Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species.

Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.

Interleukin-36 cytokines are overexpressed in the skin and sera of patients with bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune bullous disease, characterized by autoantibodies targeting BP180 and BP230. The role of interleukin (IL)-36, a potent chemoattractant for granulocytes, in BP remains elusive.The expression of IL-36 cytokines (IL-36α, ß, γ) and their antagonists (IL-36Ra and IL-38) was analysed in the skin and serum samples of patients with BP (n = 31), psoriasis (n = 10) and healthy controls (HC) (n = 14) by quantitative polymerase chain reaction and enzyme linked immunosorbent assay, respectively. Skin and serum levels of all cytokines were correlated with the Bullous Pemphigoid Disease Area Index (BPDAI) score and with the serum concentration of pathogenic antibodies.IL-36α, IL-36ß, IL-36γ and IL-36Ra were significantly (p < 0.05) overexpressed in BP skin compared to HC, without remarkable differences relative to psoriasis skin. The expression of IL-38 was significantly (p < 0.05) higher in BP compared to psoriasis skin.IL-36α and γ, but not ß, serum concentrations were significantly (p < 0.05) higher in BP compared to HC. IL-36γ was significantly (p < 0.05) more expressed in the serum of psoriasis patients than BP. The serum concentration of IL-36Ra and IL-38 were similar between BP and HC, while IL-38 serum levels were significantly (p < 0.05) higher in BP compared to psoriasis patients. Serum IL-36α correlated significantly with BPDAI (r = 0.5 p = 0.001).IL-36 agonists are increased in BP patients, both locally and systemically. Serum IL-36α might represent a potential biomarker for BP. An inefficient balance between IL-36 agonists and antagonists is likely to occur during BP inflammation.

Risk Factors for Pediatric Sepsis in the Emergency Department: A Machine Learning Pilot Study.

OBJECTIVE: To identify underappreciated sepsis risk factors among children presenting to a pediatric emergency department (ED). METHODS: A retrospective observational study (2017-2019) of children aged 18 years and younger presenting to a pediatric ED at a tertiary care children's hospital with fever, hypotension, or an infectious disease International Classification of Diseases (ICD)-10 diagnosis. Structured patient data including demographics, problem list, and vital signs were extracted for 35,074 qualifying ED encounters. According to the Improving Pediatric Sepsis Outcomes Classification, confirmed by expert review, 191 patients met clinical sepsis criteria. Five machine learning models were trained to predict sepsis/nonsepsis outcomes. Top features enabling model performance (N = 20) were then extracted to identify patient risk factors. RESULTS: Machine learning methods reached a performance of up to 93% sensitivity and 84% specificity in identifying patients who received a hospital diagnosis of sepsis. A random forest classifier performed the best, followed by a classification and regression tree. Maximum documented heart rate was the top feature in these models, with importance coefficients (ICs) of 0.09 and 0.21, which represent how much an individual feature contributes to the model. Maximum mean arterial pressure was the second most important feature (IC 0.05, 0.13). Immunization status (IC 0.02), age (IC 0.03), and patient zip code (IC 0.02) were also among the top features enabling models to predict sepsis from ED visit data. Stratified analysis revealed changes in the predictive importance of risk factors by race, ethnicity, oncologic history, and insurance status. CONCLUSIONS: Machine learning models trained to identify pediatric sepsis using ED clinical and sociodemographic variables confirmed well-established predictors, including heart rate and mean arterial pressure, and identified underappreciated relationships between sepsis and patient age, immunization status, and demographics.

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects.

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.

Childhood Obesity Is Associated with Poor Academic Skills and Coping Mechanisms.

