Development of an Orally Bioavailable LCK PROTAC Degrader as a Potential Therapeutic Approach to T-Cell Acute Lymphoblastic Leukemia.

Despite significant advances over recent years, the treatment of T cell acute lymphoblastic leukemia (T-ALL) remains challenging. We have recently shown that a subset of T-ALL cases exhibited constitutive activation of the lymphocyte-specific protein tyrosine kinase (LCK) and were consequently responsive to treatments with LCK inhibitors and degraders such as dasatinib and dasatinib-based PROTACs. Here we report the design, synthesis and in vitro/vivo evaluation of SJ45566, a potent and orally bioavailable LCK PROTAC.

Blood Stored In EDTA Tubes Provides Accurate Peanut Basophil Activation Test Results For 48 hours.

BACKGROUND: The peanut basophil activation test (BAT) has demonstrated excellent diagnostic accuracy with heparinized blood, but its clinical utility is limited by the short stability of samples stored in this anticoagulant. OBJECTIVE: Using EDTA anticoagulated blood, these investigations determined if Peanut BAT sample stability can be extended to 2 days, the minimum stability requirement for diagnostic tests currently offered through American reference laboratories. METHODS: Peanut non-allergic control (NAC), peanut IgE sensitized (PS), and peanut allergic (PA) children aged 6 months through 17 years were recruited from members of Kaiser Permanente Southern California. EDTA anti-coagulated blood samples were collected from participants, shipped to a centralized laboratory, and stored at 4oC for peanut BAT testing 1 and 2 days later. RESULTS: Peanut BAT results for 23 unblinded participants were used to establish sample rejection and interpretation criteria that were subsequently validated in a prospective double-blind study involving 112 additional children (39-NAC, 36-PS, 37-PA). Of 105 blinded blood samples tested on each study day, 88 (84%) day-1 and 90 (86%) day-2 peanut BAT results were considered interpretable, with diagnostic accuracies of 95.5% and 94.4%, respectively. Moreover, all interpretable PA results were considered positive (100% sensitivity). CONCLUSION: Using EDTA anti-coagulated blood samples collected remotely, 1 and 2 days before testing, study results highlight the favorable diagnostic performance characteristics of the peanut BAT and provide further evidence that the test could be readily operationalized for clinical use by interested commercial reference laboratories.

Challenges in diagnosis of calcaneal fractures: an examination using the WIDI SIM platform.

INTRODUCTION: The calcaneus is the most commonly fractured tarsal bone. Diagnosis is often challenging due to subtle radiographic changes and requires timely identification to prevent complications, including subtalar arthritis, neurovascular injury, malunion, osteomyelitis, and compartment syndrome. Treatment varies based on fracture type, with non-surgical methods for non-displaced stress fractures and surgical interventions for displaced or intra-articular fractures. METHODS: This study utilized the Wisdom in Diagnostic Imaging Simulation (WIDI SIM) platform, an emergency imaging simulation designed to assess radiology resident preparedness for independent call. During an 8-hour simulation, residents were tested on 65 cases across various imaging modalities of varying complexity, including normal studies. A single, unique case of calcaneal fracture was included within the simulation in four separate years of testing. Cases were assessed using a standardized grading rubric by subspecialty radiology faculty, with errors subsequently classified by type. RESULTS: A total of 1279 residents were tested in five separate years on the findings of calcaneal fractures of 5 different patients. Analysis revealed a consistent pattern of missed diagnoses across all training years, primarily attributed to observational errors. There was limited improvement with training progression as all training years exhibited similar average performance levels. CONCLUSIONS: Calcaneal fractures pose a diagnostic challenge due to their frequent subtle radiographic findings, especially in stress fractures. Simulation-based evaluations using WIDI SIM highlighted challenges in radiology residents' proficiency in diagnosing calcaneal fractures. Addressing these challenges through targeted education and exposure to diverse cases is essential to improve diagnostic accuracy and reduce complications with calcaneal fractures.

