BACKGROUND:It is well established that there are different asthma phenotypes, but whereas determinants of atopic asthma (AA) are well studied, little is known about non-atopic asthma (NAA). We compared risk factors for atopy, AA in atopics and NAA in non-atopics in children in a wide variety of countries. METHODS:Using four studies, across 23 countries, we assessed asthma status and atopy (skin prick tests) for children aged 6-17, plus risk factors from housing, heating, pets, family, diet and air quality categories. Using mixed-effects logistic regression models, we assessed risk factors over four pathways: pathway 1-non-atopic non-asthma to NAA; pathway 2-non-atopic non-asthma to atopy (no asthma); pathway 3-atopic non-asthma to AA; pathway 4-non-atopic non-asthma to AA. We compared the log odds of risk factors between pathways using the Pearson correlation coefficient (PCC). RESULTS:Our final sample of 32 741 children comprised 67% with neither atopy nor asthma, 15% with atopy but without asthma, 8% with AA and 10% with NAA. Risk factors were similar between pathway 1 and pathway 3 (PCC=0.81, 95% CI 0.68 to 0.94). In contrast, risk factors differed between pathway 2 and pathway 3 (PCC=-0.06, 95% CI -0.29 to 0.17). DISCUSSION:These findings indicate that although atopy increases the risk of asthma, the risk factors for subsequently developing asthma are generally the same in those with and without atopy. This raises important questions about the role of atopy in asthma, particularly whether it is an inherent part of the aetiological process or is coincidental.

The Causes And MEchanisms foR non-atopic Asthma in children (CAMERA) study was designed to investigate risk factors and mechanisms of non-atopic asthma in children and young adults in Brazil, Ecuador, Uganda, and New Zealand. Initial epidemiological analyses using existing datasets identified and compared risk factors for both atopic and non-atopic asthma. The focus of this paper is the protocol for sample collection and analysis of clinical data on possible non-atopic mechanisms. In each of the four centres, the CAMERA study will enroll 160 participants aged 10–28 years, equally distributed among atopic asthmatics (AA), non-atopic asthmatics (NAA), atopic non-asthmatics and non-atopic non-asthmatics. Participants will be new recruits or returning World ASthma Phenotypes (WASP) study participants. Phase I consists of skin prick tests to define atopy, a general CAMERA questionnaire that covers respiratory and general health to identify asthma cases, followed by an asthma control questionnaire for asthmatics only. Phase II consists of a stress questionnaire and the following clinical assessments: lung function, nasal cytology, blood sampling, in vitro whole blood stimulation to assess IFN-γ production, hair cortisol concentration, dry air and capsaicin challenges, plus in a subset, cold air challenges. Analyses will compare inflammatory, physiological and clinical parameters across the four groups overall and by country. Here, we present the protocol for the CAMERA study, to provide relevant methodological details for CAMERA publications and to allow other centres globally to conduct similar analyses. The findings of this mechanistic multi-centre study will inform new and phenotype-specific prevention and treatment approaches. Not applicable.

BACKGROUND:Component-resolved diagnostics allow detailed assessment of IgE sensitization to multiple allergenic molecules (component-specific IgEs, or c-sIgEs) and may be useful for asthma diagnosis. However, to effectively use component-resolved diagnostics across diverse settings, it is crucial to account for geographic differences. OBJECTIVE:We investigated spatial determinants of c-sIgE networks to facilitate development of diagnostic algorithms applicable globally. METHODS:We used multiplex component-resolved diagnostics array to measure c-sIgE to 112 proteins in an international collaboration of several studies: WASP (World Asthma Phenotypes; United Kingdom, New Zealand, Brazil, Ecuador, and Uganda), U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes; 7 European countries), and MAAS (Manchester Asthma and Allergy Study, a UK population-based birth cohort). Hierarchical clustering on low-dimensional representation of co-occurrence networks ascertained sensitization and c-sigE clusters across populations. Cross-country comparisons focused on a common subset of 18 c-sIgEs. We investigated sensitization networks across regions in relation to asthma severity. RESULTS:Sensitization profiles shared similarities across regions. For 18 c-sIgEs shared across study populations, the response structure enabled differentiation between different geographic areas and study designs, revealing 3 clusters: (1) Uganda, Ecuador, and Brazil, (2) U-BIOPRED children and adults, and (3) New Zealand, United Kingdom, and MAAS. Spectral clustering identified differences between clusters. We observed constant, almost parallel shifts between severe and nonsevere asthma in each country. CONCLUSIONS:Patterns of c-sIgE response reflect geographic location and study design. However, despite geographic differences in c-sIgE networks, there is a remarkably consistent shift between networks of subjects with nonsevere and severe asthma.

