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Recommendations for or against the use of interventions need to consider both desirable and undesirable effects as well as patients' values and preferences (V&P). In the decision‐making context, patients' V&P represent the relative importance people place on the outcomes resulting from a decision. Therefore, the balance between desirable and undesirable effects from an intervention should depend not only on the difference between benefits and harms but also on the value that patients place on them. V&P are therefore one of the criteria to be considered when formulating guideline recommendations in the Evidence‐to‐Decision framework developed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Working Group. Patients' V&P may be quantified through utilities, which can be elicited using direct methods (e.g., standard gamble or time trade‐off) or indirect methods (using validated instruments to measure health‐related quality of life, such as EQ‐5D). The GRADE approach recommends conducting systematic reviews to summarise all the available evidence and assess the degree of certainty on V&P. In this article, we discuss the importance of considering patients' V&P and provide examples of how they are considered in the 2024 person‐centred Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. [ABSTRACT FROM AUTHOR]

Background: Introducing peanut products early can prevent peanut allergy (PA). The "Addendum guidelines for the prevention of PA in the United States" (PPA guidelines) recommend early introduction of peanut products to low and moderate risk infants and evaluation prior to starting peanut products for infants at high risk for PA (those with severe eczema and/or egg allergy). Rapid adoption of guidelines could aid in lowering the prevalence of PA. The Intervention to Reduce Early (Peanut) Allergy in Children (iREACH) trial was designed to promote PPA guideline adherence by pediatric clinicians. Methods: A two‐arm, cluster‐randomized, controlled clinical trial was designed to measure the effectiveness of an intervention that included clinician education and accompanying clinical decision support tools integrated in electronic health records (EHR) versus standard care. Randomization was at the practice level (n = 30). Primary aims evaluated over an 18‐month trial period assess adherence to the PPA guidelines using EHR documentation at 4‐ and 6‐month well‐child care visits aided by natural language processing. A secondary aim will evaluate the effectiveness in decreasing the incidence of PA by age 2.5 years using EHR documentation and caregiver surveys. The unit of observation for evaluations are individual children with clustering at the practice level. Conclusion: Application of this intervention has the potential to inform the development of strategies to speed implementation of PPA guidelines. [ABSTRACT FROM AUTHOR]

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one‐airway‐one‐disease," coined over 20 years ago, is a simplistic approach of the links between upper‐ and lower‐airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper‐ and lower‐airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one‐airway‐one‐disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll‐Like Receptors and IL‐17 for rhinitis alone as a local disease; IL‐33 and IL‐5 for allergic and non‐allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono‐ or pauci‐sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases. [ABSTRACT FROM AUTHOR]

On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled "Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities." During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission. Methods: We determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-<48mo). We tested for association with remission, sustained unresponsiveness (SU), and desensitization in the OIT groups, as well as peanut component specific IgG4 (psIgG4) using generalized linear models and adjusting for relevant covariates and ancestry. Results: While not quite statistically significant, a higher proportion of HLADQA1* 01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among noncarriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects. Conclusions: Findings across three clinical trials show a pattern of a gene environment interaction between HLA and oral peanut exposure. Age, and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT. [ABSTRACT FROM AUTHOR]

There is mounting evidence that environmental exposures can result in effects on health that can be transmitted across generations, without the need for a direct exposure to the original factor, for example, the effect of grandparental smoking on grandchildren. Hence, an individual's health should be investigated with the knowledge of cross‐generational influences. Epigenetic factors are molecular factors or processes that regulate genome activity and may impact cross‐generational effects. Epigenetic transgenerational inheritance has been demonstrated in plants and animals, but the presence and extent of this process in humans are currently being investigated. Experimental data in animals support transmission of asthma risk across generations from a single exposure to the deleterious factor and suggest that the nature of this transmission is in part due to changes in DNA methylation, the most studied epigenetic process. The association of father's prepuberty exposure with offspring risk of asthma and lung function deficit may also be mediated by epigenetic processes. Multi‐generational birth cohorts are ideal to investigate the presence and impact of transfer of disease susceptibility across generations and underlying mechanisms. However, multi‐generational studies require recruitment and assessment of participants over several decades. Investigation of adult multi‐generation cohorts is less resource intensive but run the risk of recall bias. Statistical analysis is challenging given varying degrees of longitudinal and hierarchical data but path analyses, structural equation modelling and multilevel modelling can be employed, and directed networks addressing longitudinal effects deserve exploration as an effort to study causal pathways. [ABSTRACT FROM AUTHOR]

This report presents the proceedings from a workshop titled "Microbiome, Metabolism and Immunoregulation of Asthma" that was held virtually May 13 and 14, 2021. The workshop was jointly sponsored by the American Thoracic Society (Assembly on Allergy, Immunology, and Inflammation) and the National Institute of Allergy and Infectious Diseases. It convened an interdisciplinary group of experts with backgrounds in asthma immunology, microbiome science, metabolomics, computational biology, and translational pulmonary research. The main purpose was to identify key scientific gaps and needs to further advance research on microbial and metabolic mechanisms that may contribute to variable immune responses and disease heterogeneity in asthma. Discussions were structured around several topics, including 1) immune and microbial mechanisms of asthma pathogenesis in murine models, 2) the role of microbes in pediatric asthma exacerbations, 3) dysregulatedmetabolic pathways in asthma associated with obesity, 4) metabolism effects on macrophage function in adipose tissue and the lungs, 5) computational approaches to dissect microbiome-metabolite links, and 6) potential confounders of microbiome-disease associations in human studies. This report summarizes the major points of discussion, which included identification of specific knowledge gaps, challenges, and suggested directions for future research. These include questions surrounding mechanisms by which microbiota and metabolites shape host health versus an allergic or asthmatic state; direct and indirect influences of other biological factors, exposures, and comorbidities on these interactions; and ongoing technical and analytical gaps for clinical translation. [ABSTRACT FROM AUTHOR]