Public transport use and mortality among older adults in England: A cohort study.

BACKGROUND: Most evidence on transport use and mortality has focused on the commute to work. This study aims to fill a gap by assessing relationships between public transport use and mortality among older adults. METHODS: Data come from a cohort of 10,186 individuals aged 50 or older who participated in the English Longitudinal Study of Ageing (ELSA), with survey data linked to mortality records over 16 years (2002-2018). We assessed a binary measure of public transport use and frequency of use from 'every day or nearly every day' to 'never'. Cox proportional-hazards regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for associations between public transport use and mortality. Analyses were adjusted for a range of covariates including socio-demographic factors, chronic disease, and self-reported problems with daily living activities. RESULTS: Overall, 3371 participants (33.1%) died within the study period. Mortality was lower among public transport users (21.3%) compared with non-users (64.2%). Adjusted analyses found that users had 34% lower mortality than non-users (HR 0.66 (95% CI 0.61;0.71)). Adjusted analyses showed similar association sizes across frequencies of public transport use, with those using public transport every day or nearly every day having 41% lower mortality than never users (HR 0.59 (0.49;0.71)). Associations were similar among those with and without a longstanding illness. CONCLUSION: The use of public transport among older adults is linked to lower levels of mortality. Reductions in provision of public transport services could be detrimental to both transportation and population health.

Structural Insights into the Roles of PARP4 and NAD + in the Human Vault Cage.

Vault is a massive ribonucleoprotein complex found across Eukaryota. The major vault protein (MVP) oligomerizes into an ovular cage, which contains several minor vault components (MVCs) and is thought to transport transiently bound "cargo" molecules. Vertebrate vaults house a poly (ADP-ribose) polymerase (known as PARP4 in humans), which is the only MVC with known enzymatic activity. Despite being discovered decades ago, the molecular basis for PARP4's interaction with MVP remains unclear. In this study, we determined the structure of the human vault cage in complex with PARP4 and its enzymatic substrate NAD + . The structures reveal atomic-level details of the protein-binding interface, as well as unexpected NAD + -binding pockets within the interior of the vault cage. In addition, proteomics data show that human vaults purified from wild-type and PARP4-depleted cells interact with distinct subsets of proteins. Our results thereby support a model in which PARP4's specific incorporation into the vault cage helps to regulate vault's selection of cargo and its subcellular localization. Further, PARP4's proximity to MVP's NAD + -binding sites could support its enzymatic function within the vault.

Methods, precision, and analytical sensitivity of a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction.

INTRODUCTION: Fibrinolysis is a critical aspect of the hemostatic system, with assessment of fibrinolytic potential being critical to predict bleeding and clotting risk. We describe the method for a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction (the "modified mini-euglobulin clot lysis assay [ECLA]"), its analytic sensitivity to alterations in key fibrinolytic substrates/regulators, and its initial applications in acute and convalescent disease cohorts. METHODS: The modified mini-ECLA requires 50 µL of plasma, a maximal read time of 3 h (with most results available within 60 min), and is entirely performed in a 96-well microplate. Assay measurements were obtained in a variety of commercial control and deficient plasmas representing clinically relevant hypo- and hyperfibrinolytic states, and in three distinct adolescent cohorts with acute or convalescent illness: critically ill, following endotracheal intubation; acute COVID-19-related illness; and ambulatory, 3 months following a venous thromboembolic event. RESULTS: In 100% and 75% deficient plasmas, hypofibrinolysis for plasminogen-deficient, fibrinolysis for alpha-2-antiplasmin-deficient, and hyperfibrinolysis for plasminogen activator inhibitor-1-deficient plasmas were observed. CONCLUSION: The modified mini-ECLA Clot Lysis Time Ratio ("CLTR") demonstrated moderate-strength correlations with the Clot Formation and Lysis (CloFAL) assay, is analytically sensitive to altered fibrinolytic states in vitro, and correlates with clinical outcomes in preliminarily-studied patient populations.

