Treatment of harmful gambling: a scoping review of United Kingdom-based intervention research.

BACKGROUND: Understanding and treating the harm caused by gambling is a growing international psychiatric and public health challenge. Treatment of gambling harm may involve psychological and pharmacological intervention, in conjunction with peer support. This scoping review was conducted to identify, for the first time, the characteristics and extent of United Kingdom (UK) based gambling treatment research. We reviewed studies conducted among people seeking treatment for disordered or harmful gambling in the UK, the settings, research designs, and outcome measures used, and to identify any treatment research gaps. METHODS: Systematic searches of PsycInfo, PsycArticles, Scopus, PubMed, and Web of Science databases were carried out for gambling treatment research or evaluation studies conducted in the UK. Studies were included if they evaluated the effectiveness of an intervention or treatment designed to improve symptoms of harmful or problematic gambling, reported outcomes of interventions on treatment adherence, gambling symptoms, or behaviours using standardised measures, were conducted in the UK, and were published since 2000. RESULTS: Eight studies met the inclusion criteria. Four were retrospective chart reviews, two were single-participant case reports, one described a retrospective case series, and one employed a cross-sectional design. None used an experimental design. CONCLUSION: The limited number of studies included in this review highlights a relative paucity of gambling treatment research conducted in UK settings. Further work should seek to identify potential barriers and obstacles to conducting gambling treatment research in the UK.

Potential of Large Language Models in Health Care: Delphi Study.

BACKGROUND: A large language model (LLM) is a machine learning model inferred from text data that captures subtle patterns of language use in context. Modern LLMs are based on neural network architectures that incorporate transformer methods. They allow the model to relate words together through attention to multiple words in a text sequence. LLMs have been shown to be highly effective for a range of tasks in natural language processing (NLP), including classification and information extraction tasks and generative applications. OBJECTIVE: The aim of this adapted Delphi study was to collect researchers' opinions on how LLMs might influence health care and on the strengths, weaknesses, opportunities, and threats of LLM use in health care. METHODS: We invited researchers in the fields of health informatics, nursing informatics, and medical NLP to share their opinions on LLM use in health care. We started the first round with open questions based on our strengths, weaknesses, opportunities, and threats framework. In the second and third round, the participants scored these items. RESULTS: The first, second, and third rounds had 28, 23, and 21 participants, respectively. Almost all participants (26/28, 93% in round 1 and 20/21, 95% in round 3) were affiliated with academic institutions. Agreement was reached on 103 items related to use cases, benefits, risks, reliability, adoption aspects, and the future of LLMs in health care. Participants offered several use cases, including supporting clinical tasks, documentation tasks, and medical research and education, and agreed that LLM-based systems will act as health assistants for patient education. The agreed-upon benefits included increased efficiency in data handling and extraction, improved automation of processes, improved quality of health care services and overall health outcomes, provision of personalized care, accelerated diagnosis and treatment processes, and improved interaction between patients and health care professionals. In total, 5 risks to health care in general were identified: cybersecurity breaches, the potential for patient misinformation, ethical concerns, the likelihood of biased decision-making, and the risk associated with inaccurate communication. Overconfidence in LLM-based systems was recognized as a risk to the medical profession. The 6 agreed-upon privacy risks included the use of unregulated cloud services that compromise data security, exposure of sensitive patient data, breaches of confidentiality, fraudulent use of information, vulnerabilities in data storage and communication, and inappropriate access or use of patient data. CONCLUSIONS: Future research related to LLMs should not only focus on testing their possibilities for NLP-related tasks but also consider the workflows the models could contribute to and the requirements regarding quality, integration, and regulations needed for successful implementation in practice.

Transformer Models in Healthcare: A Survey and Thematic Analysis of Potentials, Shortcomings and Risks.

Large Language Models (LLMs) such as General Pretrained Transformer (GPT) and Bidirectional Encoder Representations from Transformers (BERT), which use transformer model architectures, have significantly advanced artificial intelligence and natural language processing. Recognized for their ability to capture associative relationships between words based on shared context, these models are poised to transform healthcare by improving diagnostic accuracy, tailoring treatment plans, and predicting patient outcomes. However, there are multiple risks and potentially unintended consequences associated with their use in healthcare applications. This study, conducted with 28 participants using a qualitative approach, explores the benefits, shortcomings, and risks of using transformer models in healthcare. It analyses responses to seven open-ended questions using a simplified thematic analysis. Our research reveals seven benefits, including improved operational efficiency, optimized processes and refined clinical documentation. Despite these benefits, there are significant concerns about the introduction of bias, auditability issues and privacy risks. Challenges include the need for specialized expertise, the emergence of ethical dilemmas and the potential reduction in the human element of patient care. For the medical profession, risks include the impact on employment, changes in the patient-doctor dynamic, and the need for extensive training in both system operation and data interpretation.