The effect of thyroid function on semen parameters has been studied in pathological conditions in small studies. With this research work, we aimed to study thyroid hormone effects on semen parameters in 130 men who were evaluated for couple subfertility. Our study was cross-sectional. We noted semen volume, sperm concentration, total sperm count, testosterone levels and thyrotropin (TSH) levels. The analysis included ordinary least squares regression (OLS-R), quantile regression (QR) and segmented line regression (SR). Using OLS-R, a weak negative correlation was found between the logTSH levels and semen volume (r = −0.16, r2 = 0.03, p = 0.05). In Q-R, each incremental unit increase in logTSH decreased the mean semen volume between −0.78 ± 0.44 and −1.33 ± 0.34 mL (40–60th response quantile) and between −1.19 ± 0.71 and −0.61 ± 0.31 mL (70–90th response quantile) (p = 0.049). With SR, a biphasic relationship of sperm concentration with TSH was noted (positive turning to negative, peaking at TSH = 1.22 μIU/mL). Thus, a weak negative association between the TSH levels and semen volume was noted, showing a trough within the usual normal range for TSH. Moreover, a biphasic relationship between the sperm concentration and TSH was also noted, peaking at approximately mid-normal TSH levels. Based on our results, TSH explained slightly less than 3% of the variation in semen volume and 7% of the sperm concentration (thus, other factors, which were not studied here, have a more important effect on it). [ABSTRACT FROM AUTHOR]

Background: The optimal technique for the displaced greater tuberosity (GT) fractures remains unclear; those in favor of arthroscopic techniques emphasize on the feasibility of arthroscopic reduction and fixation, while others report that anatomic reduction and osteosynthesis of the fracture are optimal through open surgery. Therefore, we performed this study to evaluate the clinical results of arthroscopic fixation for displaced and/or comminuted GT fractures using a bridging arthroscopic technique. Materials and methods: We studied the files of 11 patients (4 men, 7 women; mean age, 55 years; range, 28–74 years), with an isolated, displaced GT fracture treated with arthroscopic reduction and double-row suture anchor fixation technique from December 2016 to October 2018. All patients were operated at a mean time from their injury of 23 days (range, 1–85 days) using an arthroscopic technique. Any concomitant pathology that was arthroscopically identified was identified and repaired after arthroscopic fixation of the GT fracture. The mean follow-up was 12 months (range, 6–18 months). We evaluated pain using a 0–10 point visual analog scale (VAS), shoulder range of motion, fracture healing, Constant-Murley Shoulder Outcome Score, and patients' satisfaction from the operation. Results: Postoperative radiographs showed anatomic reduction without any displacement of the GT fracture in eight patients and residual displacement of < 3 mm in three patients. All patients significantly improved in VAS score from 8.4 points (range, 7–10 points) preoperatively to 0.9 points (range, 0–3 points) postoperatively. Range of motion was 153 degrees forward flexion (range, 130–170 degrees), 149 degrees abduction (range, 120–170 degrees), 42 degrees external rotation (range, 20–70), and internal rotation between T10 and L3 spinal level. The final mean Constant-Murley Shoulder Outcome Score was 85.8 points (range, 76–94 points); correlation analysis showed that the patients with the higher greater tuberosity fracture displacement had the worst postoperative score (Pearson correlation coefficient –0,85; p = 0.0009), and the patients with nonanatomic reduction had close to average score. All patients were very satisfied with the end result of the operation, even the 3 patients with residual fracture displacement. No patient experienced any postoperative complications. Conclusions: Arthroscopic reduction and fixation of displaced GT fractures is a feasible minimally invasive procedure for optimal fracture healing and patients satisfaction. [ABSTRACT FROM AUTHOR]

Background: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen‐specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma. Methods: Ten adults (18‐37 years) followed by 25 children (8‐14 years) with well‐controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381‐11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen–induced T‐cell activation and IL‐5 production were measured in peripheral blood mononuclear cells. Results: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380‐0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach‐specific IgE (P =.03), lower cockroach‐specific IgG/IgE ratios (children, P =.002), and increased cockroach‐specific IL‐5–producing T lymphocytes (P =.045). The NAC was well tolerated. Conclusion: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies. [ABSTRACT FROM AUTHOR]