Cryo-EM Structures of Clostridium perfringens Enterotoxin Bound to its Human Receptor, Claudin-4.

Pathogenic strains of Clostridium perfringens secrete an enterotoxin (CpE) that causes prevalent, severe, and sometimes deadly gastrointestinal disorders in humans and domesticated animals. CpE binds selectively to membrane protein receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally construct tight junctions that regulate epithelial paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE small complexes. Small complexes are building blocks for assembling oligomeric ß-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here we present structures of CpE in complexes with its native claudin receptor in humans, claudin-4, at 4.0 and 2.8 Å using cryogenic electron microscopy. The structures reveal the overall architecture of the small complex, that the small complex can be kinetically trapped, and resolve its key features; like the residues used in claudin/CpE complex binding, the orientation of CpE relative to the membrane, and CpE-induced structural changes to claudin-4. Further, the structures allude to the biophysical procession from small complex to cytotoxic ß-barrel pore used by CpE during pathogenesis and the role of trypsin in this process. In full, this work elucidates the structure and mechanism of claudin-bound CpE pore assembly and provides strategies to obstruct its formation to treat CpE-induced gastrointestinal diseases.

High-Sensitivity Troponin T, NT-proBNP, and Cognitive Outcomes in SPRINT.

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; Pinteraction=0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.

Methylprednisolone dosing for pediatric critical asthma: a single-center cohort study.

OBJECTIVE: We aimed to characterize intravenous (IV) methylprednisolone (MP) dosing regimens and clinical outcomes for children hospitalized for critical asthma (CA). METHODS: A single-center, retrospective review was performed of children admitted to the pediatric intensive care unit (PICU) for CA between September 2015 and October 2019. Patients 5-to 17-year-olds, initiated on continuous nebulized albuterol, and prescribed at least one dose of IV MP were included. The primary outcome was to characterize PICU MP dosing. Cohorts were then compared by MP dosing: conservative-dose methylprednisolone (CDMP, ≤ 0.5 mg/kg/dose every 6 h) and standard-dose methylprednisolone (SDMP, > 0.5 mg/kg/dose every 6 h). Clinical efficacy endpoints were the duration of continuous nebulized albuterol and PICU length of stay (LOS). Safety endpoints included corticosteroid-related adverse events. RESULTS: Of 168 children studied, 50 (29.8%) were prescribed CDMP and 118 (70.2%) SDMP. The overall mean MP dose was 31.3 ± 19.6 mg (weight-adjusted: 0.77 ± 0.32 mg/kg/dose). Compared to those prescribed SDMP, those prescribed CDMP had a shorter median duration of continuous nebulized albuterol (12.8 [IQR: 10.5-20] versus 17.3 [IQR: 11.3-29.7] hours, p = 0.019) and median PICU LOS (0.9 [IQR: 0.7-1.4] versus 1.2 [IQR: 0.9-1.8] days, p = 0.012). No corticosteroid-related adverse events were observed. In adjusted models, weight-adjusted IV MP dose was not associated with PICU LOS or duration of continuous nebulized albuterol. CONCLUSIONS: Intravenous MP dosing for pediatric CA varied widely in our study sample. Prospective, controlled trials are required to validate our observations including clinical efficacy and safety endpoints.

The Amphibian Genomics Consortium: advancing genomic and genetic resources for amphibian research and conservation.

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomics resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomics resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, antipredator strategies, and resilience and adaptive responses. They also serve as critical models for understanding widespread genomic characteristics, including evolutionary genome expansions and contractions given they have the largest range in genome sizes of any animal taxon and multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The advent of long-read sequencing technologies, along with computational techniques that enhance scaffolding capabilities and streamline computational workload is now enabling the ability to overcome some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC) in early 2023. This burgeoning community already has more than 282 members from 41 countries (6 in Africa, 131 in the Americas, 27 in Asia, 29 in Australasia, and 89 in Europe). The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and outline how the AGC can enable amphibian genomics research to "leap" to the next level.