Background:Asthma is a complex disease and a severe global public health problem resulting from interactions between genetic background and environmental exposures. It has been suggested that gut microbiota may be related to asthma development; however, such relationships needs further investigation. Objective:This study aimed to characterize the gut microbiota as well as the nasal lavage cytokine profile of asthmatic and nonasthmatic individuals. Methods:Stool and nasal lavage samples were collected from 29 children and adolescents with type 2 asthma and 28 children without asthma in Brazil. Amplicon sequencing of the stool bacterial V4 region of the 16S rRNA gene was performed using Illumina MiSeq. Microbiota analysis was performed by QIIME 2 and PICRUSt2. Type 2 asthma phenotype was characterized by high sputum eosinophil counts and positive skin prick tests for house dust mite, cockroach, and/or cat or dog dander. The nasal immune marker profile was assessed using a customized multiplex panel. Results:Stool microbiota differed significantly between asthmatic and nonasthmatic participants (P = .001). Bacteroides was more abundant in participants with asthma (P < .05), while Prevotella was more abundant in nonasthmatic individuals (P < .05). In people with asthma, the relative abundance of Bacteroides correlated with IL-4 concentration in nasal lavage samples. Inference of microbiota functional capacity identified differential fatty acid biosynthesis in asthmatic compared to nonasthmatic subjects. Conclusion:The stool microbiota differed between asthmatic and nonasthmatic young people in Brazil. Asthma was associated with higher Bacteroides levels, which correlated with nasal IL-4 concentration.

BACKGROUND:The clinical efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) have been well-established; however, less is known about outcomes in patients undergoing preemptive ASA before transcatheter mitral valve replacement (TMVR). AIMS:The goal of this study is to characterize the procedural characteristics and examine the clinical outcomes of ASA in both HCM and pre-TMVR. METHODS:This retrospective study compared procedural characteristics and outcomes in patient who underwent ASA for HCM and TMVR. RESULTS:In total, 137 patients were included, 86 in the HCM group and 51 in the TMVR group. The intraventricular septal thickness (mean 1.8 vs. 1.2 cm; p < 0.0001) and the pre-ASA LVOT gradient (73.6 vs. 33.8 mmHg; p ≤ 0.001) were higher in the HCM group vs the TMVR group. The mean volume of ethanol injected was higher (mean 2.4 vs. 1.7 cc; p < 0.0001). The average neo-left ventricular outflow tract area increased significantly after ASA in the patients undergoing TMVR (99.2 ± 83.37 mm2 vs. 196.5 ± 114.55 mm2; p = <0.0001). The HCM group had a greater reduction in the LVOT gradient after ASA vs the TMVR group (49.3 vs. 18 mmHg; p = 0.0040). The primary composite endpoint was higher in the TMVR group versus the HCM group (50.9% vs. 25.6%; p = 0.0404) and had a higher incidence of new permanent pacemaker (PPM) (25.5% vs. 18.6%; p = 0.3402). The TMVR group had a higher rate of all-cause mortality (9.8% vs. 1.2%; p = 0.0268). CONCLUSIONS:Preemptive ASA before TMVR was performed in patients with higher degree of clinical comorbidities, and correspondingly is associated with worse short-term clinical outcomes in comparison to ASA for HCM patients. ASA before TMVR enabled percutaneous mitral interventions in a small but significant minority of patients that would have otherwise been excluded. The degree of LVOT and neoLVOT area increase is significant and predictable.

Primary tumoral calcinosis is a rare and benign condition characterized by calcium salt deposition in periarticular soft tissues. It typically presents as a firm, rubbery mass that arises around large joints. While an estimated 250 cases have been described since its discovery, very few cases have been identified in the hand. We present a case of multiple calcified masses in the hand, one of which required meticulous dissection from a digital neurovascular bundle, and our technique for surgical excision. We present this case to lower the threshold for clinical suspicion of tumoral calcinosis for patients who present with a soft tissue mass in the hand. Furthermore, we recommend prompt surgical excision due to low success rates of alternative treatment options and to prevent potential neurovasculature or tendon injury.

