Parental Report of Indoor Air Pollution is Associated with Respiratory Morbidities In Bronchopulmonary Dysplasia.

OBJECTIVE: To determine the association between indoor air pollution and respiratory morbidities in children with bronchopulmonary dysplasia recruited from the multicenter Bronchopulmonary Dysplasia (BPD) Collaborative. STUDY DESIGN: A cross-sectional study was performed among participants less than 3 years old in the BPD Collaborative Outpatient Registry. Indoor air pollution was defined as any reported exposure to tobacco or marijuana smoke, electronic cigarette emissions, gas stoves, and/or wood stoves. Clinical data included acute care use and chronic respiratory symptoms in the past 4 weeks. RESULTS: A total of 1,011 subjects born at a mean gestational age of 26.4 ± 2.2 weeks were included. Most (66.6%) had severe BPD. Over 40% of subjects were exposed to at least one source of indoor air pollution. The odds of reporting an emergency department visit (OR 1.7 [1.18, 2.45], antibiotic use (OR 1.9 [1.12, 3.21]), or a systemic steroid course (OR 2.18 [1.24, 3.84]) were significantly higher in subjects reporting exposure to secondhand smoke (SHS) compared with those without SHS exposure. Subjects reporting exposure to air pollution (not including SHS) also had a significantly greater odds (OR 1.48 [1.08, 2.03]) of antibiotic use as well. Indoor air pollution exposure (including SHS) was not associated with chronic respiratory symptoms or rescue medication use. CONCLUSION: Exposure to indoor air pollution, especially SHS, was associated with acute respiratory morbidities, including ED visits, antibiotics for respiratory illnesses, and systemic steroid use.

Screening of a kinase inhibitor library identified novel targetable kinase pathways in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly invasive breast cancer subtype that is challenging to treat due to inherent heterogeneity and absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Kinase signaling networks drive cancer growth and development, and kinase inhibitors are promising anti-cancer strategies in diverse cancer subtypes. Kinase inhibitor screens are an efficient, valuable means of identifying compounds that suppress cancer cell growth in vitro, facilitating the identification of kinase vulnerabilities to target therapeutically. The Kinase Chemogenomic Set is a well-annotated library of 187 kinase inhibitor compounds that indexes 215 kinases of the 518 in the known human kinome representing various kinase networks and signaling pathways, several of which are understudied. Our screen revealed 14 kinase inhibitor compounds effectively inhibited TNBC cell growth and proliferation. Upon further testing, three compounds, THZ531, THZ1, and PFE-PKIS 29, had the most significant and consistent effects across a range of TNBC cell lines. These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC.

Interdisciplinary clinical bronchopulmonary dysplasia programs: development, evolution, and maturation.

Multidisciplinary bronchopulmonary dysplasia (BPD) programs provide improved and consistent medical management, care of the developing infant, family support, and smoother transitions in care resulting in improved survival, pulmonary, and extra-pulmonary outcomes. This review summarizes the benefits of interdisciplinary BPD management, as well as strategies for initial programmatic development, program growth, and maintenance at centers across the United States factoring in institutional, provider, and parent reported goals that were derived from a consensus conference on BPD management.

A causal link between autoantibodies and neurological symptoms in long COVID.

Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms. Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.

Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease, associated with premature birth, that arises during the infantile period. It is an evolving disease process with an unchanged incidence due to advancements in neonatal care which allow for the survival of premature infants of lower gestational ages and birth weights. Currently, there are few effective interventions to prevent BPD. However, careful attention to BPD phenotypes and comprehensive care provided by an interdisciplinary team have improved care. Interventions early in the disease course hold promise for improving long-term survival and outcomes in adulthood for this high-risk population.

Factors associated with liberation from home mechanical ventilation and tracheostomy decannulation in infants and children with severe bronchopulmonary dysplasia.

OBJECTIVE: To identify factors associated with the timing of ventilator liberation and tracheostomy decannulation among infants with severe bronchopulmonary dysplasia (sBPD) who required chronic outpatient invasive ventilation. STUDY DESIGN: Multicenter retrospective study of 154 infants with sBPD on outpatient ventilators. Factors associated with ventilator liberation and decannulation were identified using Cox regression models and multilevel survival models. RESULTS: Ventilation liberation and decannulation occurred at median ages of 27 and 49 months, respectively. Older age at transition to a portable ventilator and at discharge, higher positive end expiratory pressure, and multiple respiratory readmissions were associated with delayed ventilator liberation. Surgical management of gastroesophageal reflux was associated with later decannulation. CONCLUSIONS: Ventilator liberation timing was impacted by longer initial admissions and higher ventilator pressure support needs, whereas decannulation timing was associated with more aggressive reflux management. Variation in the timing of events was primarily due to individual-level factors, rather than center-level factors.