OBJECTIVE: To assess the relationship between obesity and select childhood flourishing markers including academic skills and coping strategies. STUDY DESIGN: Cross-sectional study utilizing parental reported data for children aged 10-17 years (n = 22 914) from the 2016 National Survey of Children's Health. Multiple binary regressions assessed the association between body mass index-for-age and 5 school-related and behavioral childhood flourishing markers independently and combined, including completing homework, showing interest in learning, finishing tasks, staying calm when challenged, and caring about academics. Analyses were adjusted for age, sex, depression, sleep, digital media exposure, poverty, and parental education level. RESULTS: Only 28.9% of children with obesity were reported to have all 5 markers, compared with 38% with overweight, and 40.5% with normal body mass index. In an adjusted model, children with obesity had significantly decreased odds of demonstrating 4 of 5 markers: showing interest in learning (aOR, 0.78; 95% CI, 0.62-0.97), finishing tasks (aOR, 0.77; 95% CI, 0.63-0.94), staying calm when challenged (aOR, 0.73; 95% CI, 0.59-0.90), and caring about academics (aOR, 0.69; 95% CI, 0.55-0.86). Completing homework was not associated with obesity. Youth with obesity also had 23% decreased odds (aOR, 0.77; 95% CI, 0.61-0.98) of meeting the combined measure for flourishing markers. CONCLUSIONS: Childhood obesity is associated with poor academic skills and coping strategies which may lead to worse individual and public health outcomes. Further studies are needed to create validated flourishing measures and identify interventions that promote healthy youth behavior and academic success.

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits.

Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.

Clinical and functional characterization of two novel ZBTB20 mutations causing Primrose syndrome.

Primrose syndrome (PS) is a rare disorder characterized by macrocephaly, tall stature, intellectual disability, autistic traits, and disturbances of glucose metabolism with insulin-resistant diabetes and distal muscle wasting occurring in adulthood. The disorder is caused by functional dysregulation of ZBTB20, a transcriptional repressor controlling energetic metabolism and developmental programs. ZBTB20 maps in a genomic region that is deleted in the 3q13.31 microdeletion syndrome, which explains the clinical overlap between the two disorders. A narrow spectrum of amino acid substitutions in a restricted region of ZBTB20 encompassing the first and second zinc-finger motifs have been reported thus far. Here, we characterize clinically and functionally the first truncating mutation [(c.1024delC; p.(Gln342Serfs*42)] and a missense change affecting the third zinc-finger motif of the protein [(c.1931C > T; p.(Thr644Ile)]. Our data document that both mutations have dominant negative impact on wild-type ZBTB20, providing further evidence of the specific behavior of PS-causing mutations on ZBTB20 function.

The Intersection of the Pathogenic Processes Underlying Psoriasis and the Comorbid Condition of Obesity.

In the past decade, our understanding of psoriasis pathogenesis has made significant steps forward, leading to the development of multiple game-changing therapies. While psoriasis primarily affects the skin, it is increasingly recognized as a systemic disease that can have effects beyond the skin. Obesity is associated with more severe forms of psoriasis and can potentially worsen the systemic inflammation and metabolic dysfunction seen in psoriatic patients. The exact mechanisms underlying the link between these two conditions are not fully understood, but it is believed that chronic inflammation and immune dysregulation play a role. In this review, we examine the existing body of knowledge regarding the intersection of pathogenic processes responsible for psoriasis and obesity. The ability of biological therapies to reduce systemic and obesity-related inflammation in patients with psoriasis will be also discussed.

Retrieval-Based Diagnostic Decision Support: Mixed Methods Study.

BACKGROUND: Diagnostic errors pose significant health risks and contribute to patient mortality. With the growing accessibility of electronic health records, machine learning models offer a promising avenue for enhancing diagnosis quality. Current research has primarily focused on a limited set of diseases with ample training data, neglecting diagnostic scenarios with limited data availability. OBJECTIVE: This study aims to develop an information retrieval (IR)-based framework that accommodates data sparsity to facilitate broader diagnostic decision support. METHODS: We introduced an IR-based diagnostic decision support framework called CliniqIR. It uses clinical text records, the Unified Medical Language System Metathesaurus, and 33 million PubMed abstracts to classify a broad spectrum of diagnoses independent of training data availability. CliniqIR is designed to be compatible with any IR framework. Therefore, we implemented it using both dense and sparse retrieval approaches. We compared CliniqIR's performance to that of pretrained clinical transformer models such as Clinical Bidirectional Encoder Representations from Transformers (ClinicalBERT) in supervised and zero-shot settings. Subsequently, we combined the strength of supervised fine-tuned ClinicalBERT and CliniqIR to build an ensemble framework that delivers state-of-the-art diagnostic predictions. RESULTS: On a complex diagnosis data set (DC3) without any training data, CliniqIR models returned the correct diagnosis within their top 3 predictions. On the Medical Information Mart for Intensive Care III data set, CliniqIR models surpassed ClinicalBERT in predicting diagnoses with <5 training samples by an average difference in mean reciprocal rank of 0.10. In a zero-shot setting where models received no disease-specific training, CliniqIR still outperformed the pretrained transformer models with a greater mean reciprocal rank of at least 0.10. Furthermore, in most conditions, our ensemble framework surpassed the performance of its individual components, demonstrating its enhanced ability to make precise diagnostic predictions. CONCLUSIONS: Our experiments highlight the importance of IR in leveraging unstructured knowledge resources to identify infrequently encountered diagnoses. In addition, our ensemble framework benefits from combining the complementary strengths of the supervised and retrieval-based models to diagnose a broad spectrum of diseases.