Spatial variations and mobility of mercury (Hg) and Hg associations with other potentially toxic elements (PTEs) were studied in soil samples from Alaba, the largest e-waste recycling site in Nigeria and West Africa. Total Hg concentration was determined in surface soil samples from various locations using cold vapour atomic absorption spectrometry (CVAAS) following microwave-assisted acid extraction, while sequential extraction was used to determine operationally defined mobility. The concentrations of the PTEs arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), mercury (Hg), nickel (Ni), lead (Pb) and zinc (Zn) metals were determined using inductively coupled plasma mass spectrometry (ICP-MS) following microwave-assisted digestion with aqua regia. Total Hg concentration ranged from < 0.07 to 624 mg/kg and was largely dependent on the nature and intensity of e-waste recycling activities carried out. Mobile forms of Hg, which may be HgO (a known component of some forms of e-waste), accounted for between 3.2 and 23% of the total Hg concentration, and were observed to decrease with increasing organic matter (OM). Non-mobile forms accounted for >74% of the total Hg content. In the main recycling area, soil concentrations of Cd, Cd, Cu, Hg, Mn, Ni, Pb and Zn were above soil guideline values (Environment Agency in Science Report, 2009; Kamunda et al., 2016). Strong associations were observed between Hg and other PTEs (except for Fe and Zn) with the correlational coefficient ranging from 0.731 with Cr to 0.990 with As in April, but these correlations decreased in June except for Fe. Hazard quotient values > 1 at two locations suggest that Hg may pose health threats to people working at the e-waste recycling site. It is therefore recommended that workers should be investigated for symptoms of Hg exposure. [ABSTRACT FROM AUTHOR]

Seamless human–robot collaboration requires the equipping of robots with cognitive capabilities that enable their awareness of the environment, as well as the actions that take place inside the assembly cell. This paper proposes an AI-based system comprised of three modules that can capture the operator and environment status and process status, identify the tasks that are being executed by the operator using vision-based machine learning, and provide customized operator support from the robot side for shared tasks, automatically adapting to the operator's needs and preferences. Moreover, the proposed system is able to assess the ergonomics in human–robot shared tasks and adapt the robot pose to improve ergonomics using a heuristics-based search algorithm. An industrial case study derived from the elevator manufacturing sector using a high payload collaborative robot is presented to demonstrate that collaboration efficiency can be enhanced through the use of the discussed system. [ABSTRACT FROM AUTHOR]

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life. [ABSTRACT FROM AUTHOR]

Allergic diseases of the (upper and lower) airways, the skin and the gastrointestinal tract, are on the rise, resulting in impaired quality of life, decreased productivity, and increased healthcare costs. As allergic diseases are mostly tissue‐specific, local sampling methods for respective biomarkers offer the potential for increased sensitivity and specificity. Additionally, local sampling using noninvasive or minimally invasive methods can be cost‐effective and well tolerated, which may even be suitable for primary or home care sampling. Non‐ or minimally invasive local sampling and diagnostics may enable a more thorough endotyping, may help to avoid under‐ or overdiagnosis, and may provide the possibility to approach precision prevention, due to early diagnosis of these local diseases even before they get systemically manifested and detectable. At the same time, dried blood samples may help to facilitate minimal‐invasive primary or home care sampling for classical systemic diagnostic approaches. This EAACI position paper contains a thorough review of the various technologies in allergy diagnosis available on the market, which analytes or biomarkers are employed, and which samples or matrices can be used. Based on this assessment, EAACI position is to drive these developments to efficiently identify allergy and possibly later also viral epidemics and take advantage of comprehensive knowledge to initiate preventions and treatments. [ABSTRACT FROM AUTHOR]

Sweet potato (Ipomoea batatas L.) is a new tuber crop grown in Greece. It constitutes an innovative dietary component for both humans and animals, due to its nutritional properties. The cultivation of sweet potato focuses on the growth of both tubers and plants. Nitrogen is considered an essential element for almost all crops. This study set out to compare the effect of nitrogen inhibitors on yield components of sweet potato. In the literature, it is stated that in sweet potato cultivation nitrogen mainly affects the plants' growth such as the tuber's yield and some quality characteristics such as dry matter and protein content. To furthermore explore this particular area, field experiments took place in West Greece, during the years 2018 and 2019. Several urea combination treatments were used in the experimental process. The treatments were urea (46-0-0), urea with urease inhibitor (UI), urea with nitrification inhibitor (NI), urea with double inhibitors (UI + NI) and control (without fertilizer) in a randomised complete block design. Leaf area index (LAI) was significantly affected by the fertilizer marking the highest value of 5.35 under urea + UI + NI treatment. Marketable yield was profoundly affected by the fertilizer in the experimental years and ranged from 18,180 to 23,230 Kg · ha−1 whereas non-marketable yield was not affected by the fertilizer. A considerable impact of fertilizers was noticed on yield where the highest value was 30,923 Kg · ha−1 under urea + NI + UI treatment. The percentage of nitrogen on tubers and upper parts was significantly affected by the fertilizers. Nitrogen markers, such as nitrogen use efficiency (NUE), nitrogen harvest index and nitrogen agronomic efficiency (NAE), were used to evaluate nitrogen release. A significant positive correlation was noticed between marketable yield and NUE (0.774). Also, the significant increase in yield showed a positive correlation with NAE (0.727). For yield components of sweet potato, the highest values were observed in urea with double inhibitors treatment in both experimental years. [ABSTRACT FROM AUTHOR]

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence‐based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good‐quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow‐up of patients. [ABSTRACT FROM AUTHOR]