Adaptive sampling method to monitor low-risk pathways with limited surveillance resources.

The rise of globalization has led to a sharp increase in international trade with high volumes of containers, goods, and items moving across the world. Unfortunately, these trade pathways also facilitate the movement of unwanted pests, weeds, diseases, and pathogens. Each item could contain biosecurity risk material, but it is impractical to inspect every item. Instead, inspection efforts typically focus on high-risk items. However, low risk does not imply no risk. It is crucial to monitor the low-risk pathways to ensure that they are and remain low risk. To do so, many approaches would seek to estimate the risk to some precision, but increasingly lower risks require more samples. On a low-risk pathway that can be afforded only limited inspection resources, it makes more sense to assign fewer samples to the lower risk activities. We approach the problem by introducing two thresholds. Our method focuses on letting us know whether the risk is below certain thresholds, rather than estimating the risk precisely. This method also allows us to detect a significant change in risk. Our approach typically requires less sampling than previous methods, while still providing evidence to regulators to help them efficiently and effectively allocate inspection effort.

Symptomatic Calcified Uterine Fibroids Refractory to Repeat Uterine Artery Embolization: A Case Report.

Uterine leiomyomas, also known as uterine fibroids, are a commonly encountered condition with a diverse clinical presentation. Uterine fibroids are benign, smooth muscle tumors of the uterus arising from a single myometrial cell. The presentation can vary from asymptomatic incidental findings to causing a wide array of gynecological symptoms, including abnormal uterine bleeding, infertility, chronic pelvic pain, and bulk-related symptoms. There are several management approaches depending on the patient's clinical manifestations and goals. This is a unique case of a patient with symptomatic calcified uterine fibroids refractory to medical management and two uterine artery embolizations presenting with persistent abnormal uterine bleeding and chronic pelvic pain. Preservation of the uterus was desired, so an open myomectomy was subsequently performed. The patient was asymptomatic at two weeks follow-up, and further follow-up was unable to be obtained.  When considering interventions for symptomatic uterine fibroids, it is essential to consider the patient's preference for uterine-sparing methods and desire to preserve fertility. It is necessary that all modes of treatment and their potential future implications be discussed so that patients can make well-informed decisions regarding all aspects of their care. Further studies are needed comparing the outcomes of uterine-sparing interventions for symptomatic uterine fibroids so that the best possible shared decision-making can take place.

Real-time imaging of axonal membrane protein life cycles.

The construction of neuronal membranes is a dynamic process involving the biogenesis, vesicular packaging, transport, insertion and recycling of membrane proteins. Optical imaging is well suited for the study of protein spatial organization and transport. However, various shortcomings of existing imaging techniques have prevented the study of specific types of proteins and cellular processes. Here we describe strategies for protein tagging and labeling, cell culture and microscopy that enable the real-time imaging of axonal membrane protein trafficking and subcellular distribution as they progress through some stages of their life cycle. First, we describe a process for engineering membrane proteins with extracellular self-labeling tags (either HaloTag or SNAPTag), which can be labeled with fluorescent ligands of various colors and cell permeability, providing flexibility for investigating the trafficking and spatiotemporal regulation of multiple membrane proteins in neuronal compartments. Next, we detail the dissection, transfection and culture of dorsal root ganglion sensory neurons in microfluidic chambers, which physically compartmentalizes cell bodies and distal axons. Finally, we describe four labeling and imaging procedures that utilize these enzymatically tagged proteins, flexible fluorescent labels and compartmentalized neuronal cultures to study axonal membrane protein anterograde and retrograde transport, the cotransport of multiple proteins, protein subcellular localization, exocytosis and endocytosis. Additionally, we generated open-source software for analyzing the imaging data in a high throughput manner. The experimental and analysis workflows provide an approach for studying the dynamics of neuronal membrane protein homeostasis, addressing longstanding challenges in this area. The protocol requires 5-7 days and expertise in cell culture and microscopy.

Australian consensus: Treatment goals for moderate to severe psoriasis in the era of targeted therapies - Considerations for paediatric patients.

BACKGROUND: Treatment goals have been established in Australia to facilitate the management of adults with moderate to severe psoriasis. The Australasian College of Dermatologists sought to determine if and how these adult treatment goals could be modified to accommodate the needs of paediatric and adolescent patients. METHODS: A modified Delphi approach was used. Comprehensive literature review and guideline evaluation resulted in the development of statements and other questions to establish current clinical practices. Two rounds of anonymous voting were undertaken, with a collaborative meeting held in between to discuss areas of discordance. Overall, consensus was defined as achievement of ≥75% agreement in the range 7-9 on a 9-point scale (1 strongly disagree; 9 strongly agree). RESULTS: Consensus was achieved on 23/29 statements in round 1 and 17/18 statements in round 2. There was a high level of concordance with treatment criteria in the adult setting. The limitations of applying assessment tools developed for use in adult patients to the paediatric setting were highlighted. Treatment targets in the paediatric setting should include objective metrics for disease severity and psychological impact on the patients and their family, and be based on validated, age-appropriate tools. CONCLUSION: While the assessment, classification and management of moderate to severe psoriasis in paediatric patients aligns with metrics established for adults, it is vital that nuances in the transition from childhood to adolescence be taken into account. Future research should focus on psoriasis severity assessment scales specific to the paediatric setting.