RAS-activated PI3K/AKT signaling sustains cellular senescence via P53/P21 axis in experimental models of psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated skin disease in which upper epidermal keratinocytes exhibit a senescent-like phenotype. In psoriatic skin, a variety of inflammatory cytokines can activate intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/AKT signaling and RAS effectors. AKT and RAS participate to cellular senescence, but currently their role in senescence responses occurring in psoriasis have not yet been investigated. OBJECTIVE: The role of AKT molecular axis and RAS activation was evaluated in the context of cellular senescence in psoriasis disease. METHODS: RAS/AKT involvement in senescence was analyzed in psoriatic keratinocytes cultures subjected to multiple passages to promote senescence in vitro, as well as in skin lesions of patients affected by psoriasis. The impact of pharmacological inhibition of PI3K/AKT pathway on senescence and inflammation responses was tested in senescent psoriatic keratinocytes and in a psoriasiform dermatitis murine model induced by RAS overexpression in the upper epidermis of mice. RESULTS: We found AKT hyperactivation associated to the upregulation of senescence markers, in senescent psoriatic keratinocyte cultures, as well as in skin lesions of psoriatic patients. AKT-induced senescence was sustained by constitutive RAS activation, and down-stream responses were mediated by P53/P21 axis. PI3K/AKT inhibition contrasted senescence processes induced by cytokines in psoriatic keratinocytes. Additionally, RAS-induced psoriasis-like dermatitis in mice was accompanied by AKT upregulation, increase of senescence marker expression and by skin inflammation. In this model, both senescence and inflammation were significantly reduced by selective AKT inhibition. CONCLUSION: Therefore, targeting RAS-AKT pathway could be a promising novel strategy to counteract multiple psoriasis symptoms.

Comparing Sexual Orientation and Gender Identity Documentation Between Adolescent and Pediatric Primary Care Clinics.

PURPOSE: Recent literature suggests that sexual orientation and gender identity (SOGI) documentation is poor. We hypothesized that an adolescent clinic would have higher rates of SOGI documentation than a pediatric primary care clinic. METHODS: We performed a single-center, retrospective, observational study of patients ages 10-26 presenting to the primary care or adolescent medicine clinics of a tertiary care hospital from 2019 to 2021. Electronic medical record (EMR) data were analyzed using Python and Stata/MP 16.1. RESULTS: Patients in the adolescent clinic were five times more likely to have to have complete SOGI documentation compared to primary care. Gender diverse youth were over six times more likely to have a recorded sexual orientation than cisgender youth across both clinics. CONCLUSION: Adolescent providers document SOGI more often than primary care providers. Sexual orientation information for cisgender patients remains poor across environments. This study emphasizes the need for ongoing provider education on SOGI documentation.

Bedside exclusion of pulmonary embolism in children without radiation (BEEPER): a national study of the Pediatric Emergency Care Applied Research Network-Study protocol.