Background: Allergy to German cockroach (CR) is common in urban environments and is an important allergen in children with asthma. Objective: We hypothesize that the evolution of allergic sensitization and clinical disease is associated with distinct patterns of allergen‐specific T cell reactivity. To test this hypothesis, a subset of high‐risk inner‐city children participating in the URECA (Urban Environment and Childhood Asthma) birth cohort were selected to evaluate CR‐specific T cell reactivity from three distinct groups based on acquisition of aeroallergen sensitivity from ages 2 to 10: low atopy with minimal to no sensitivity (n = 26), early‐onset allergic sensitization (n = 25) and late‐onset allergic sensitization (n = 25). Methods: Using pools of previously identified CR‐derived T cell epitopes, we characterized the allergen‐specific T cell response in these 76 subjects from blood samples obtained at age 10. CR‐specific production of IL‐5, IFNγ and IL‐10 was measured by ELISPOT following two‐week in vitro culture with CR extract. Results: T cell responses were significantly higher in the early‐onset atopy group compared to low atopy (P = 0.01), and a trend for higher cytokine production in the late onset compared to the low atopy cohort was also observed (P = 0.06). T cell responses were similar between early‐ and late‐onset cohorts. Furthermore, a comparison of T cell reactivity between asthmatic and non‐asthmatic individuals revealed significantly higher cytokine production in asthmatics compared to non‐asthmatics (P = 0.02) within both the CR‐allergic and non‐allergic cohorts. Conclusions and clinical relevance: In conclusion, the present study reports that higher T cell reactivity is associated with allergen sensitization and asthma. Interestingly, no significant difference in T cell reactivity was observed in allergic children with early‐onset versus late‐onset atopy. [ABSTRACT FROM AUTHOR]

Rationale: Allergic inflammation has been linked to increased susceptibility to viral illnesses, but it is unclear whether this association is causal.Objectives: To test whether omalizumab treatment to reduce IgE would shorten the frequency and duration of rhinovirus (RV) illnesses in children with allergic asthma.Methods: In the PROSE (Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations) study, we examined children with allergic asthma (aged 6-17 yr; n = 478) from low-income census tracts in eight U.S. cities, and we analyzed virology for the groups randomized to treatment with guidelines-based asthma care (n = 89) or add-on omalizumab (n = 259). Weekly nasal mucus samples were analyzed for RVs, and respiratory symptoms and asthma exacerbations were recorded over a 90-day period during the fall seasons of 2012 or 2013. Adjusted illness rates (illnesses per sample) by treatment arm were calculated using Poisson regression.Measurements and Main Results: RVs were detected in 97 (57%) of 171 exacerbation samples and 2,150 (36%) of 5,959 nonexacerbation samples (OR, 2.32; P < 0.001). Exacerbations were significantly associated with detection of rhinovirus C (OR, 2.85; P < 0.001) and rhinovirus A (OR, 2.92; P < 0.001), as well as, to a lesser extent, rhinovirus B (OR, 1.98; P = 0.019). Omalizumab decreased the duration of RV infection (11.2 d vs. 12.4 d; P = 0.03) and reduced peak RV shedding by 0.4 log units (95% confidence interval, -0.77 to -0.02; P = 0.04). Finally, omalizumab decreased the frequency of RV illnesses (risk ratio, 0.64; 95% confidence interval, 0.49-0.84).Conclusions: In children with allergic asthma, treatment with omalizumab decreased the duration of RV infections, viral shedding, and the risk of RV illnesses. These findings provide direct evidence that blocking IgE decreases susceptibility to RV infections and illness. Clinical trial registered with www.clinicaltrials.gov (NCT01430403). [ABSTRACT FROM AUTHOR]

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6–17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population. [ABSTRACT FROM AUTHOR]

Importance: Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment.Objective: To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up.Design, Setting, and Participants: A randomized double-blind, placebo-controlled, 3-parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015.Interventions: Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation).Main Outcomes and Measures: Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy.Results: Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was -0.18 (95% CI, -1.25 to 0.90; [P = .75]).Conclusions and Relevance: Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up.Trial Registration: clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16. [ABSTRACT FROM AUTHOR]

Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. [ABSTRACT FROM AUTHOR]

Background: Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives: Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results: The addendum provides 3 separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions: Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. [ABSTRACT FROM AUTHOR]

The article reports on the policies framed by National Institute of Allergy and Infectious Diseases (NIAID) in 2008 for children and adults suffering from food allergy and 2010 Guidelines for the Diagnosis and Management of Food Allergy in U.S. on peanut allergy prevention. The recommendation from the expert panel and addendum guidelines are discussed.

Background Food allergy is an important public health problem because it affects children and adults, can be severe and even life-threatening, and may be increasing in prevalence. Beginning in 2008, the National Institute of Allergy and Infectious Diseases, working with other organizations and advocacy groups, led the development of the first clinical guidelines for the diagnosis and management of food allergy. A recent landmark clinical trial and other emerging data suggest that peanut allergy can be prevented through introduction of peanut-containing foods beginning in infancy. Objectives Prompted by these findings, along with 25 professional organizations, federal agencies, and patient advocacy groups, the National Institute of Allergy and Infectious Diseases facilitated development of addendum guidelines to specifically address the prevention of peanut allergy. Results The addendum provides three separate guidelines for infants at various risk levels for the development of peanut allergy and is intended for use by a wide variety of health care providers. Topics addressed include the definition of risk categories, appropriate use of testing (specific IgE measurement, skin prick tests, and oral food challenges), and the timing and approaches for introduction of peanut-containing foods in the health care provider's office or at home. The addendum guidelines provide the background, rationale, and strength of evidence for each recommendation. Conclusions Guidelines have been developed for early introduction of peanut-containing foods into the diets of infants at various risk levels for peanut allergy. [ABSTRACT FROM AUTHOR]