Slab steepening and rapid mantle wedge replacement during back-arc rifting in the New Hebrides.

The effects of the composition and angle of the subducting slab and mantle wedge flow on tectonic and magmatic processes in island arcs and associated back-arcs are poorly understood. Here we analyse the ages and compositions of submarine lavas from the flanks and the floor of the back-arc Futuna Trough some 50 km east of Tanna Island in the New Hebrides arc front. Whereas >2.5 Ma-old back-arc lavas formed from an enriched mantle source strongly metasomatized by a slab component, the younger lavas show less slab input into a depleted mantle wedge. The input of the slab component decreased over the past 2.5 million years while the enriched mantle was replaced by depleted peridotite. The change of Futuna Trough lava compositions indicates rapid (10 s of km/million years) replacement of the mantle wedge by corner flow and slab steepening due to rollback, causing extensional stress and back-arc rifting in the past 2.5 million years.

Evaluation of Fine Needle Biopsy (FNB) for Endoscopic Ultrasound (EUS)-guided Tissue Acquisition of Pancreatic Masses to Negate the Need for Rapid On-site Evaluation: A Randomized Control Trial.

Background and Objectives: The benefits of rapid on-site evaluation (ROSE) of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solid masses have not been convincingly shown in large, randomized trials. New equipment using EUS-guided fine needle biopsy (FNB) allows for more material to be acquired that may obviate the need for ROSE. This study aimed to evaluate if EUS-FNB without ROSE was non-inferior to EUS-FNA with ROSE in solid pancreatic masses (SPMs). Methods: Patients with SPMs requiring tissue sampling were randomly assigned to undergo either EUS-FNA with ROSE or EUS-FNB without ROSE. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy and secondary endpoints were specimen quality, complication rates, and procedure time. Results: Seventy-eight patients were randomized and analyzed (39 EUS-FNA with ROSE and 39 EUS-FNB without ROSE). Non-significantly different diagnostic accuracies were noted in both groups (97% with ROSE and 100% without ROSE, P < 0.371). The bloodiness of histologic samples and complication rates were not significantly different between groups. A significantly shorter mean sampling procedural time was noted for EUS-FNB over EUS-FNA with ROSE (30.4 ± 10.4 vs 35.8 ± 9.8 minutes, P < .02). Conclusions: EUS-FNB demonstrated equal diagnostic accuracy with shorter procedure times in evaluating SPMs compared to EUS-FNA with ROSE. These new-generation FNB needles may obviate the need for ROSE.

The birth of pediatric urology in the United States: From pioneers to subcertification.