Background: The Pulmonary Embolism Rule Out Criteria (PERC) Peds rule, derived from the PERC rule, was derived to estimate a low pretest probability for pulmonary embolism (PE) in children but has not been prospectively validated. Objective: The objective of this study was to present a protocol for an ongoing multicenter prospective observational study that evaluates the diagnostic accuracy of the PERC-Peds rule. Methods: This protocol is identified by the acronym, BEdside Exclusion of Pulmonary Embolism without Radiation in children. The study aims were designed to prospectively validate, or if necessary, refine, the accuracy of PERC-Peds and D-dimer in excluding PE among children with clinical suspicion or testing for PE. Multiple ancillary studies will examine clinical characteristics and epidemiology of the participants. Children aged 4 through 17 years were being enrolled at 21 sites through the Pediatric Emergency Care Applied Research Network (PECARN). Patients taking anticoagulant therapy are excluded. PERC-Peds criteria data, clinical gestalt, and demographic information are collected in real time. The criterion standard outcome is image-confirmed venous thromboembolism within 45 days, determined from independent expert adjudication. We assessed interrater reliability of the PERC-Peds, frequency of PERC-Peds use in routine clinical care, and descriptive characteristics of missed eligible and missed patients with PE. Results: Enrollment is currently 60% complete with an anticipated data lock in 2025. Conclusions: This prospective multicenter observational study will not only test whether a set of simple criteria can safely exclude PE without need for imaging but also provide a resource to fill a critical knowledge gap about clinical characteristics of children with suspected and diagnosed PE.

Excellence in Communication and Emergency Leadership (ExCEL): Pediatric Critical Care Resource Utilization Workshop for Residents.

Introduction: Efficiently locating critical equipment and prompt defibrillator usage are crucial steps when managing a critically ill patient or a code. However, resident experience in this area is limited. This workshop focused on the identification of critical care equipment in the pediatric code cart and transport bag along with timely, appropriate, and effective use of the defibrillator when needed. Methods: The workshop utilized a combination of traditional didactics and hands-on skills stations to instruct learners on the location of pediatric critical care equipment and the proper use of a defibrillator. It was designed for residents across all levels of training who care for pediatric patients (including pediatrics, medicine-pediatrics, triple board [pediatrics, psychiatry, and child psychiatry], family medicine, and emergency medicine residents) and can be adapted for different session durations and group sizes. Results: This workshop was conducted at two separate institutions, with a total of 95 resident participant encounters. Participants strongly agreed that the workshop was effective in teaching our learning objectives. Residents reported high levels of confidence in their ability to recognize and identify the location of critical care equipment in the code cart and transport bags and to appropriately use the defibrillator for both defibrillation and synchronized cardioversion. Discussion: This workshop provided residents with instruction and practice in locating and utilizing pediatric critical care equipment. The structure and timetable of this curriculum can be adapted to the needs of individual institutions' programs and different numbers of workshop participants.

The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands.

PI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders.

Extracellular Nucleophosmin Is Increased in Psoriasis and Correlates With the Determinants of Cardiovascular Diseases.

We previously showed that genotoxic stress induced an active extracellular release of nucleophosmin (NPM) in human cardiac mesenchymal progenitor cells, and that serum deprivation provokes NPM secretion from human endothelial cells, eliciting inflammation via nuclear factor kappa B (NF-kB) transcriptional activation. In this study, we wanted to determine whether NPM was similarly modulated in the skin and plasma of psoriatic patients (Pso). We found that NPM was induced in 6 skin biopsies compared to 6 normal skin biopsies and was markedly increased in lesional (LS) vs. non-lesional skin (NLS) biopsies. Moreover, NPM was also increased at the transcriptional levels in LS vs. NLS. Both the innate stimuli, such as lipopolysaccharides and Poly inositol-cytosine and adaptive stimuli, that is, cytokine mix, were able to induce the extracellular release of NPM in immortalized keratinocytes and human skin fibroblasts in the absence of cytotoxicity. Interestingly, NPM interacts with Toll-like receptor (TLR)4 in these cells and activates an NF-kB-dependent inflammatory pathway upregulating interleukin IL-6 and COX-2 gene expression. Finally, circulating NPM was increased in the plasma of 29 Pso compared to 29 healthy controls, and positively correlates with psoriasis area severity index (PASI) and with determinants of cardiovascular diseases (CVDs), such as pulse wave velocity, systolic pressure, and left ventricular mass. Furthermore, NPM positively correlates with miR-200c circulating levels, which we previously showed to increase in Pso and correlate with CVD progression. Our data show that circulating miR-200c is physically associated with extracellular NPM, which most probably is responsible for its extracellular release and protection upon cytokine mix via a TLR4-mechanism. In conclusion, NPM is increased in psoriasis both in the skin and plasma and might be considered a novel biologic target to counteract chronic inflammation associated with CVD risk.

