Exposures and coexisting conditions in pediatric nodular tracheobronchitis.

BACKGROUND: The aim of our study was to investigate the prevalence of coexisting conditions and exposures in children with nodular tracheobronchitis diagnosed by flexible bronchoscopy. METHODS: We conducted a single-center retrospective review of 100 children diagnosed with nodular tracheobronchitis by flexible bronchoscopy between 2012 and 2023. RESULTS: Common coexisting diagnoses included gastroesophageal reflux disease (GERD, 50%), dysphagia/aspiration (40%), asthma (30%), recurrent croup (30%), tracheostomy dependence (19%) and eosinophilic esophagitis (EOE) (12%). Bronchoalveolar lavage (BAL) demonstrated cellular inflammation with elevated proportions of neutrophils in 63%, and lymphocytes in 24%. Among 88 patients in whom bacterial cultures were performed, 52% were positive, with Moraxella, Haemophilus, Streptococcal and Pseudomonas species predominating. Among 30 patients who underwent viral testing, 57% were positive, with rhinovirus (82%) and adenovirus (29%) predominating. Patients with neutrophilic inflammation were more likely to have a positive respiratory bacterial culture and/or viral polymerase chain reaction (p = 0.003, 0.005). Evaluation of the gastrointestinal tract included 79 patients with a history of esophagogastroduodenoscopy, 45 patients with a videofluoroscopic swallow study (VFSS), and 45 patients with multi-channel intraluminal impedance and pH testing. The majority of VFSS were abnormal (60%) demonstrating either laryngeal penetration (33%) or intratracheal aspiration (27%). Median pH reflux and impedance proximal reflux indices were 3.8% and 0.5% respectively. CONCLUSION: Potential contributing factors in the pathophysiology of nodular tracheobronchitis include bacterial and viral infections, GERD, dysphagia/aspiration, and EOE. When nodular tracheobronchitis is observed during bronchoscopy, further evaluation to assess for these conditions should be considered.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

The Feasibility and Efficacy of Warrior Health and Fitness: A 3-Month Fitness and Nutrition Program for Veterans.

INTRODUCTION: Veterans are at risk for mental and physical health problems but may not seek traditional health care services. Wellness-based interventions, including exercise and nutrition, have been associated with improvements in physical and mental health among this population. This study explores the acceptability, feasibility, and efficacy of a 3-month health and fitness program for veterans. MATERIALS AND METHODS: Participants in 2 time-based cohorts from 2019 to 2023 (cohort 1: n = 261; cohort 2: n = 256) were cleared by a physician to participate. Participants then completed a fitness test and self-reported surveys (e.g., quality of life, sleep, and pain) before and after the 3-month program. Participants were recruited to participate at one of three sites: Boston, MA Fort Myers, FL, or Tampa, FL. The 3-month program consisted of weekly, supervised group fitness and one-on-one sessions, nutritional consultations, yoga, and other wellness activities. Primary program outcomes were measured by fitness assessments, self-report surveys, program completion, and program satisfaction. Fitness assessments included measures of weight, body mass index, grip strength, waist to hip ratio, body fat, lean mass, fat mass, heart rate, and blood pressure (BP). Self-report measures included quality of life, depression, loneliness, sleep quality, pain intensity, and pain interference. RESULTS: In cohort 1, significant improvements were found for measures of weight (P = .01), left-handed grip strength (P < .01), body fat percent (P < .01), and quality of life (P < .01). In cohort 2, significant improvements were found for measures of waist:hip ratio (P = .02), right and left-handed grip strength (P < .01), body mass index (P = .02), body fat percent (P < .01), and quality of life (P = .02). For both cohorts, pain intensity (cohort 1: P = .01, cohort 2: P < .001) and pain interference (cohort 1: P = .02, cohort 2: P < .001) increased significantly. CONCLUSIONS: These data suggest that a 3-month health and fitness program for veterans is acceptable and feasible and may improve physical and mental health outcomes. Considerations for program retention and assessment completion are discussed.

A review of the flortaucipir literature for positron emission tomography imaging of tau neurofibrillary tangles.

Alzheimer's disease is defined by the presence of ß-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer's disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer's disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer's disease; non-Alzheimer's disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer's disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer's disease.

