mTOR signaling regulates aberrant epithelial cell proliferative and migratory behaviors characteristic of airway mucous metaplasia in asthma.

In asthma, the airway epithelium is hyperplastic, hypertrophied, and lined with numerous large MUC5AC-containing goblet cells (GC). Furthermore, the normal epithelial architecture is disorganized with numerous, what we here describe as, ectopic goblet cells (eGC) deep within the thickened epithelial layer disconnected from the lumenal surface. mTOR is a highly conserved pathway that regulates cell size and proliferation. We hypothesized that the balance between mTOR and autophagy signaling regulates key features of the asthma epithelial layer. Airway histological sections from subjects with asthma had increased frequency of eGC and increased levels of mTOR phosphorylation target-Ribosomal S6. Using human airway epithelial cells (hAECs) with IL-13 stimulation and timed withdrawal to stimulate resolution, we found that multiple key downstream phosphorylation targets downstream from the mTOR complex were increased during early IL-13-mediated mucous metaplasia, and then significantly declined during resolution. The IL-13-mediated changes in mTOR signaling were paralleled by morphologic changes with airway epithelial hypertrophy, hyperplasia, and frequency of eGC. We then examined the relationship between mTOR and autophagy using mice deficient in autophagy protein Atg16L1. Despite having increased cytoplasmic mucins, mouse AECs from Atg16L1 deficient mice had no significant difference in mTOR downstream signaling. mTOR inhibition with rapamycin led to a loss of IL-13-mediated epithelial hypertrophy, hyperplasia, ectopic GC distribution, and reduction in cytoplasmic MUC5AC levels. mTOR inhibition was also associated with a reduction in aberrant IL-13-mediated hAEC proliferation and migration. Our findings demonstrate that mTOR signaling is associated with mucous metaplasia and is crucial to the disorganized airway epithelial structure and function characteristic of muco-obstructive airway diseases such as asthma. Graphical Abstract Key Concepts: The airway epithelium in asthma is disorganized and characterized by cellular proliferation, aberrant migration, and goblet cell mucous metaplasia.mTOR signaling is a dynamic process during IL-13-mediated mucous metaplasia, increasing with IL-13 stimulation and declining during resolution.mTOR signaling is strongly increased in the asthmatic airway epithelium.mTOR signaling is associated with the development of key features of the metaplastic airway epithelium including cell proliferation and ectopic distribution of goblet cells and aberrant cellular migration.Inhibition of mTOR leads to decreased epithelial hypertrophy, reduced ectopic goblet cells, and cellular migration.

Restless legs syndrome is prevalent in adults with cystic fibrosis and impacts sleep quality.

BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor disorder that is prevalent in chronic inflammatory conditions. RLS prevalence, risk factors, and impact on sleep in CF have not been extensively characterized to date. METHODS: An initial cohort was examined, including 75 persons with CF (PwCF) and 75 control subjects, to look at the prevalence and severity of RLS. A second validation cohort of 191 PwCF was then enrolled from two CF centers to examine risk factors for RLS. A diagnosis of RLS was made according to the International RLS Study Group (IRLSSG) criteria. Sleep quality was identified using the Pittsburgh sleep quality index (PSQI). Epworth sleepiness scale (ESS) was used to measure daytime sleepiness. We then analyzed laboratory and clinical risk factors and sleep symptoms for potential risk factors for RLS. RESULTS: In the initial cohort, 36 % of PwCF had RLS, and 9 % of these had significant RLS. In contrast, only 15 % of controls had RLS, and none had significant RLS. In the second larger validation cohort with 191 subjects, a comparable prevalence of RLS was identified. Higher hemoglobin A1c, use of SSRI/SNRI medications, worse PSQI and ESS sleep quality scores, lower lung function, and higher antibiotic usage were significantly associated with a diagnosis of RLS. By multivariate multinominal logistic regression analysis, higher HbA1c and worse PSQI global sleep quality scores were independent predictors of significant RLS. CONCLUSIONS: RLS is highly prevalent in CF. Higher HbA1c and poor sleep quality, signified by higher PSQI, were each independent predictors of RLS.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Fractional exhaled nitric oxide in the assessment of exercise-induced bronchoconstriction: A multicenter retrospective analysis of UK-based athletes.