Deep inspiration-induced bronchoprotection and bronchodilation are impaired in asthma. We evaluated the effect of inhaled glucocorticosteroids on these phenomena. Two groups of subjects with asthma, 9 with moderate/severe hyperresponsiveness to methacholine, and 12 with mild/borderline hyperresponsiveness to methacholine, received inhaled fluticasone (880 microg daily) for 12 weeks. Serial bronchoprovocations were performed at Weeks 0, 6, and 12. The impact of deep inspirations on the airway response to methacholine was evaluated on the basis of inspiratory vital capacity and FEV(1). Fluticasone produced a wide spectrum of changes in the beneficial effects of deep inspiration, but the mean changes were not significant. The magnitude of the steroid-induced changes in bronchoprotection by deep inspiration correlated with baseline log PC(20) (the provocative concentration of methacholine causing a 20% fall in FEV(1); higher log PC(20) predicted improvement of the deep inspiration effect). The steroid-induced changes led to the emergence of strong positive correlations between the effects of deep inspiration and the methacholine log PC(20) that did not exist at baseline. We conclude that deep inspiration-induced bronchoprotection can be restored by inhaled glucocorticosteroids only in individuals with mild hyperresponsiveness. After steroid treatment, the beneficial effects of deep inspiration become significant determinants of the magnitude of airway hyperresponsiveness. [ABSTRACT FROM AUTHOR]

While airways have some degree of baseline tone, the level and variability of this tone is not known. It is also unclear whether there is a difference in airway tone or in the variability of airway tone between asthmatic and healthy individuals. This study examined airway tone and intraindividual airway tone heterogeneity (variance of airway tone) in vivo in 19 individuals with asthma compared with 9 healthy adults. All participants underwent spirometry, body plethysmography, and high-resolution computed tomography at baseline and after maximum bronchodilation with albuterol. Airway tone was defined as the percent difference in airway diameter after albuterol at total lung capacity compared with baseline. The amount of airway tone in each airway varied both within and between subjects. The average airway tone did not differ significantly between the two groups (P = 0.09), but the intraindividual airway tone heterogeneity did (P = 0.016). Intraindividual airway tone heterogeneity was strongly correlated with airway tone (r = 0.78, P < 0.0001). Also, it was negatively correlated with the magnitude of the distension of the airways from functional residual capacity to total lung capacity at both baseline (r = −0.49, P = 0.03) and after maximum bronchodilation (r = −0.51, P = 0.02) in the asthma, but not the healthy group. However, we did not find any relationship between intraindividual airway tone heterogeneity and conventional lung function outcomes. Intraindividual airway tone heterogeneity appears to be an important characteristic of airway pathophysiology in asthma. [ABSTRACT FROM AUTHOR]

The article focuses on the effects of omalizumab on T lymphocyte function in inner-city children with asthma. Topics discussed include role for regulatory T cells in allergen immunotherapy; IL-13 mRNA expression and T regulatory cell numbers/percentages related to the efficacy of omalizumab therapy; and low precursor frequency of T cells in the peripheral blood.

Context: Chronic rhinosinusitis (CRS) is a common condition in the US general population, yet little is known about its underlying molecular cause. Chronic rhinosinusitis is a consistent feature of the autosomal recessive disorder cystic fibrosis (CF).Objective: To determine whether mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which is responsible for CF, predispose to CRS.Design: Case-control study conducted from 1996 to 1999 in which the DNA of CRS patients and controls was typed for 16 mutations that account for 85% of CF alleles in the general population. Chronic rhinosinusitis patients with 1 CF mutation were evaluated for a CF diagnosis by sweat chloride testing, nasal potential difference measurement, and DNA analysis for additional mutations.Setting: Otolaryngology-head and neck clinic of a US teaching hospital.Participants: One hundred forty-seven consecutive adult white patients who met stringent diagnostic criteria for CRS and 123 CRS-free white control volunteers of similar age range, geographic region, and socioeconomic status.Main Outcome Measures: Presence of CF mutations by DNA analysis among CRS patients vs controls.Results: Eleven CRS patients were found to have a CF mutation (DeltaF508, n = 9; G542X, n = 1; and N1303K, n = 1). Diagnostic testing excluded CF in 10 of these patients and led to CF diagnosis in 1. Excluding this patient from the analyses, the proportion of CRS patients who were found to have a CF mutation (7%) was significantly higher than in the control group (n = 2 [2%]; P =.04, both having DeltaF508 mutations). Furthermore, 9 of the 10 CF carriers had the polymorphism M470V, and M470V homozygotes were overrepresented in the remaining 136 CRS patients (P =.03).Conclusion: These data indicate that mutations in the gene responsible for CF may be associated with the development of CRS in the general population. JAMA. 2000;284:1814-1819. [ABSTRACT FROM AUTHOR]

Rationale Nasal allergen provocations may be useful in investigating the pathophysiology of allergic rhinitis and effects of treatments. Objective To use grass pollen nasal allergen challenge ( NAC) to investigate the effects of allergen immunotherapy in a cross-sectional study. Methods We studied nasal and cutaneous responses in untreated subjects with seasonal grass-pollen allergic rhinitis ( n = 14) compared with immunotherapy-treated allergics ( n = 14), plus a nonatopic control group ( n = 14). Volunteers underwent a standardized NAC with 2000 biological units of timothy grass allergen (equivalent to 1.3 μg major allergen, Phl p5). Nasal fluid was collected and analysed by Immuno CAP and multiplex assays. Clinical response was assessed by symptom scores and peak nasal inspiratory flow ( PNIF). Cutaneous response was measured by intradermal allergen injection. Retrospective seasonal symptom questionnaires were also completed. Results Immunotherapy-treated patients had lower symptom scores ( P = 0.04) and higher PNIF ( P = 0.02) after challenge than untreated allergics. They had reduced early ( P = 0.0007) and late ( P < 0.0001) skin responses, and lower retrospective seasonal symptom scores ( P < 0.0001). Compared to untreated allergics, immunotherapy-treated patients had reduced nasal fluid concentrations of IL-4, IL-9 and eotaxin (all P < 0.05, 8 h level and/or area under the curve comparison), and trends for reduced IL-13 ( P = 0.07, area under the curve) and early-phase tryptase levels ( P = 0.06). Conclusions Nasal allergen challenge is sensitive in the detection of clinical and biological effects of allergen immunotherapy and may be a useful surrogate marker of treatment efficacy in future studies. [ABSTRACT FROM AUTHOR]