Humans have lived from equator to poles for millennia but are now increasingly intruding into the wild spaces of other species and steadily extruding ourselves from our own wild spaces, with a profound impact on: our relationship with the natural world; survival of other species; pollution; climate change; etc. We have yet to grasp how these changes directly impact our own health. The primary focus of this paper is on the beneficial influence of proximity to the natural environment. We summarize the evidence for associations between exposure to green space and blue space and improvements in health. In contrast, grey space - the urban landscape - largely presents hazards as well as reducing exposure to green and blue space and isolating us from the natural environment. We discuss various hypotheses that might explain why green, blue, and grey space affect health and focus particularly on the importance of the biodiversity hypothesis and the role of microbiota. We discuss possible mechanisms and exposure routes - air, soil, and water. We highlight the problem of exposure assessment, noting that many of our current tools are not fit for the purpose of understanding exposure to green and blue space, aerosols, soils, and water. We briefly discuss possible differences between indigenous perspectives on the nature of our relationship with the environment and the more dominant international-science view. Finally, we present research gaps and discuss future directions, particularly focusing on the ways in which we might - even in the absence of a full understanding of the mechanisms by which blue, green, and grey space affect our health - begin to implement policies to restore some balance to our environment of with the aim of reducing the large global burden of ill health.

Objective An imbalance in autonomic nervous system (ANS) activity may play a role in asthma, but it is unclear whether this is associated with specific pathophysiology. This study assessed ANS activity by measuring heart rate variability (HRV) in eosinophilic (EA) and non-eosinophilic asthma (NEA) and people without asthma. Methods HRV, combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), skin prick tests to measure atopy, and spirometry tests were conducted in teenagers and young adults (14-21 years) with (n = 96) and without (n = 72) generally well-controlled asthma. HRV parameters associated with sympathetic and parasympathetic ANS branches were analyzed. EA and NEA were defined using a 2.5% sputum eosinophil cut-point. Airway hyperreactivity (AHR) was defined as >= 15% reduction in FEV1 following saline challenge. Results HRV parameters did not differ between asthmatics and non-asthmatics or EA and NEA. They were also not associated with markers of inflammation, lung function or atopy. However, increased absolute low frequency (LF mu s(2); representing increased sympathetic nervous system (SNS) activity) was found in asthmatics who used beta-agonist medication compared to those who did not (median: 1611, IQR 892-3036 vs 754, 565-1592; p < 0.05) and increased normalized low frequency (LF nu) was found in those with AHR compared to without AHR (64, 48-71 vs 53, 43-66; p < 0.05). Conclusion ANS activity (as measured using HRV analysis) is not associated with pathophysiology or inflammatory phenotype in young asthmatics with generally well-controlled asthma. However, enhanced SNS activity can be detected in asthmatics with AHR or who use beta-agonist medication.

The World Asthma Phenotypes (WASP) study is being conducted in five centres in Brazil, Ecuador, Uganda, New Zealand and the United Kingdom, with a range of prevalence levels and exposures, and a likely range of phenotype distributions. Here we present the main findings with regards to asthma inflammatory phenotypes. We recruited 998 cases and 356 controls: 204/40 in Brazil, 176/67 in Ecuador, 207/50 in Uganda, 235/132 in New Zealand, and 176/67 in the United Kingdom. All centres studied children and adolescents (age-range 8–20 years), with the exception of the UK centre which involved 26–27 year olds. The proportion of participants who produced sputum samples was 87%, with a range from 74% (Brazil) to 91% (Ecuador), and of these 62% were countable with regards to the inflammatory cell types.The proportions of asthma cases who were classified as eosinophilic or mixed granulocytic asthma (the two inflammatory phenotypes which involve eosinophilia) was 39% overall: 35% in Brazil, 32% in Ecuador, 33% in Uganda, 50% in New Zealand, and 28% in the United Kingdom. The non-eosinophilic asthmatics (NEA) had similar chronic severity (e.g. in terms of attacks in the previous year) to the eosinophilic asthmatics (EA). Of the 61% of cases with NEA, 50% showed no signs of inflammation (paucigranulocytic), with 11% having neutrophilic inflammation. This is the first time that sputum induction has been used in a standardised manner to compare asthma inflammatory phenotypes in high income countries (HICs) and low-and-middle-income countries (LMICs). It confirms that most cases are non-eosinophilic, with the proportions ranging from 50% to 72%, across these varied environments; most of these non-eosinophilic cases were paucigranulocytic, with no sign of airways inflammation.