INTRODUCTION: Exercise-induced bronchoconstriction (EIB) is not only highly prevalent in people with asthma, but can also occur independently, particularly in athletes. Fractional exhaled nitric oxide (FeNO) is an indirect biomarker of type 2 airway inflammation that has an established role in the assessment and management of asthma. The aim was to evaluate the value of FeNO in the assessment of EIB in athletes. METHOD: Multicenter retrospective analysis. In total, 488 athletes (male: 76%) performed baseline FeNO, and spirometry pre- and post-indirect bronchial provocation via eucapnic voluntary hyperpnea (EVH). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for established FeNO thresholds-that is, intermediate (≥25 ppb) and high FeNO (≥40 ppb and ≥ 50 ppb)-and were evaluated against objective evidence of EIB (≥10% fall in FEV1 ). The diagnostic accuracy of FeNO was calculated using receiver operating characteristics area under the curve (ROC-AUC). RESULTS: Thirty-nine percent of the athletes had a post-EVH fall in FEV1 consistent with EIB. FeNO values ≥25 ppb, ≥40 ppb, and ≥ 50 ppb were observed in 42%, 23%, and 17% of the cohort, respectively. The sensitivity of FeNO ≥25 ppb was 55%, which decreased to 37% and 27% at ≥40 ppb and ≥ 50 ppb, respectively. The specificity of FeNO ≥25 ppb, ≥40 ppb, and ≥ 50 ppb was 66%, 86%, and 89%, respectively. The ROC-AUC for FeNO was 0.656. CONCLUSIONS: FeNO ≥40 ppb provides good specificity, that is, the ability to rule-in a diagnosis of EIB. However, due to the poor sensitivity and predictive values, FeNO should not be employed as a replacement for indirect bronchial provocation in athletes.

Effect of epithelial-specific MyD88 signaling pathway on airway inflammatory response to organic dust exposure.

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC+ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC+ cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC+ cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP+ airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Hyponatraemic seizure secondary to primary polydipsia following urological surgery.

An 82-year-old man presented to the emergency department with delirium, vomiting and an initial hyponatraemia of 112 mmol/L the day after successful transurethral vaporisation of the prostate. He had a tonic-clonic seizure in the acute surgical unit and was managed subsequently in the intensive care unit with a controlled rate of hypertonic saline. Initial work-up for the cause of hyponatraemia revealed a low urine osmolality, suggestive of relative excess water intake. Detailed examination of the operation notes revealed no discrepancy between intraoperative irrigating fluid input and output. Careful collateral history revealed that the patient had drunk 8 L of water in the 24 hours following the operation, after taking advice to 'drink plenty of water' literally. This case highlights the importance of conveying specific advice to patient, the lower incidence of transurethral resection syndrome in resections using saline as an irrigation fluid and outlines the pathway for investigation and management for hyponatraemia.

Breathing Pattern Disorders Distinguished from Healthy Breathing Patterns Using Optoelectronic Plethysmography.

There is no gold standard diagnostic method for breathing pattern disorders (BPD) which is commonly diagnosed through the exclusion of other pathologies. Optoelectronic plethysmography (OEP) is a 3D motion capture technique that provides a comprehensive noninvasive assessment of chest wall during rest and exercise. The purpose of this study was to determine if OEP can distinguish between active individuals classified with and without BPD at rest and during exercise. Forty-seven individuals with a healthy breathing pattern (HBP) and twenty-six individuals with a BPD performed a submaximal exercise challenge. OEP measured the movement of the chest wall through the calculation of timing, percentage contribution, and phase angle breathing pattern variables. A mixed model repeated measures ANOVA analysed the OEP variables between the groups classified as HBP and BPD at rest, during exercise, and after recovery. At rest, regional contribution variables including ribcage percentage contribution (HBP: 71% and BPD: 69%), abdominal ribcage contribution (HBP: 13% and BPD: 11%), abdomen percentage contribution (HBP: 29% and BPD: 31%), and ribcage and abdomen volume index (HPB: 2.5 and BPD: 2.2) were significantly (p < 0.05) different between groups. During exercise, BPD displayed significantly (p < 0.05) more asynchrony between various thoracic compartments including the ribcage and abdomen phase angle (HBP: -1.9 and BPD: -2.7), pulmonary ribcage and abdomen phase angle (HBP: -0.5 and BPD, 0.5), abdominal ribcage and shoulders phase angle (HBP: -0.3 and BPD: 0.6), and pulmonary ribcage and shoulders phase angle (HBP: 0.2 and BPD: 0.6). Additionally, the novel variables inhale deviation (HBP: 8.8% and BPD: 19.7%) and exhale deviation (HBP: -10.9% and BPD: -17.6%) were also significantly (p < 0.05) different between the groups during high intensity exercise. Regional contribution and phase angles measured via OEP can distinguish BPD from HBP at rest and during exercise. Characteristics of BPD include asynchronous and thoracic dominant breathing patterns that could form part of future objective criteria for the diagnosis of BPD.