Rhinitis is an umbrella term that encompasses many different subtypes, several of which still elude complete characterization. The concept of phenotyping, being the definition of disease subtypes on the basis of clinical presentation, has been well established in the last decade. Classification of rhinitis entities on the basis of phenotypes has facilitated their characterization and has helped practicing clinicians to efficiently approach rhinitis patients. Recently, the concept of endotypes, that is, the definition of disease subtypes on the basis of underlying pathophysiology, has emerged. Phenotypes/endotypes are dynamic, overlapping, and may evolve into one another, thus rendering clear-cut definitions difficult. Nevertheless, a phenotype-/endotype-based classification approach could lead toward the application of stratified and personalized medicine in the rhinitis field. In this PRACTALL document, rhinitis phenotypes and endotypes are described, and rhinitis diagnosis and management approaches focusing on those phenotypes/endotypes are presented and discussed. We emphasize the concept of control-based management, which transcends all rhinitis subtypes. [ABSTRACT FROM AUTHOR]

Background Cat allergen is widely distributed in homes and schools; allergic sensitization is common. Objective To develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation. Methods Nineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6 μg/ mL Fel d1, and matched diluent-only provocation. Clinical response to 8 h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6 h post-challenge. Results A dose-response to allergen was seen in symptom scores and PNIF, maximal at 10 000 BU/ mL (4.87 μg/ mL Fel d1), P < 0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5 min after challenge ( P < 0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8 h ( P < 0.05 to P < 0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r = −0.79, P < 0.0001; IL-13, r = −0.60, P = 0.006). Surface expression of CD63 and CD107a was greater at 6 h than at baseline, both in the presence (both P < 0.05) and absence (CD63, P < 0.01; CD107a, P < 0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day. Conclusions Cat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials. [ABSTRACT FROM AUTHOR]

Background Several studies have demonstrated the time course of inflammatory mediators in nasal fluids following nasal allergen challenge ( NAC), whereas the effects of NAC on cells in the periphery are unknown. We examined the time course of effector cell markers (for basophils, dendritic cells and T cells) in peripheral blood after nasal grass pollen allergen challenge. Methods Twelve participants with seasonal allergic rhinitis underwent a control (diluent) challenge followed by NAC after an interval of 14 days. Nasal symptoms and peak nasal inspiratory flow ( PNIF) were recorded along with peripheral basophil, T-cell and dendritic cell responses (flow cytometry), T-cell proliferative responses (thymidine incorporation), and cytokine expression ( Fluoro Spot assay). Results Robust increases in nasal symptoms and decreases in PNIF were observed during the early (0-1 h) response and modest significant changes during the late (1-24 h) response. Sequential peaks in peripheral blood basophil activation markers were observed ( CD107a at 3 h, CD63 at 6 h, and CD203cbright at 24 h). T effector/memory cells ( CD4+ CD25lo) were increased at 6 h and accompanied by increases in CD80+ and CD86+ plasmacytoid dendritic cells (p DCs). Ex vivo grass antigen-driven T-cell proliferative responses and the frequency of IL-4+ CD4+ T cells were significantly increased at 6 h after NAC when compared to the control day. Conclusion Basophil, T-cell, and dendritic cell activation increased the frequency of allergen-driven IL-4+ CD4+ T cells, and T-cell proliferative responses are detectable in the periphery after NAC. These data confirm systemic cellular activation following a local nasal provocation. [ABSTRACT FROM AUTHOR]

Background: Deep inspirations (DIs) can prevent (bronchoprotection; BP) and reverse (bronchodilation; BD) methacholine (Mch)-induced bronchoconstriction, but this effect is reduced or absent in people with asthma or airways hyperresponsiveness (AHR). The mechanisms of this defect are unknown. Objective: To indirectly examine the role of guanosine 3′,5′-cyclic monophosphate (cGMP) by testing the hypothesis that the phosphodiesterase (PDE) V inhibitor, sildenafil, would improve DI-induced BP in individuals with AHR. Methods: Thirty-two individuals were screened and 15 met all the inclusion/exclusion criteria (7 subjects with AHR and 8 healthy subjects). A single-dose Mch challenge inducing a 20% reduction in FEV1 in the absence of DIs was first identified. Thereafter, every study participant had 4 pairs of visits, each pair testing DI-induced BP and BD against the single-dose Mch, with no drug, or pretreatment with 25, 50 and 100 mg of sildenafil, respectively, in consecutive order. Results: Sildenafil did not influence baseline lung function. However, in the absence of DIs, the drug caused a dose-dependent attenuation of the Mch-induced decrease in FEV1 by 17% (median value; 25th percentile: 1, 75th percentile: 16), 35% (-3, 61) and 37% (13, 79) for the 25-, 50- and 100-mg doses, respectively (p = 0.0004). No differences between the two participant groups were found. There were no effects of sildenafil on DI-induced BP or BD. Conclusion: We infer from these results that the mechanism responsible for the defective ability of DIs to protect the airways from bronchoconstriction is unlikely to be due to dysregulation of cGMP. Of importance, a potential role for PDE V inhibition as a bronchoprotector treatment needs to be explored. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct.Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction.Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%–21%), compared with Madison (6%).Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population. [ABSTRACT FROM PUBLISHER]