INTRODUCTION: Pediatric urology is a subspecialty of urology that emerged from a culture in which children with urological disorders were cared for by general urologists and general pediatric surgeons. The development of pediatric urology as a subspecialty was years in the making, highlighted by individuals who recognized that children with urological conditions were not just "small adults," but required special experience and training. Subspecialization was initiated by persistent visionaries who recognized the need for a trained cadre of experts to provide better care for children. It took the coordinated effort of all subgroups and leaderships in pediatric urology to push these efforts over the goal line. The focus of this review is to highlight certain individuals who played major roles in this vision and to document the efforts of many to coordinate the pathways to sub-specialization. METHODS: The careers of Meredith F. Campbell and Frank B. Bicknell were researched to identify their rationale and roles in developing pediatric urology as a distinct medical specialty in the United States. In addition, the minutes of the meetings of the Pediatric Urology Advisory Council (PUAC) with the American Board of Urology (ABU) were reviewed. The origins of the Society for Pediatric Urology (SPU) and the American Academy of Pediatrics Section of Urology (AAP-SOU) were researched. The contributions of each to the certification of pediatric urology as a distinct subspecialty was delineated. RESULTS: Campbell was Chair of Urology at the New York University (NYU) School of Medicine and wrote prolifically about pediatric urology. He published one of the first practical textbooks in pediatric urology, almost completely self-written, in 1937. Bicknell, a general urologist in Michigan on the faculty at Wayne State University School of Medicine, led the initiative to create the Society for Pediatric Urology (SPU) that first met at the 1951 annual American Urological Association (AUA) meeting in Chicago and included nine attendees. Subsequently, John Lattimer (College of Physicians and Surgeons at Columbia University) organized a well-attended meeting of urologists interested in pediatrics at the 1964 annual AAP meeting in New York City. This led to the formation of the AAP Section on Urology. Integral to the justification for the development of a subspecialty was evidence of a published corpus of content. In addition to published textbooks devoted exclusively to pediatric urology, this was further fulfilled by the AAP Section on Urology Pediatric Supplement to the Journal of Urology, first published in 1986, and later with the Journal of Pediatric Urology in 2005. The SPU and the AAP Section on Urology came together to form the Pediatric Urology Advisory Council (PUAC) in 2000, which worked with the ABU to create subspecialty certification in pediatric urology with an independent exam, first administered in 2008 to 176 applicants. CONCLUSION: The metaphor "We have stood on the shoulders of giants" is apt for pediatric urology: Meredith Campbell, Frank Bicknell, David Innes Williams (Hospital for Sick Children, London), and J. Herbert Johnston (Alder Hay Hospital, Liverpool) come to mind among the first generation of pediatric urology pioneers, and others among their colleagues also had significant impact. Clearly this is a story of persistence and attention to detail on the part of those giants and those who followed. Pediatric urology became a distinct discipline after the SPU and AAP-SOU came together to create a robust cohort of pediatric urologists who through education and negotiation were able to help the ABU and the American Board of Medical Specialties (ABMS) recognize that subspecialization would lead to better care for children with urologic disorders. This benchmark set a high bar for future subspecialization in urology and other fields.

Malaria and other infections induce polyreactive antibodies that impact SARS-CoV-2 seropositivity estimations in endemic settings.

Anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence is used to estimate the proportion of individuals within a population previously infected, to track viral transmission, and to monitor naturally and vaccine-induced immune protection. However, in sub-Saharan African settings, antibodies induced by higher exposure to pathogens may increase unspecific seroreactivity to SARS-CoV-2 antigens, resulting in false positive responses. To investigate the level and type of unspecific seroreactivitiy to SARS-CoV-2 in Africa, we measured immunoglobulin G (IgG), IgA, and IgM to a broad panel of antigens from different pathogens by Luminex in 602 plasma samples from African and European subjects differing in coronavirus disease 2019, malaria, and other exposures. Seroreactivity to SARS-CoV-2 antigens was higher in prepandemic African than in European samples and positively correlated with antibodies against human coronaviruses, helminths, protozoa, and especially Plasmodium falciparum. African subjects presented higher levels of autoantibodies, a surrogate of polyreactivity, which correlated with P. falciparum and SARS-CoV-2 antibodies. Finally, we found an improved sensitivity in the IgG assay in African samples when using urea as a chaotropic agent. In conclusion, our data suggest that polyreactive antibodies induced mostly by malaria are important mediators of the unspecific anti-SARS-CoV-2 responses, and that the use of dissociating agents in immunoassays could be useful for more accurate estimates of SARS-CoV-2 seroprevalence in African settings.

TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.

Objectives: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined. Methods: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel. Results: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN. Discussion: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.

Do acting interns need residents? A comparison of acting intern experience on hospital medicine resident versus nonresident teams.

BACKGROUND: The clinical demands for hospitalist groups have grown at academic medical centers, without similar growth of teaching opportunities for faculty. Traditional resident teaching teams are often crowded with learners which can limit acting intern (or subintern) patient encounters. Medical students are often placed on nonresident teaching teams, although there are few studies on learner experience on a nonresident teaching team model. METHODS: To address these concerns, we created two nonresident teaching teams composed of one attending and two acting interns. We compared acting intern experience on the nonresident teaching teams to the traditional resident teams to determine if there were significant differences in student experience by reviewing course evaluation data on the two team models. RESULTS: Of the 276 students who completed the Internal Medicine Acting Internship from 2019 to 2023, 224 students (81%) completed the course evaluation. The course was highly rated, and the ratings were similar in both models demonstrating that the nonresident teaching team model is an effective option for acting interns. CONCLUSION: The nonresident teaching team model can offload crowded teaching teams, add additional acting intern experiences, and add teaching opportunities for hospital medicine attendings.