Dust-exposed construction workers have an increased risk of respiratory symptoms, but the efficacy of dust-control measures remains unclear. This study compared respiratory symptoms, using a modified European Community Respiratory Health Survey questionnaire, between construction workers (n = 208) and a reference group of bus drivers and retail workers (n = 142). Within the construction workers, we assessed the effect of collective (on-tool vacuum/'wet-cut' systems) and personal (respirators) exposure controls on symptom prevalence. Logistic regression assessed differences between groups, adjusted for age, ethnicity, and smoking status. Construction workers were more likely to cough with phlegm at least once a week (OR 2.4, 95% CI 1.2-4.7) and cough with phlegm ≥3 months/year for ≥2 years (OR 2.8, CI 1.2-7.0), but they had similar or fewer asthma symptoms. Construction workers who had worked for 11-20 years reported more cough/phlegm symptoms (OR 5.1, 1.7-15.0 for cough with phlegm ≥3 months/year for ≥2 years) than those who had worked <10 years (OR 1.9, 0.6-5.8), when compared to the reference group. Those who used 'wet-cut' methods reported less cough with phlegm, although the evidence for this association was weak (OR 0.4, CI 0.2-1.1 for cough with phlegm at least once a week); use of on-tool extraction showed a similar trend. No associations between respiratory protective equipment-use and symptoms were found. In conclusion, construction workers reported more symptoms suggestive of bronchitis, particularly those employed in the industry for >10 years. Use of collective dust exposure controls might protect against these symptoms, but this requires confirmation in a larger study.

2026 Objectives Evaluate the traditional delivery methods of nuclear medicine education at an approved academic center. Highlight key themes, utilizing qualitative feedback from clinical stakeholders, leading to the identification of emerging learning and assessments paradigms. Evaluation of a current cohort of postgraduate students will inform the value of such developments. Methods Traditional educational methods were evaluated using an on-line questionnaire. Initial findings were analyzed and mapped against current guidelines relating to workforce development and optimal service provision. Focus group discussions highlighted new learning approaches which were subsequently introduced into the current curriculum. An on-line questionnaire provided to the current students was used to obtain quality feedback. Results Findings from the evaluation of traditional delivery and assessment methods demonstrated a lack of practical based training, which impacted upon the practitioners9 ability to relate theory to specific clinical practice. Findings also highlighted the limited use of electronic (e)-learning tools to support delivery methods. Findings from the focus group further reinforced the initial opinions and provided the researchers with the opportunity to investigate new learning and teaching paradigms. These included a further utilization of e-based learning, alongside blended. actions and problem based learning approaches. New assessment models were also developed which encapsulated the identified learning approaches. Positive feedback from current students indicated the relevance of the aforementioned new learning approaches to both current practice and potential development opportunities. Conclusions The development of a new approach to the delivery of nuclear medicine education has demonstrated a positive impact on practitioners in clinical practice. It is hoped this will further enhance future workforce development and embrace on-going technological advances

Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust peripheral biomarkers are yet to be identified. Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum cytokines, growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of inflammation following pre-treatment with ALS serum. Principal components analysis of all proteome profile data showed no clustering of control or ALS sera, and no individual serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed proteins between control and ALS sera showed a medium effect size (Cohen’s d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20 proteins were predominantly pro-angiogenic and growth factors, including fractalkine, BDNF, EGF, PDGF, Dkk-1, MIF and angiopoietin-2. S100β, a protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum cytokine levels may not be robust biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and growth factors may identify a peripheral signature of ALS pathogenesis.