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10?9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma. [ABSTRACT FROM AUTHOR]

Deep inspirations modulate airway caliber and airway closure and their effects are impaired in asthma. The association between asthma and obesity raises the question whether the deep inspiration (DI) effect is also impaired in the latter condition. We assessed the DI effects in obese and nonobese nonasthmatics. Thirty-six subjects (17 obese, 19 nonobese) underwent routine methacholine (Mch)challenge and 30 of them also had a modified bronchoprovocation in the absence of Dis. Lung function was monitored with spirometry and forced oscillation (FO) [resistance (R) at 5 Hz (R5), at 20 Hz (R20), R5-R20 and the integrated area of low-frequency reactance (AX)]. The response to Mch, assessed with area under the dose-response curves (AUC), was consistently greater in the routine challenge in the obese (mean ± SE, obese vs. nonobese AUC: R5:15.7 ± 2.3 vs. 2.4 ± 2.0, P < 0.0005; R20:5.6 ± 1.4 vs. 1.4 ± 1.2, P = 0.027; R5-R20: 10.2 ± 1.6 vs. 0.9 ± 0.1.4, P < 0.0005; AX: 115.6 ± 22.0 vs. 1.5 ± 18.9, P < 0.0005), but differences between groups in the modified challenge were smaller, indicating reduced DI effects in obesity. Given that DI has bronchodilatory and bronchoprotective effects, we further assessed these components separately. In the obese subjects, DI prior to Mch enhanced Mch-induced bronchoconstriction, but DI after Mch resulted in bronchodilation that was of similar magnitude as in the nonobese. We conclude that obesity is characterized by increased Mch responsiveness, predominantly of the small airways, due to a DI effect that renders the airways more sensitive to the stimulus. [ABSTRACT FROM AUTHOR]

Context: Mitotic kinase enzymes regulate critical stages of mitosis and are amenable to pharmacological inhibition. Since natural products have been a rich source of antimitotic inhibitors, we postulated that natural products would also provide effective inhibitors of mitotic kinases. Objective: To explore unique marine and terrestrial natural product sources for new anticancer drug leads, we screened our natural product extract library for polo-like kinase-1 (Plk1) kinase inhibitors. Materials and methods: Extracts of the lichen Parmotrema sp. (Parmeliaceae) exhibited in vitro inhibitory activity. Bioassay-guided fractionation of the Parmotrema sp. extract led to the isolation of depside inhibitors. Results: A new depside 1 has been isolated from the Sri Lankan lichen Parmotrema sp. along with the known metabolites 2 (ββ-collatolic acid) and 3 (ββ-alectoronic acid). The structure of depside 1 was elucidated by spectroscopic analysis. The three depsides 1-- 3 exhibited moderate inhibition of purified recombinant Plk1 kinase with IC50 of 2.8, 0.7, and 1.7 µµM, respectively, at 1 µµM ATP. Inhibitory activity was also observed at high concentrations of ATP, suggesting the potential for activity in a cellular environment. The depsides were also tested against a panel of 23 other recombinant kinases and were found to possess up to 30-fold selectivity toward Plk1. Discussion and conclusion: These data suggest that the depsides 1-- 3 may serve as core structures that can be further explored as potential inhibitors of Plk1 and other kinases. [ABSTRACT FROM AUTHOR]

Background: Cystitis is a common infection. The alarmingly high resistance rates exhibited by contemporary uropathogens necessitate the re-evaluation of old antibiotics. Objectives: To evaluate the effectiveness and safety of fosfomycin compared with other antibiotics for the treatment of patients with cystitis. Methods: We performed a meta-analysis of randomized controlled trials (RCTs), generated from searches performed in PubMed, Scopus and Cochrane CENTRAL, which involved patients with cystitis treated with fosfomycin versus other antibiotics. Results: Twenty-seven trials (eight double-blind) were included. Sixteen of these 27 trials involved exclusively non-pregnant female patients, 3 involved adult mixed populations of older age, 5 involved pregnant patients and 3 involved paediatric patients. Regarding clinical success, no difference was found in the comprehensive analysis regarding all comparators combined [10 RCTs, 1657 patients, risk ratio (RR)=1.00, 95% confidence interval (CI)=0.98-1.03] in trials involving non-pregnant females and in trials involving mixed populations. Insufficient relevant data were provided from trials involving paediatric and pregnant patients. No difference between fosfomycin and comparators was also found in all comparisons regarding the remaining effectiveness outcomes (namely microbiological success/relapse/re-infection). Fosfomycin had a comparable safety profile with the evaluated comparators in non-pregnant women, mixed and paediatric populations, whereas it was associated with significantly fewer adverse events in pregnant women (4 RCTs, 507 patients, RR=0.35, 95% CI=0.12-0.97). Conclusions: In the era of high drug resistance rates, reported even among community-acquired uropathogens, fosfomycin may provide a valuable alternative option for the treatment of cystitis in non-pregnant and pregnant women and in elderly and paediatric patients. [ABSTRACT FROM AUTHOR]