Psychological Status as an Effect Modifier of the Association Between Allergy Symptoms and Allergy Testing.

OBJECTIVE: Patient-reported outcome measures, while valuable, may not correlate with diagnostic test results. To better understand this potential discrepancy, our objective was to determine whether psychological health is an effect modifier of the association between patient-reported allergy outcome scores and allergy test results. STUDY DESIGN: Prospective outcomes study. SETTING: Tertiary care hospital and community-based clinic. METHODS: This study included 600 patients at least 18 years of age who presented for symptoms related to allergic rhinitis and completed the related sinonasal outcome test (SNOT), which includes validated nasal, allergy, and psychological domains. Stratified analyses of odds ratios and Spearman correlation coefficients were utilized to assess for effect modification by psychological status. RESULTS: Worse patient-reported allergic rhinitis symptoms were significantly associated with positive allergy test results (odds ratio [OR] 1.69, 95% confidence interval [CI] 1.22-2.34, P = .002) in patients with better psychological health. In contrast, there was no association in patients with worse psychological health (OR 1.06, 95% CI 0.36-3.10, P = .92). These findings were corroborated by assessments of correlation: allergy domain scores were positively correlated with allergy testing scores (Spearman rho 0.18, 95% CI 0.10-0.25, P < .001) in patients with better psychological health, while there was no correlation in patients with worse psychological health (-0.02, 95% CI -0.16-0.12, P = .77). CONCLUSIONS: Psychological status was an effect modifier of the association between allergy domain and allergy testing data. When assessing the relationship between subjective measures, such as sinonasal validated instruments, and objective measures, such as allergy test results, accounting for effect modifiers such as psychological state can provide clinical and research-related insights.

Invasive Mechanical Ventilation and Risk of Hospital-Acquired Venous Thromboembolism.

BACKGROUND: This study sought to estimate the overall cumulative incidence and odds of Hospital-acquired venous thromboembolism (VTE) among critically ill children with and without exposure to invasive ventilation. In doing so, we also aimed to describe the temporal relationship between invasive ventilation and hospital-acquired VTE development. METHODS: We performed a retrospective cohort study using Virtual Pediatric Systems (VPS) data from 142 North American pediatric ICUs among children < 18 y of age from January 1, 2016-December 31, 2022. After exclusion criteria were applied, cohorts were identified by presence of invasive ventilation exposure. The primary outcome was cumulative incidence of hospital-acquired VTE, defined as limb/neck deep venous thrombosis or pulmonary embolism. Multivariate logistic regression was used to determine whether invasive ventilation was an independent risk factor for hospital-acquired VTE development. RESULTS: Of 691,118 children studied, 86,922 (12.4%) underwent invasive ventilation. The cumulative incidence of hospital-acquired VTE for those who received invasive ventilation was 1.9% and 0.12% for those who did not (P < .001). The median time to hospital-acquired VTE after endotracheal intubation was 6 (interquartile range 3-14) d. In multivariate models, invasive ventilation exposure and duration were each independently associated with development of hospital-acquired VTE (adjusted odds ratio 1.64 [95% CI 1.42-1.86], P < .001; and adjusted odds ratio 1.03 [95% CI 1.02-1.03], P < .001, respectively). CONCLUSIONS: In this multi-center retrospective review from the VPS registry, invasive ventilation exposure and duration were independent risk factors for hospital-acquired VTE among critically ill children. Children undergoing invasive ventilation represent an important target population for risk-stratified thromboprophylaxis trials.