Role of innate lymphoid cells in paediatric severe therapy resistant asthma

Background Children with severe therapy-resistant asthma (STRA) have poor control despite maximal therapy. The pattern of airway inflammation in severe disease may therefore be less steroid sensitive. Innate lymphoid cells (ILCs) are immune cells of lymphoid morphology that do not express typical antigen receptors but mirror the functions of T cells. They are classified into three groups. ILC2s express CD127 and CRTH2, secrete Th2 cytokines, express GATA3 and are induced by IL-33 which is steroid resistant and increased in paediatric STRA. I hypothesised that airway ILC2s are increased in STRA and are steroid resistant, thus contributing to disease pathology. I characterised ILC2s in induced sputum (IS), broncho-alveolar lavage (BAL) and peripheral blood (PBMC) in children with STRA compared to non-asthmatic controls and investigated their response to systemic steroids. Methods BAL, PBMCs and IS were obtained from 18 STRA children and 16 with chronic inflammation (CI) undergoing a clinically indicated bronchoscopy. IS was obtained in an additional 13 children with STRA and 6 with CI. Cells were analysed by multi-parametric flow cytometry for ILC and Th2 markers. Assessments of sputum ILCs were performed in STRA before and after systemic steroids. In vitro cultures of PBMCs were undertaken to determine ILC and T cell responses to allergen and steroids. Results ILC2s were identified in IS from STRA, but not CI, and were significantly higher in BAL and sputum than PBMCs in STRA. Th2 cells were ten-fold higher than ILC2s in all compartments. Sputum ILC2s decreased following systemic steroids and PBMC cultures showed a significant reduction in ILC2s with steroids. Conclusion ILC2s were elevated in children with STRA and were more abundant in airways than peripherally. However, Th2 cells were the predominant lymphoid airway cell type. Unlike IL-33, ILC2s were steroid sensitive thus their contribution in mediating severe, steroid resistant disease remains uncertainOpen Acces

Laboratory investigations on bituminous concrete mixtures utilizing foundry sand

Foundry sand is a byproduct of the molding industry, produced during the molding and core-making production processes. Sands are reused several times before being discarded. This research work reports the effect of foundry sand (FS) mineral filler (MF) aggregate on characteristics of bituminous concrete grading-2 (BC-2) mixtures and compares the test results with the traditional BC-2 mixtures. The Marshall mixture design method is adopted to assess the optimal bitumen content at 4% air voids for bituminous concrete grading-2 specimens prepared using 0, 25, 50, 75, and 100 percent FSMF (Foundry Sand Mineral Filler) content. Split tensile strength test and water resistivity test were conducted to study the performance characteristics of BC-2 mixes. Laboratory test results showed that by increasing percentage of foundry sand mineral filler (FSMF) aggregate in bituminous grading – 2 mixtures, stability, split tensile strength, and moisture resistance augmented

Analysis of Damping in Soil as Applied to Machine Foundations

The parameters needed for the design of machine foundations are usually evaluated from the model block resonance test conducted at a given site. Sometimes it may not be possible to attain complete resonance and the test results may be limited to the ascending part of the response. In this paper the possible effect of damping on the values of the design parameters evaluated from the ascending part of response is examined and the nature of damping which gives realistic values of design parameters is presented

“Will anybody listen?” parents’ views on childhood asthma care:a qualitative study