Background Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans. Objective Our aims were to determine the genomic basis of cockroach sensitization and the specific response to cockroach antigen. Methods We investigated the Th1/Th2 cytokine profile of co-cultured plasmacytoid dendritic cells (pDCs) and CD4+ T cells and the ‘transcript signature’ of the immune response to cockroach antigen using high-throughput expression profiling of co-cultured cells. Results We observed significantly elevated levels of IL-13, IL-10, and TNF-α, but undetectable levels of IL-12p70 and IFN-α, when cultures were exposed to crude cockroach antigen. A significant difference was observed for IL-13 between cockroach-allergic and non-allergic individuals ( P=0.039). Microarray analyses demonstrated a greater response at 48 h compared with 4 h, with 50 genes being uniquely expressed in cockroach antigen-treated cells, including CD14, S100A8, CCL8, and IFI44L. The increased CD14 expression was further observed in purified pDCs, human monocytic THP-1 cells, and the supernatant of co-cultured pDCs and CD4+ T cells on exposure to cockroach extract. Furthermore, the most differential expression of CD14 between cockroach allergy and non-cockroach allergy was only observed among individuals with the CC ‘high-risk’ genotype of the CD14− 260C/T. Ingenuity Pathways Analysis analyses suggested the IFN signalling as the most significant canonical pathway. Conclusion Our results suggest that these differentially expressed genes, particularly CD14, and genes in the IFN signalling pathway may be important candidates for further investigation of their role in the immune response to cockroach allergen. Cite this as: P. Gao, D. N. Grigoryev, N. M. Rafaels, D. Mu, J. M. Wright, C. Cheadle, A. Togias, T. H. Beaty, R. A. Mathias, J. T. Schroeder and K. C. Barnes, Clinical & Experimental Allergy, 2010 (40) 1353–1364. [ABSTRACT FROM AUTHOR]

Airway responsiveness to methacholine (Mch) in the absence of deep inspirations (DIs) is lower in athletes compared with sedentary individuals. In this prospective study, we tested the hypothesis that a training exercise program reduces the bronchoconstrictive effect of Mch. Ten healthy sedentary subjects (M/F: 3/7; mean ± SD age: 22 ± 3 yr) entered a 10-wk indoor rowing exercise program on rowing ergometer and underwent Mch bronchoprovocation in the absence of DIs at baseline, at weeks 5 and 10, as well as 4-6 wk after the training program was completed. Exercise-induced changes on airway cells and markers of airway inflammation were also assessed by sputum induction and venous blood samples. Mean power output during the 1,000 m test was 169 ± 49 W/stroke at baseline, 174 ± 49 W/stroke at 5 wk, and 200 ± 60 W/stroke at 10 wk of training (P < 0.05). The median Mch dose used at baseline was 50 mg/ml (range 25-75 mg/ml) and remained constant per study design. At the pretraining evaluation, the percent reduction in the primary outcome, the inspiratory vital capacity (IVC) after inhalation of Mch in the absence of DIs was 31 ± 13%; at week 5, the Mch-induced reduction in IVC was 22 ± 19%, P = 0.01, and it further decreased to 15 ± 11% at week 10 (P = 0.0008). The percent fall in IVC 4-6 wk after the end of training was 15 ± 11% (P = 0.87 vs. end of training). Changes in airway cells were not associated with changes in airway responsiveness. Our data show that a course of exercise training can attenuate airway responsiveness against Mch inhaled in the absence of DIs in healthy subjects and suggest that a sedentary lifestyle may favor development of airways hyperresponsiveness. [ABSTRACT FROM AUTHOR]

Background Although nasal challenge with allergen has often been used to evaluate the efficacy of therapeutic modalities used for the treatment of allergic rhinitis, the reproducibility of this model in quantitatively evaluating efficacy has not been rigorously examined. Objective To examine the reproducibility of the suppressive effects of an intranasal corticosteroid on the clinical and biochemical outcomes of a nasal allergen challenge during two identical treatment periods using the same subjects. Methods In a single-blind study, 25 seasonal allergic subjects with positive skin tests to grass or ragweed were studied outside of their pollen season. Subjects underwent a baseline, three-dose allergen challenge. Beginning 1 week later, subjects received two 7-day courses of intranasal beclomethasone (168 μg b.i.d.) separated by a 1-month washout period. Nasal challenges with allergen were performed after each treatment period. The nasal allergic response was evaluated by counting sneezes, recording symptom scores and measuring levels of albumin (an index of vascular permeability), lysozyme (an index of serous glandular secretion) and kinins (proinflammatory peptides) in recovered nasal lavages. Results Compared with the baseline challenge, each course of beclomethasone significantly reduced sneezing, symptom scores, albumin and kinins, but not lysozyme. Reproducibility analysis of the net changes from diluent challenge in the two beclomethasone treatment periods, showed the following intraclass correlation coefficients: sneezing (0.92), lysozyme (0.82), symptom scores (0.72), albumin (0.64) and kinins (0.28). Conclusion We conclude that the nasal challenge model is a reproducible method to evaluate the efficacy of anti-allergic medications. For nasal corticosteroid trials, sneezing, symptom scores and albumin levels are recommended as the most reproducibly suppressive outcome measures. Cite this as: D. Proud, D. K. Riker and A. Togias, Clinical & Experimental Allergy, 2010 (40) 738–744. [ABSTRACT FROM AUTHOR]