Background: Neural and remodeling mechanisms may play a role in asthma, particularly noneosinophilic asthma (NEA).Objective: To assess sputum mediators associated with neural, remodeling, and inflammatory mechanisms in eosinophilic asthma (EA), NEA, and participants without asthma.Methods: A total of 111 participants with and 62 without asthma (14-21 years old) underwent sputum induction, exhaled nitric oxide, atopy, and spirometry tests. There were 24 mediators measured in sputum using enzyme-linked immunosorbent assay or bead array. Eosinophilic asthma (n = 52) and NEA (n = 59) were defined using a sputum eosinophil level cut-point of greater than or equal to 2.5%. Results: Elevated levels of nociceptin (median: 39.1 vs 22.4 ng/mL, P = .03), periostin (33.8 vs 9.4 ng/mL, P = .01), and ECP; (220.1 vs 83.7 ng/mL, P = .03) were found in patients with asthma compared with those without asthma. Nociceptin was elevated in EA (54.8 vs 22.4 ng/mL, P = .02) compared with participants without asthma. Eosinophilic asthma had higher levels of inflammatory mediators (ECP: 495.5 vs 100.3 ng/mL, P & LE; .01; interleukin-1b: 285.3 vs 209.3 pg/mL, P = .03; histamine: 5805.0 vs 3172.5 pg/mL, P < .01) and remodeling mediators (VEGF-A); 3.3 vs 2.5 ng/mL, P = .03; periostin: 47.7 vs 22.1 ng/mL, P = .04) than NEA. Whereas macrophages were associated with neural mediators, for example, neurokinin A (r = 0.27, P = .01) and nociceptin (r = 0.30, P = .02), granulocytes were associated with inflammatory and remodeling mediators (eg, ECP and VEGF-A correlated with neutrophils (r = 0.53 and r = 0.33, respectively, P < .01) and eosinophils (r = 0.53 and r = 0.29 respectively, P & LE; .01).Conclusion: Elevated levels of nociceptin and inflammatory and remodeling markers were found in EA, but no evidence for neural and remodeling pathways was found in NEA. Neural and remodeling mechanisms seem to coexist with inflammation.& COPY; 2023 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

ABSTRACT Background: Neural mechanisms may play an important role in non-eosinophilic asthma. This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic and non-eosinophilic asthma and non-asthmatics. Methods: Thirty-eight asthmatics and nineteen non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), atopy, and spirometry tests, followed by capsaicin challenge. Eosinophilic (EA) and non-eosinophilic asthma (NEA) were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity (AHR) was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. Results: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared to non-asthmatics (n=19) (geometric mean C5: 58.3μM, 95% confidence interval 24.1-141.5 vs 193.6μM, 82.2-456.0; p<0.05). There was a similar (but non-significant) difference in capsaicin sensitivity in NEA compared with EA (n=18), (58.3μM, 24.1-141.5 vs 191.0μM, 70.9-514.0; p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control, or treatment were observed. Conclusion: Non-eosinophilic asthma, but not eosinophilic asthma, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of non-eosinophilic asthma.

Background Indoor dampness has consistently been associated with respiratory symptoms and exacerbations. The causal mechanisms may involve increased microbial exposures. However, the evidence regarding the influence of indoor microbial exposures under damp- and non-damp conditions on the risk of asthma and allergy has been inconclusive. Objective The aim of this study was to investigate the association between dampness and microbial exposure with allergy and respiratory health in Danish adults using a cross-sectional design. Methods From 1,866 participants of the Health2006 cohort, we selected three non-overlapping groups: 196 at random, 107 with confirmed atopy, and 99 without atopy. Bedroom dust was sampled using electrostatic dust fall collectors and analysed for endotoxin, β-(1,3)-D-glucan, 19 microbial species or groups, and total fungal load. Household moisture-related problems and asthma were self-reported by questionnaire. Atopy was determined by skin-prick-testing and lung function was measured by spirometry. Results Household moisture damage was positively associated with asthma outcomes, although this was statistically significant only in atopics for self-reported asthma (odds ratio (OR) 3.52; 95%CI 1.01–12.7). Mould odor was positively associated with wheezing (OR 6.05; 95%CI 1.19–30.7) in atopics. Inconsistent associations were found for individual microbial exposures and health outcomes. Inverse associations were observed between microbial diversity and rhinitis in the random sample and both doctor-diagnosed and self-reported asthma in non-atopics. Conclusions In conclusion, our findings suggest that household moisture damage may increase the risk of asthma and wheeze with mould odor in atopics. In addition, asthma and allergy may be affected by the indoor microbial composition in urban domestic environments. Further studies are needed to identify and understand the causal agents and underlying mechanisms behind the potential effects of environmental microbial exposure on human health.