Sign Language Studies with Chimpanzees in Sanctuary.

Adult chimpanzees Tatu and Loulis lived at the Fauna Foundation sanctuary. They had acquired signs of American Sign Language (ASL) while young and continued to use them as adults. Caregivers with proficiency in ASL maintained daily sign language records during interactions and passive observation. Sign checklists were records of daily vocabulary use. Sign logs were records of signed interactions with caregivers and other chimpanzees. This study reports sign use from eight years of these records. Tatu and Loulis used a majority of their base vocabularies consistently over the study period. They used signs that they had acquired decades earlier and new signs. Their utterances served a variety of communicative functions, including responses, conversational devices, requests, and descriptions. They signed to caregivers, other chimpanzees, including those who did not use signs, and to themselves privately. This indicates the importance of a stimulating and interactive environment to understand the scope of ape communication and, in particular, their use of sign language.

TRPA1 Antagonist LY3526318 Inhibits the Cinnamaldehyde-Evoked Dermal Blood Flow Increase: Translational Proof of Pharmacology.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.

Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. METHODS: Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. RESULTS: PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). DISCUSSION: These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Highlights: Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.

Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511.

Neurorehabilitation robotics: how much control should therapists have?

Robotic technologies for rehabilitating motor impairments from neurological injuries have been the focus of intensive research and capital investment for more than 30 years. However, these devices have failed to convincingly demonstrate greater restoration of patient function compared to conventional therapy. Nevertheless, robots have value in reducing the manual effort required for physical therapists to provide high-intensity, high-dose interventions. In most robotic systems, therapists remain outside the control loop to act as high-level supervisors, selecting and initiating robot control algorithms to achieve a therapeutic goal. The low-level physical interactions between the robot and the patient are handled by adaptive algorithms that can provide progressive therapy. In this perspective, we examine the physical therapist's role in the control of rehabilitation robotics and whether embedding therapists in lower-level robot control loops could enhance rehabilitation outcomes. We discuss how the features of many automated robotic systems, which can provide repeatable patterns of physical interaction, may work against the goal of driving neuroplastic changes that promote retention and generalization of sensorimotor learning in patients. We highlight the benefits and limitations of letting therapists physically interact with patients through online control of robotic rehabilitation systems, and explore the concept of trust in human-robot interaction as it applies to patient-robot-therapist relationships. We conclude by highlighting several open questions to guide the future of therapist-in-the-loop rehabilitation robotics, including how much control to give therapists and possible approaches for having the robotic system learn from therapist-patient interactions.

Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial.

Importance: Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. Objective: To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. Design, Setting, and Participants: TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-ß. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels. Interventions: Randomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction. Main Outcomes and Measures: Change in plasma biomarker levels after donanemab treatment. Results: In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, -0.04 [95% CI, -0.07 to -0.02]; P = .002 and -0.04 [95% CI, -0.07 to -0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-ß 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively). Conclusions and Relevance: Significant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03367403.

Disturbance cue communication is shaped by emitter diet and receiver background risk in Trinidadian guppies.

In animal communication systems, individuals that detect a cue (i.e., "receivers") are often influenced by characteristics of the cue emitter. For instance, in many species, receivers avoid chemical cues that are released by emitters experiencing disturbance. These chemical "disturbance cues" appear to benefit receivers by warning them about nearby danger, such as a predator's approach. While the active ingredients in disturbance cues have been largely unexplored, by-products of metabolized protein are thought to play a role for some species. If so, the content (quality) and volume (quantity) of the emitter's diet should affect their disturbance cues, thus altering how receivers perceive the cues and respond. Guppies Poecilia reticulata are a species known to discriminate among disturbance cues from different types of donors, but dietary variation has yet to be explored. In this study, we found evidence that diet quality and quantity can affect disturbance cues released by guppy emitters (i.e., experimental "donors"). Receivers discriminated between donor cue treatments, responding more strongly to cues from donors fed a protein-rich bloodworm diet (Experiment 1), as well as an overall larger diet (Experiment 2). We also found that receivers exposed to higher background risk were more sensitive to disturbance cue variation, with the strongest avoidance responses displayed by high-risk receivers toward disturbance cues from donors fed the high-quality diet. Therefore, diet, and perhaps protein specifically, affects either the concentration or composition of disturbance cues released by guppies. Such variation may be important in information signaling in social species like the guppy.

