly potent in favoring these structures. In each, Ser is in either the PPII or ß conformation, with the Ser Oγ capable of engaging in a hydrogen bond with the amide N-H of the i + 2 (type I ß-turn or 310-helix; Ser χ1 t) or i + 3 (α-helix; Ser χ1 g+) residue. Non-proline cis amide bonds can also be stabilized by C-H/O interactions.

Mechanistic Basis of the Cu(OAc)2 Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.