Efficacy of a high-intensity home stretching device and traditional physical therapy in non-operative management of adhesive capsulitis - a prospective, randomized control trial.

BACKGROUND: Historically, in-person physical therapy serves as a foundational component of nonoperative treatment of adhesive capsulitis (AC). This study compares the effectiveness of an at-home high-intensity stretch (HIS) device to traditional physical therapy (PT) and to PT in combination with the HIS device. We hypothesize that the HIS device will be as effective as PT alone or as combination therapy in the first-line treatment of AC and use of the HIS device will exhibit improvement at higher rate. METHODS: Thirty-four patients with idiopathic adhesive capsulitis and a minimum of 12 months follow-up were included in this study. Patients were randomized into one of the three groups: HIS device, PT alone, or HIS device + PT. Passive range of motion (ROM), American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) scores were measured. Additionally, patient satisfaction, compliance and complications were recorded. Paired t-test, ANOVA and Chi-squared tests were used in analysis. RESULTS: Final ROM in all planes improved for all groups compared to baseline (p < 0.001), with only HIS device group able to restore > 95% of contralateral ROM in all planes at final follow-up. Patients with PT alone were on average slowest to improve ROM from baseline, at 3 months, 6 months, and 1 year in all planes except internal rotation. ASES and SST scores improved for all groups when compared to baseline (p < 0.001). Use of HIS-device resulted in greater improvement in SST and ASES Total scores compared to PT alone (p = 0.045, and p = 0.048, respectively). CONCLUSIONS: Use of an at-home high-intensity stretching device for conservative treatment of idiopathic adhesive capsulitis improves outcomes in ROM and in ASES and SST scores both when used as an adjunct to physical therapy and when used alone. TRIAL REGISTRATION: The study protocol was registered at www. CLINICALTRIALS: gov (20/05/2022, NCT05384093).

Modelling the impact of hybrid immunity on future COVID-19 epidemic waves.

BACKGROUND: Since the emergence of SARS-CoV-2 (COVID-19), there have been multiple waves of infection and multiple rounds of vaccination rollouts. Both prior infection and vaccination can prevent future infection and reduce severity of outcomes, combining to form hybrid immunity against COVID-19 at the individual and population level. Here, we explore how different combinations of hybrid immunity affect the size and severity of near-future Omicron waves. METHODS: To investigate the role of hybrid immunity, we use an agent-based model of COVID-19 transmission with waning immunity to simulate outbreaks in populations with varied past attack rates and past vaccine coverages, basing the demographics and past histories on the World Health Organization Western Pacific Region. RESULTS: We find that if the past infection immunity is high but vaccination levels are low, then the secondary outbreak with the same variant can occur within a few months after the first outbreak; meanwhile, high vaccination levels can suppress near-term outbreaks and delay the second wave. Additionally, hybrid immunity has limited impact on future COVID-19 waves with immune-escape variants. CONCLUSIONS: Enhanced understanding of the interplay between infection and vaccine exposure can aid anticipation of future epidemic activity due to current and emergent variants, including the likely impact of responsive vaccine interventions.

Beyond antiviral: role of IFN-I in brain development.

Interferons and central nervous system resident macrophages, microglia, are well-known for their respective roles in antiviral defense and phagocytosis. Using a classic experimental paradigm for examining activity-dependent neural plasticity, Escoubas, Dorman, et al. recently identified a role for microglial type I interferon signaling in the clearance of unwanted neurons during mouse brain development.

Trait impulsivity influences behavioural and physiological responses to threat in a virtual environment.

Trait impulsivity represents a tendency to take action without forethought or consideration of consequences. This trait is multifaceted and can be decomposed into attentional, motor and non-planning subtypes of impulsivity. The purpose of the current study was to investigate how subtypes of trait impulsivity responded to different degrees of threat within room-scale virtual reality (VR) with respect to behaviour and level of physiological activation. Thirty-four participants were required to negotiate a virtual environment (VE) where they walked at height with the continuous threat of a virtual 'fall.' Behavioural measures related to the speed of movement, interaction frequency and risk were collected. Participants also wore ambulatory sensors to collect data from electrocardiogram (ECG) and electrodermal activity (EDA). Our results indicated that participants who scored highly on non-planning impulsivity exhibited riskier behaviour and higher skin conductance level (SCL). Participants with higher motor impulsivity interacted with more objects in the VE when threat was high, they also exhibited contradictory indicators of physiological activation. Attentional impulsivity was associated with a greater number of falls across the VE. The results demonstrate that subtypes of trait impulsivity respond to threats via different patterns of behaviour and levels of physiological activation, reinforcing the multifaceted nature of the trait.

Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice.

Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.

Graspable foods and tools elicit similar responses in visual cortex.

Extrastriatal visual cortex is known to exhibit distinct response profiles to complex stimuli of varying ecological importance (e.g., faces, scenes, and tools). The dominant interpretation of these effects is that they reflect activation of distinct "category-selective" brain regions specialized to represent these and other stimulus categories. We sought to explore an alternative perspective: that the response to these stimuli is determined less by whether they form distinct categories, and more by their relevance to different forms of natural behavior. In this regard, food is an interesting test case, since it is primarily distinguished from other objects by its edibility, not its appearance, and there is evidence of food-selectivity in human visual cortex. Food is also associated with a common behavior, eating, and food consumption typically also involves the manipulation of food, often with the hands. In this context, food items share many properties in common with tools: they are graspable objects that we manipulate in self-directed and stereotyped forms of action. Thus, food items may be preferentially represented in extrastriatal visual cortex in part because of these shared affordance properties, rather than because they reflect a wholly distinct kind of category. We conducted fMRI and behavioral experiments to test this hypothesis. We found that behaviorally graspable food items and tools were judged to be similar in their action-related properties, and that the location, magnitude, and patterns of neural responses for images of graspable food items were similar in profile to the responses for tool stimuli. Our findings suggest that food-selectivity may reflect the behavioral affordances of food items rather than a distinct form of category-selectivity.

Transitioning children using home invasive mechanical ventilation from hospital to home: Discharge criteria, disparities, and ethical considerations.

Children using home invasive mechanical ventilation (HIMV), a valuable therapeutic option for chronic respiratory failure, constitute a growing population. Transitioning children using HIMV from hospital to home care is a complex process that requires a multidisciplinary approach involving healthcare professionals, caregivers, and community resources. Medical stability, caregiver competence, and home environment suitability are essential factors in determining discharge readiness. Caregiver education and training play a pivotal role in ensuring safe and effective home care. Simulation training and staged education progression are effective strategies for equipping caregivers with necessary skills. Resource limitations, inadequate home nursing support, and disparities in available community resources are common obstacles to successful HIMV discharge. International perspectives shed light on diverse healthcare systems and challenges faced by caregivers worldwide. While standardizing guidelines for HIMV discharge may be complex, collaboration among healthcare providers and the development of evidence-based regional guidelines can improve outcomes for children using HIMV and their caregivers. This review seeks to synthesize literature, provide expert guidance based on experience, and highlight components to safely discharge children using HIMV. It further assesses disparities and divergences within regional and international healthcare systems while addressing relevant ethical considerations.

Paediatric indications and dosing guidance for advanced targeted treatments in Australia.

As with adults, paediatric patients may benefit from a number of advanced targeted therapies for inflammatory skin disease. This brief report aims to be an accessible reference tool with respect to regulatory approval and reimbursement of these treatments within Australia.

Improved tracheostomy-dependent patient outcomes after implementation of the Pediatric Resident Education in Pulmonary (PREP) Boot Camp.

INTRODUCTION: Children with tracheostomies are high risk for morbidity and mortality. Pediatric resident physicians are not routinely taught skills to care for this vulnerable patient population. Few reports link educational interventions to improved patient outcomes. This study evaluates the impact of an intensive educational training program on pediatric residents' observed skills and tracheostomy-dependent patient outcomes. METHODS: Pediatric post-graduate year 2 (PGY2) resident physicians rotating through the inpatient pediatric pulmonology month at Children's Hospital Colorado July 2018-2019 participated in the Pediatric Resident Education in Pulmonary (PREP) Boot Camp, an intensive educational program with an interactive lecture and simulation experience on patients with tracheostomy-dependence. PGY2s who partook in PREP and PGY3s who rotated before PREP initiation were invited to be studied. Primary outcomes included: (1) resident skills assessed by direct observation during simulation encounters and (2) rates of intensive care unit (ICU) transfers in tracheostomy-dependent patients following acute events before and after introduction of PREP. We hypothesized that increased education would enhance resident skills and improve patient outcomes by decreasing the rate of ICU transfers. RESULTS: PGY2 residents retained skills learned during PREP up to 11 months following initial participation, and significantly outperformed their PGY3 counterparts. There was a significant decrease in ICU transfer rate in patients with tracheostomies admitted to the pulmonary team during the 19 months following initiation of PREP. CONCLUSIONS: Enhanced early education may improve resident physicians' ability to care for complex patients with tracheostomies and could improve outcomes in this high-risk population.