Isolation and Whole-Genome Sequencing of Four Antibiotic-Producing Pseudomonas Strains.

Here, we report the isolation, whole-genome sequencing, and annotation of four novel Pseudomonas isolates. We also evaluate the biosynthetic potential of each genome.

Perspectives on Cognitive Phenotypes and Models of Vascular Disease.

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Exploring Workers' Subjective Experiences of Habit Formation in Cybersecurity: A Qualitative Survey.

Employee behaviors remain at the center of the cybersecurity of workplaces, despite the challenges they face in doing so. Time pressures and competing demands mean that users tend to rely on habitual behaviors that often run counter to good cybersecurity practice. One possible solution may be to encourage positive habit formation. Designing such interventions, however, relies on knowledge of the perception and experience of habit formation in the context of cybersecurity. To this end, a qualitative survey containing open-ended questions was completed by 195 participants (mean age = 35.51, 53 percent female) recruited via an online participant panel. Participants were asked what cybersecurity behaviors they perform at work and how they believe any habits were prompted, formed, and maintained. Thematic analysis identified three over-arching themes: (a) forming habits unavoidably or unconsciously (some were mandated, or formed without conscious awareness), (b) consciously cultivating habits (including the roles of intrinsic motivation and external prompts), and (c) social and organizational influences (including the influence of occupational culture, social modeling, previous experiences, and information gathering practices). Based on these findings, we present guidelines for supporting workplace cybersecurity habit formation reflecting these subjective experiences, namely introducing automatic solutions, facilitating external cues, fostering interest in cybersecurity issues among employees, creating a positive cybersecurity occupational culture and highlighting positive behavior, and providing access to accessible cybersecurity information to employees. These results constitute a first step in identifying how habits can be exploited for positive cybersecurity behavior change in a way that accounts for the reliance on habitual behaviors in busy, time-pressured workplaces.

Relationship of the Calcitonin Gene-Related Peptide Monoclonal Antibody Galcanezumab Pharmacokinetics and Capsaicin-Induced Dermal Blood Flow in Healthy Subjects.

Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h-1 (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC50 ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC50 after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.

Building the Next Generation of Humanized Hemato-Lymphoid System Mice.

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these "humanized" mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

Overexpression of Substance P in pig airways increases MUC5AC through an NF-kß pathway.

Substance P (SP) is a tachykinin that regulates airway mucous secretion in both health and disease. Our study aimed to determine whether overexpression of SP without pre-existing inflammation was sufficient to induce changes in mucin secretion and transport in small airways. Utilizing porcine precision-cut lung slices, we measured the impact of AAV-mediated overexpression of SP on airway physiology ex vivo. Immunofluorescence signal intensity for MUC5AC was significantly increased in SP-overexpressed precision-cut lung slices compared to GFP controls. No difference in MUC5B signal intensity between treatments was detected. SP-overexpressed precision-cut lung slices also exhibited decreased IL10 mRNA, an important inhibitor of mucous cell metaplasia. Overt deficits in mucociliary transport were not noted, though a trend for decreased mean transport speed was detected in methacholine-challenged airways overexpressing SP compared to GFP controls. Pharmacologic inhibition of the NF-kß pathway abrogated the effects of overexpression of SP on both MUC5AC and IL10. Collectively, these data suggest that overexpression of SP in the absence of existing inflammation increases MUC5AC via activation of the NF-kß pathway. Thus, these data further highlight SP as a key driver of abnormal mucous secretion and underscore NF-kß signaling as a pathway of potential therapeutic intervention.

Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states.

Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.

Knowledge, Attitudes, and Practices of Pediatric Long-term Care Facility Staff Regarding Infection Control for Acute Respiratory Infections and Influenza Vaccination.

We surveyed clinical staff and on-site teachers working at pediatric long-term care facilities regarding prevention and control of acute respiratory infections and influenza in staff and residents. We uncovered knowledge gaps, particularly among teachers and clinical staff working <5 years at sites, thereby elucidating areas for targeted staff education.