Associations between Second-Hand Tobacco Smoke Exposure and Cardiorespiratory Fitness, Physical Activity, and Respiratory Health in Children.

BACKGROUND: Cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a plethora of positive health effects. Many UK children fail to meet the recommended level of PA, with an observed decline in CRF levels over recent decades. Second-hand tobacco smoke (SHS) is responsible for a significant proportion of the worldwide burden of disease, but little is understood regarding the impact of SHS exposure on CRF and PA in children. The aim of this study was to test the associations between SHS exposure and CRF, PA, and respiratory health in children. METHOD: Children (9-11 years) from UK primary schools in deprived areas participated (n = 104, 38 smoking households). Surveys determined household smoking, and exhaled carbon monoxide was used to indicate children's recent SHS exposure. CRF (VO2peak) was assessed via maximal treadmill protocol using breath-by-breath analysis. Fractional exhaled nitric oxide and spirometry were utilised as indicators of respiratory health. RESULTS: Linear regression models demonstrated that SHS exposure was negatively associated with allometrically scaled VO2peak (B = -3.8, p = 0.030) but not PA or respiratory health. CONCLUSION: The results indicate that SHS is detrimental to children's CRF; given that approximately one-third of children are regularly exposed to SHS, this important finding has implications for both public health and the sport and exercise sciences.

Hydration, Eating Attitudes and Behaviors in Age and Weight-Restricted Youth American Football Players.

There is a paucity of research examining hydration and nutrition behaviors in youth American football players. A potentially unique risk factor are league restrictions based on weight (WR) or age (AR). The purpose of this study was to examine hydration status between WR and AR leagues. The secondary purpose was to describe eating patterns in players. An observational cohort design with 63 youth football players (10 ± 1 yrs, 148.2 ± 9.4 cm, 44.9 ± 15.3 kg) was utilized. Independent variables were league (AR (n = 36); WR (n = 27)) and activity type (practice (PX = 8); game (GM = 3)). Dependent variables were hydration status (urine osmolality; percent change in body mass (%BM)), eating attitudes (Children's Eating Attitude Test (ChEAT-26)) and self-reported frequency of meals. On average, players arrived activity mildly hypohydrated (830 ± 296 mOsm/kg) and %BM was minimal (-0.1 ± 0.7%) during events. Players consumed 2 ± 1 meals and 1 ± 1 snack before events. The ChEAT-26 survey reported 21.6% (n = 8) of players were at risk for abnormal eating attitudes. Among these players, eating binges, vomiting, excessive exercise and drastic weight loss were reported. Youth American football players arrived activity mildly hypohydrated and consumed enough fluid during activity to maintain euhydration. Abnormal eating attitudes and the use of unhealthy weight loss methods were reported by some youth American football players.

Neutralization of IL-33 modifies the type 2 and type 3 inflammatory signature of viral induced asthma exacerbation.

BACKGROUND: Respiratory viral infections are one of the leading causes of need for emergency care and hospitalizations in asthmatic individuals, and airway-secreted cytokines are released within hours of viral infection to initiate these exacerbations. IL-33, specifically, contributes to these allergic exacerbations by amplifying type 2 inflammation. We hypothesized that blocking IL-33 in RSV-induced exacerbation would significantly reduce allergic inflammation. METHODS: Sensitized BALB/c mice were challenged with aerosolized ovalbumin (OVA) to establish allergic inflammation, followed by RSV-A2 infection to yield four treatment groups: saline only (Saline), RSV-infected alone (RSV), OVA alone (OVA), and OVA-treated with RSV infection (OVA-RSV). Lung outcomes included lung mRNA and protein markers of allergic inflammation, histology for mucus cell metaplasia and lung immune cell influx by cytospin and flow cytometry. RESULTS: While thymic stromal lymphopoietin (TSLP) and IL-33 were detected 6 h after RSV infection in the OVA-RSV mice, IL-23 protein was uniquely upregulated in RSV-infected mice alone. OVA-RSV animals varied from RSV- or OVA-treated mice as they had increased lung eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2) and group 3 innate lymphoid cells (ILC3) detectable as early as 6 h after RSV infection. Neutralized IL-33 significantly reduced ILC2 and eosinophils, and the prototypical allergic proteins, IL-5, IL-13, CCL17 and CCL22 in OVA-RSV mice. Numbers of neutrophils and ILC3 were also reduced with anti-IL-33 treatment in both RSV and OVA-RSV treated animals as well. CONCLUSIONS: Taken together, our findings indicate a broad reduction in allergic-proinflammatory events mediated by IL-33 neutralization in RSV-induced asthma exacerbation.