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship. Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI. Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc. Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection. Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Recent Updates on the Involvement of PI3K/AKT/mTOR Molecular Cascade in the Pathogenesis of Hyperproliferative Skin Disorders.

PhosphoInositide-3 Kinase (PI3K) represents a family of different classes of kinases which control multiple biological processes in mammalian cells, such as cell growth, proliferation, and survival. Class IA PI3Ks, the main regulators of proliferative signals, consists of a catalytic subunit (α, ß, δ) that binds p85 regulatory subunit and mediates activation of AKT and mammalian Target Of Rapamycin (mTOR) pathways and regulation of downstream effectors. Dysregulation of PI3K/AKT/mTOR pathway in skin contributes to several pathological conditions characterized by uncontrolled proliferation, including skin cancers, psoriasis, and atopic dermatitis (AD). Among cutaneous cancers, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) display PI3K/AKT/mTOR signaling hyperactivation, implicated in hyperproliferation, and tumorigenesis, as well as in resistance to apoptosis. Upregulation of mTOR signaling proteins has also been reported in psoriasis, in association with enhanced proliferation, defective keratinocyte differentiation, senescence-like growth arrest, and resistance to apoptosis, accounting for major parts of the overall disease phenotypes. On the contrary, PI3K/AKT/mTOR role in AD is less characterized, even though recent evidence demonstrates the relevant function for mTOR pathway in the regulation of epidermal barrier formation and stratification. In this review, we provide the most recent updates on the role and function of PI3K/AKT/mTOR molecular axis in the pathogenesis of different hyperproliferative skin disorders, and highlights on the current status of preclinical and clinical studies on PI3K-targeted therapies.

Children With ADHD Engage in Less Physical Activity.

Background: Children with ADHD should engage in physical activity, given its known role as a treatment adjunct. Objective: The main objective of this study is to assess the relationship between ADHD diagnosis and physical activity among children in the United States. Methods: This retrospective population-based cross-sectional study used data from the 2016 caregiver reported, National Survey of Children's Health (NSCH). Results: In the adjusted binary model, children with an ADHD diagnosis had 21% lower odds of engaging in daily physical activity than their nondiagnosed counterparts. In the adjusted multinomial model, children with ADHD were increasingly unlikely to report additional days of physical activity as compared to those without a diagnosis. Conclusion: Given the known benefits of physical activity for those with ADHD, this study underscores the need for enhanced access to an important treatment adjunct for this population.

PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis.

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, ß, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.

Excellence in Communication and Emergency Leadership (ExCEL): Pediatric Primary and Secondary Survey in Trauma Workshop for Residents.

Introduction: Unintentional traumatic injury remains the leading cause of pediatric death in the United States. There is wide variation in the assessment and management of pediatric trauma patients in emergency departments. Resident education on trauma evaluation and management is lacking. This workshop focused on developing resident familiarity with the primary and secondary trauma survey in pediatric patients. Methods: This hands-on workshop utilized patient-actors and low-fidelity simulators to instruct learners on the initial assessment of trauma patients during the primary and secondary trauma surveys. It was designed for residents across all levels of training who care for pediatric trauma patients (including pediatrics, medicine-pediatrics, emergency medicine, and family medicine) and adapted for different session durations and learner group sizes. Results: Eighteen residents participated in this workshop at two separate institutions. Participants strongly agreed that the workshop was relevant and effective in teaching the initial primary and secondary trauma survey assessment of pediatric trauma patients. Residents also reported high levels of confidence in performing a primary and secondary trauma survey after participation in the workshop. Discussion: This workshop provided residents with instruction and practice in performing the primary and secondary trauma survey for injured pediatric patients. Additional instruction is needed on assigning Glasgow Coma Scale and AVPU (alert, voice, pain, unresponsive) scores to injured patients. The structure and time line of this curriculum can be adapted to the needs of an individual institution's program and the number of workshop participants.