Background: Asthma is the most common chronic disease in children, resulting in considerable morbidity and health care utilisation, especially in geographical areas with high deprivation. Parents play a pivotal role in children’s asthma management.Aim: To explore the views of parents whose children have asthma, regarding barriers and facilitators to receiving adequate asthma care.Design and Setting: A qualitative study conducted in an urban, multi-ethnic setting with high socioeconomic deprivation and paediatric asthma related hospital admissions.Method: The study used a pragmatic approach underpinned by a perspective of critical realism. Parents of children with asthma were recruited through purposive and convenience sampling and data collected through semi-structured interviews. Transcripts were analysed using thematic analysis, facilitated by NVivo software.Results: 10 parents participated in 9 interviews. Six themes were identified relating to: (1) the establishment of a new life dynamic following a diagnosis of asthma; (2) the turbulent and drawn-out process of asthma diagnosis; (3) the roles and expectations of the partnership established between parents and healthcare services; (4) the importance of schools in asthma management; (5) sources and access to relevant information; and (6) the importance of social support networks. Parents frequently felt unsupported and misunderstood, particularly during the diagnostic process.Conclusion: Unmet parental educational and emotional needs, particularly around the time of diagnosis were identified as a key barrier to adequate asthma management. Deeper understanding of gaps in support can instruct asthma care delivery and inform co-produced interventions, thus improving asthma outcomes in children.<br/

“Will anybody listen?” parents’ views on childhood asthma care:a qualitative study

Background: Asthma is the most common chronic disease in children, resulting in considerable morbidity and health care utilisation, especially in geographical areas with high deprivation. Parents play a pivotal role in children’s asthma management.Aim: To explore the views of parents whose children have asthma, regarding barriers and facilitators to receiving adequate asthma care.Design and Setting: A qualitative study conducted in an urban, multi-ethnic setting with high socioeconomic deprivation and paediatric asthma related hospital admissions.Method: The study used a pragmatic approach underpinned by a perspective of critical realism. Parents of children with asthma were recruited through purposive and convenience sampling and data collected through semi-structured interviews. Transcripts were analysed using thematic analysis, facilitated by NVivo software.Results: 10 parents participated in 9 interviews. Six themes were identified relating to: (1) the establishment of a new life dynamic following a diagnosis of asthma; (2) the turbulent and drawn-out process of asthma diagnosis; (3) the roles and expectations of the partnership established between parents and healthcare services; (4) the importance of schools in asthma management; (5) sources and access to relevant information; and (6) the importance of social support networks. Parents frequently felt unsupported and misunderstood, particularly during the diagnostic process.Conclusion: Unmet parental educational and emotional needs, particularly around the time of diagnosis were identified as a key barrier to adequate asthma management. Deeper understanding of gaps in support can instruct asthma care delivery and inform co-produced interventions, thus improving asthma outcomes in children.<br/

Self-reported questionnaires to assess indoor home environmental exposures in asthma patients:A scoping review

Background: The indoor home environment plays a crucial role in determining the outcome of respiratory diseases, including asthma. Researchers, clinicians, and patients would benefit from self-reported questionnaires to assess indoor home environmental exposures that may impact on respiratory health. Objective: To review self-reported instruments for assessing indoor home environmental exposures in asthma patients and to characterise their content, development, and psychometric properties.Design: A scoping review was conducted with content assessment.Methods: A literature search was conducted in Embase and PubMed using the key words housing quality, questionnaire and asthma and their index terms, covering articles published in English between January 2000 to July 2023. Articles in which questionnaires or single item questions were used to assess indoor home environmental exposures in asthma patients in middle- and high-income countries were included. We excluded articles in which the questionnaire required an interviewer or onsite observations and those conducted in low-income countries. Results: We screened 1584 articles to identify 44 studies containing self-reported questionnaires measuring indoor home environmental exposures. 36 studies (82%) were cross sectional, 35 (80%) had a sample size of greater than 1000 participants, and 29 (66%) were conducted in children. Most studies (86%, n=38) had binary (yes/no) or multiple-choice responses. 25 studies (57%) included a recall period of 12 months. 32 studies (73%) had a response rate of greater than 50%. Dampness, biological exposures (e.g. mould), and second-hand tobacco smoke were the most assessed indoor home environmental exposures. Childhood asthma (54%, n=24) and asthma symptoms (36%, n=16) were the most examined asthma related outcomes. The exposure most associated with adverse asthma outcomes was exposure to damp (79%, n=35). 13 studies (29%) had developed a self-reported instrument by adapting questions from previous studies and almost all instruments (n=42 studies, 95%) had not been validated.Conclusions: The scoping review did not identify a comprehensive, validated self-reported questionnaire for assessing indoor home environmental exposures in patients with asthma. There is need to develop and validate a robust but pragmatic self-reported instrument, incorporating the findings from this review. <br/