Is age rating enough to investigate changes in breathing motion pattern associated with aging of physically active women?

The most common way to analyze the effect of aging on breathing is to divide subjects into age groups. However, in addition to the fact that there is no consensus in the literature regarding age group division, such design critically influences the interpretation of the effects attributed to aging. Thus, this study aimed to investigate the feasibility to distinguish different age groups from the 3D kinematic variables of breathing motion (i.e., markers' coordinate as a function of time allowing the calculation of compartmental volume variations) and to analyze whether the aging could influence these variables. Seventy-three physically active women aged 19-80 years performed quiet breathing and vital capacity maneuvers. To record the thoracoabdominal breathing motion, the 3D coordinates of 32 retroreflective markers positioned on the trunk were used to estimate the volume variation of the superior thorax, inferior thorax, and abdomen. The percentage of contribution and the correlation coefficient were calculated to analyze the breathing motion pattern from the estimated volumes. The k-means cluster analysis was performed to analyze the age group classification. Linear regression was performed to investigate whether age can predict changes in the breathing motion pattern. The results showed that physically active women could not be classified into age groups from breathing motion. Despite significant p values of the linear regression, the high variability of the data suggested that age itself is not enough to predict the changes in breathing motion pattern when non-sedentary women are considered.

Novel Real-Time OEP Phase Angle Feedback System for Dysfunctional Breathing Pattern Training-An Acute Intervention Study.

Dysfunctional breathing patterns (DBP) can have an impact on an individual's quality of life and/or exercise performance. Breathing retraining is considered to be the first line of treatment to correct breathing pattern, for example, reducing ribcage versus abdominal movement asynchrony. Optoelectronic plethysmography (OEP) is a non-invasive 3D motion capture technique that measures the movement of the chest wall. The purpose of this study was to investigate if the use of a newly developed real-time OEP phase angle and volume feedback system, as an acute breathing retraining intervention, could result in a greater reduction of phase angle values (i.e., an improvement in movement synchrony) when compared to real-time OEP volume feedback alone. Eighteen individuals with a DBP performed an incremental cycle test with OEP measuring chest wall movement. Participants were randomly assigned to either the control group, which included the volume-based OEP feedback or to the experimental group, which included both the volume-based and phase angle OEP feedback. Participants then repeated the same cycle test using the real-time OEP feedback. The phase angle between the ribcage versus abdomen (RcAbPhase), between the pulmonary ribcage and the combined abdominal ribcage and abdomen (RCpAbPhase), and between the abdomen and the shoulders (AbSPhase) were calculated during both cycle tests. Significant increases in RcAbPhase (pre: -2.89°, post: -1.39°, p < 0.01), RCpAbPhase (pre: -2.00°, post: -0.50°, p < 0.01), and AbSPhase (pre: -2.60°, post: -0.72°, p < 0.01) were found post-intervention in the experimental group. This indicates that the experimental group demonstrated improved synchrony in their breathing pattern and therefore, reverting towards a healthy breathing pattern. This study shows for the first time that dysfunctional breathing patterns can be acutely improved with real-time OEP phase angle feedback and provides interesting insight into the feasibility of using this novel feedback system for breathing pattern retraining in individuals with DBP.

Exertional heat illness risk factors and physiological responses of youth football players.