Molecular Basis of Bcl-XL-p53 Interaction: Insights from Molecular Dynamics Simulations

Bcl-XL, an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-XL: BH3 peptide and Bcl-XL: SN15 peptide (a peptide derived from residues S15-N29 of p53) complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-XL and other Bcl-2 family proteins have 4 hydrophobic pockets (p1–p4), which are occupied by four systematically spaced hydrophobic residues (h1–h4) of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26) of p53 (SN15) peptide anchor into three hydrophobic pockets (p2–p4) of Bcl-XL in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-XL with p53

Physiological Small Airways Dysfunction and the Bronchodilator Response in Adults With Asthma and Its Risk Factors:A Retrospective Analysis

Background: Physiological evidence of small airways dysfunction (SAD) is present in some patients with asthma and is associated with poor disease control. It is unclear if this represents a distinct phenotype of asthma or if it is an early manifestation of the disease. The study aimed to evaluate SAD in asthma and its clinical associations.Methods: A retrospective analysis of routinely collected health data obtained from adults referred for routine spirometric assessment as part of their clinical management. The Maximal Mid-Expiratory Flow (MMEF) z-scores were used to assess the prevalence and association factors for SAD. Pre- and post-bronchodilator data of MMEF and FEV1 in patients with and without SAD or airflow obstruction (AO) were analysed.Results: A total of 1094 patients were included. 366 (33.5%) had evidence of SAD of whom 261 (71.3%) also had AO. Current smokers were at an increased risk of having SAD (OR: 2.05; 95% CI: 1.43– 2.93). 214 patients had Bronchodilator response (BDR) data with 157 (73.4%) demonstrating BDR for MMEF and 121 (56.5%) for FEV1. SAD at baseline was associated with a significant BDR for FEV1 (OR of 3.59 (95% CI: 1.77– 7.57)) and MMEF (OR of 2.89 (95% CI: 1.41– 5.95)). Males were less likely to have a positive BDR for MMEF than females (OR of 0.46; 95% CI: 0.24– 0.89).Conclusion: SAD is common in asthma and is related to the presence of AO, cigarette smoking and is associated with increased BDR for both FEV1 and MMEF. The assessment of SAD in routine clinical practice may help identify airway impairment early for the initiation of targeted therapies

Managing pre-school wheeze: A qualitative study of parents’ views and experiences

OBJECTIVE: The aim of this study was to explore parents' views and experiences of managing preschool wheeze, including opinions on the use of investigations to inform treatment pathways. DESIGN: Purposive sampling was used to recruit 16 participants from 14 families across England and Wales. Qualitative data were collected via semi-structured interviews with parents of children aged 1 to 5 years with preschool wheeze, conducted on Microsoft (MS) Teams. Data were transcribed and analysed using thematic analysis, facilitated by NVivo software package. RESULTS: Analysis generated four themes (1) Pathway to diagnosis (2) Medication management (3) Living with preschool wheeze (4) Improving preschool wheeze healthcare. Findings suggest a negative impact of preschool wheeze on families’ lives, including high levels of worry and limiting capacity for work and travel. Barriers to effective management of preschool wheeze included inconsistent terminologies and diagnostic uncertainty alongside limited education and management support. Other barriers related to parental concerns about medications, delayed investigations, and challenges with accessing specialist care. Parents were in favour of performing investigations to guide treatment pathways. CONCLUSION: Parents’ views highlight the problem of diagnosing and treating preschool wheeze at multiple system levels. To improve management and ensure services for children with preschool wheeze are effective, there is an urgent need for consistent terminology, a unified approach to guide investigations and treatments, and to upskill healthcare professionals in primary and secondary care