OBJECTIVE: To determine which intrinsic and extrinsic exertional heat illness (EHI) risk factors exist in youth American football players and observe perceptual and physiological responses of players during events (games and practices). METHODS: Cross-sectional cohort study observing 63 youth football players, varying in position. Independent variables were league (weight-restricted (WR, n = 27) and age-restricted (AR, n = 36)) and event type. Dependent variables were anthropometrics, work-to-rest ratio, and wet bulb globe temperature. Descriptive variables included preparticipation examination and uniform configuration. A subset of 16 players participated in physiological variables (heart rate and gastrointestinal temperature). Data collection occurred on 7 AR and 8 WR nonconsecutive practices and the first 3 games of the season. RESULTS: Mean values for anthropometric variables were higher (p < 0.05) in the AR league than the WR league. Work time (χ2 (1,111) = 4.232; p = 0.039) and rest time (χ2 (1,111) = 43.41; p < 0.001) were significantly greater for games, but ratios were significantly higher for practices (χ2 (1,111) = 40.62; p < 0.001). The majority of events (77%) observed were in black and red flag wet bulb globe temperature risk categories. A total of 57% of the players had a preparticipation examination, and up to 82% of events observed were in full uniforms. Individual gastrointestinal temperature and heart rate responses ranged widely and no players reached critical thresholds. CONCLUSION: Extrinsic (disproportionate work ratios, environmental conditions) and intrinsic (higher body mass index) EHI risk factors exist in youth football. Certain risk factors may be influenced by event and league type. National youth football organizations need to create thorough guidelines that address EHI risk factors for local leagues to adopt.

The impact of a heat and moisture exchange mask on respiratory symptoms and airway response to exercise in asthma.

Respiratory symptoms, including cough, are prevalent in individuals with asthma when exercising. This study investigates whether a heat and moisture exchanger (HME) face mask is effective in modulating exercise-induced bronchoconstriction (EIB) and post-exercise cough in a cold, dry environment in individuals with asthma. Twenty-six participants diagnosed with asthma (20 males, 6 females) completed three cycling exercise challenges at 8°C and 24% relative humidity in a randomised order. Participants wore either an HME mask (MASK), sham mask (SHAM), or no mask (CONT). Following a 3-min warm-up, participants completed 6-min cycling at 80% peak power output. Before and after exercise, maximal flow-volume loops were recorded. Post-exercise cough was monitored with a Leicester Cough Monitor (LCM) for 24 h. Results were analysed using repeated-measures ANOVA and Friedman's tests and data were presented as the mean±sd or median (interquartile range (IQR)). Eleven participants failed to demonstrate EIB (i.e. >10% fall in forced expiratory volume in 1 s after exercise) and were removed from analysis. The percentage fall in forced expiratory volume in 1 s following exercise in CONT was greater than MASK (MASK: -6% (7%), SHAM: -11% (11%), CONT: -13% (9%); p<0.01). No difference was found between exercise in cough count per hour over the 24-h monitoring period or the number of coughs in the first hour after exercise. HME masks can attenuate EIB when exercising in cold, dry environments. The SHAM mask may not have been entirely inert, demonstrating the challenges of running randomised control trials utilising control and sham conditions.

MyD88 regulates a prolonged adaptation response to environmental dust exposure-induced lung disease.

BACKGROUND: Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies. METHODS: Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE. RESULTS: Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge. CONCLUSIONS: MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.

Procalcitonin predicts the severity of cystic fibrosis pulmonary exacerbations and readmissions in adult patients: a prospective cohort study.

Patients with cystic fibrosis (CF) experience multiple pulmonary exacerbations throughout their lifetime, resulting in repeated antibiotic exposure and hospital admissions. Reliable diagnostic markers to guide antibiotic treatment in patients with CF, however, are lacking. Given that the CF airway is characterized by persistent and frequent bacterial infection, our goal was to determine if procalcitonin (PCT) could be used as a severity and prognostic marker of CF exacerbation. We enrolled 40 participants at the time of diagnosis of CF pulmonary exacerbation. Inclusion criteria: age ≥19 years with exacerbation requiring antibiotics as determined by the treating physician. Exclusion criteria: antibiotics initiated more than 48 hours prior to enrollment, and pregnancy. Blood samples were collected on enrollment day and after 7-10 days of treatment. Of the 40 patients enrolled, 23 (57.5%) had detectable levels of PCT (≥0.05 ng/mL). PCT levels were significantly associated with pulmonary exacerbation scores (p=0.01) and per cent decrease in forced expiratory volume in 1 second (FEV1) (p=0.01) compared with the best in the last 12 months. Those who had worsening PCT during treatment had less improvement in FEV1 (p=0.001) and were more likely to be readmitted to the hospital sooner (p<0.0001). Likewise, those who had a detectable PCT at the time of admission were more likely to be readmitted sooner (p=0.03). PCT elevation during antibiotic treatment is associated with less improvement in FEV1 and earlier readmission. A detectable PCT level occurs only in more severe CF exacerbations. Multicenter trials are needed to confirm whether PCT may play a role in the clinical care of patients with CF.