Developing a Technical-Oriented Taxonomy to Define Archetypes of Conversational Agents in Health Care: Literature Review and Cluster Analysis.

BACKGROUND: The evolution of artificial intelligence and natural language processing generates new opportunities for conversational agents (CAs) that communicate and interact with individuals. In the health domain, CAs became popular as they allow for simulating the real-life experience in a health care setting, which is the conversation with a physician. However, it is still unclear which technical archetypes of health CAs can be distinguished. Such technical archetypes are required, among other things, for harmonizing evaluation metrics or describing the landscape of health CAs. OBJECTIVE: The objective of this work was to develop a technical-oriented taxonomy for health CAs and characterize archetypes of health CAs based on their technical characteristics. METHODS: We developed a taxonomy of technical characteristics for health CAs based on scientific literature and empirical data and by applying a taxonomy development framework. To demonstrate the applicability of the taxonomy, we analyzed the landscape of health CAs of the last years based on a literature review. To form technical design archetypes of health CAs, we applied a k-means clustering method. RESULTS: Our taxonomy comprises 18 unique dimensions corresponding to 4 perspectives of technical characteristics (setting, data processing, interaction, and agent appearance). Each dimension consists of 2 to 5 characteristics. The taxonomy was validated based on 173 unique health CAs that were identified out of 1671 initially retrieved publications. The 173 CAs were clustered into 4 distinctive archetypes: a text-based ad hoc supporter; a multilingual, hybrid ad hoc supporter; a hybrid, single-language temporary advisor; and, finally, an embodied temporary advisor, rule based with hybrid input and output options. CONCLUSIONS: From the cluster analysis, we learned that the time dimension is important from a technical perspective to distinguish health CA archetypes. Moreover, we were able to identify additional distinctive, dominant characteristics that are relevant when evaluating health-related CAs (eg, input and output options or the complexity of the CA personality). Our archetypes reflect the current landscape of health CAs, which is characterized by rule based, simple systems in terms of CA personality and interaction. With an increase in research interest in this field, we expect that more complex systems will arise. The archetype-building process should be repeated after some time to check whether new design archetypes emerge.

High-performance organic pseudocapacitors via molecular contortion.

Pseudocapacitors harness unique charge-storage mechanisms to enable high-capacity, rapidly cycling devices. Here we describe an organic system composed of perylene diimide and hexaazatrinaphthylene exhibiting a specific capacitance of 689 F g-1 at a rate of 0.5 A g-1, stability over 50,000 cycles, and unprecedented performance at rates as high as 75 A g-1. We incorporate the material into two-electrode devices for a practical demonstration of its potential in next-generation energy-storage systems. We identify the source of this exceptionally high rate charge storage as surface-mediated pseudocapacitance, through a combination of spectroscopic, computational and electrochemical measurements. By underscoring the importance of molecular contortion and complementary electronic attributes in the selection of molecular components, these results provide a general strategy for the creation of organic high-performance energy-storage materials.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

AIM: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. METHODS: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. RESULTS: Sputum data were available in 48 children (acute asthma; n = 18, stable asthma; n = 17, healthy controls; n = 13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. CONCLUSION: Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.

Gambling treatment service providers' views about contingency management: a thematic analysis.

BACKGROUND: There is a need to improve retention and outcomes for treatment of problem gambling and gambling disorder. Contingency management (CM) is a behavioural intervention involving identification of target behaviours (such as attendance, abstinence, or steps towards recovery) and the provision of incentives (such as vouchers or credits towards the purchase of preferred items) contingent on objective evidence of these behaviours. Contingency management for abstinence and attendance in substance misuse treatment has a substantial evidence base but has not been widely adopted or extended to other addictive behaviours such as gambling. Potential barriers to the widespread adoption of CM may relate to practitioners' perceptions about this form of incentive-based treatment. The present study sought to explore United Kingdom (UK) gambling treatment providers' views of CM for treatment of problem gambling and gambling disorder. METHODS: We conducted semi-structured interviews with 30 treatment providers from across the UK working with people with gambling problems. Participants were provided with an explanation of CM, several hypothetical scenarios, and a structured questionnaire to facilitate discussion. Thematic analysis was used to interpret findings. RESULTS: Participants felt there could be a conflict between CM and their treatment philosophies, that CM was similar in some ways to gambling, and that the CM approach could be manipulated and reduce trust between client and therapist. Some participants were more supportive of implementing CM for specific treatment goals than others, such as for incentivising attendance over abstinence due to perceived difficulties in objectively verifying abstinence. Participants favoured providing credits accruing to services relevant to personal recovery rather than voucher-based incentives. CONCLUSIONS: UK gambling treatment providers are somewhat receptive to CM approaches for treatment of problem gambling and gambling disorder. Potential barriers and obstacles are readily addressable, and more research is needed on the efficacy and effectiveness of CM for gambling.

Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated. OBJECTIVES: The aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function. METHODS AND RESULTS: MCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC-fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)-induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis. CONCLUSION: Nintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus-predominant subgroup.

BACKGROUND: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio. We hypothesized that sputum microbiomic clusters exist in stable airways disease, which can be differentiated by the sputum γP:F ratio. METHODS: Sputum samples were collected from 63 subjects with severe asthma and 78 subjects with moderate-to-severe COPD in a prospective single centre trial. Microbial profiles were obtained through 16S rRNA gene sequencing. Topological data analysis was used to visualize the data set and cluster analysis performed at genus level. Clinical characteristics and sputum inflammatory mediators were compared across the clusters. RESULTS: Two ecological clusters were identified across the combined airways disease population. The smaller cluster was predominantly COPD and was characterized by dominance of Haemophilus at genus level (n = 20), high γP:F ratio, increased H influenzae, low diversity measures and increased pro-inflammatory mediators when compared to the larger Haemophilus-low cluster (n = 121), in which Streptococcus demonstrated the highest relative abundance at the genus level. Similar clusters were identified within disease groups individually and the γP:F ratio consistently differentiated between clusters. CONCLUSION: Cluster analysis by airway ecology of asthma and COPD in stable state identified two subgroups differentiated according to dominance of Haemophilus. The γP:F ratio was able to distinguish the Haemophilus-high versus Haemophilus-low subgroups, whether the Haemophilus-high group might benefit from treatment strategies to modulate the airway ecology warrants further investigation.

Severe exacerbations in moderate-to-severe asthmatics are associated with increased pro-inflammatory and type 1 mediators in sputum and serum.

BACKGROUND: Asthma is a heterogeneous disease and understanding this heterogeneity will enable the realisation of precision medicine. We sought to compare the sputum and serum inflammatory profiles in moderate-to-severe asthma during stable disease and exacerbation events. METHODS: We recruited 102 adults and 34 children with asthma. The adults were assessed at baseline, 3, 6, and 12-month follow-up visits. Thirty-seven subjects were assessed at onset of severe exacerbation. Forty sputum mediators and 43 serum mediators were measured. Receiver-operator characteristic (ROC) curves were constructed to identify mediators that distinguish between stable disease and exacerbation events. The strongest discriminating sputum mediators in the adults were validated in the children. RESULTS: The mediators that were significantly increased at exacerbations versus stable disease and by ≥1.5-fold were sputum IL-1ß, IL-6, IL-6R, IL-18, CXCL9, CXCL10, CCL5, TNFα, TNF-R1, TNF-R2, and CHTR and serum CXCL11. No mediators decreased ≥1.5-fold at exacerbation. The strongest discriminators of an exacerbation in adults (ROC area under the curve [AUC]) were sputum TNF-R2 0.69 (95% CI: 0.60 to 0.78) and IL-6R 0.68 (95% CI: 0.58 to 0.78). Sputum TNF-R2 and IL-6R were also discriminatory in children (ROC AUC 0.85 [95% CI: 0.71 to 0.99] and 0.80 [0.64 to 0.96] respectively). CONCLUSIONS: Severe asthma exacerbations are associated with increased pro-inflammatory and Type 1 (T1) immune mediators. In adults, sputum TNF-R2 and IL-6R were the strongest discriminators of an exacerbation, which were verified in children.

Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles.

BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1ß, IL-6, IL-6 receptor, TNF-α, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN-γ) and proportions of the phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters.

Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.

BACKGROUND: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level. OBJECTIVE: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators. METHODS: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components. RESULTS: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-ß, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin. CONCLUSION: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.

Morphological Expression of the Coherence and Relative Phase of Optical Inputs to the Photoelectrodeposition of Nanopatterned Se-Te Films.

Highly anisotropic and ordered nanoscale lamellar morphologies can be spontaneously generated over macroscopic areas, without the use of a photomask or any templating agents, via the photoelectrodeposition of Se-Te alloy films. To form such structures, the light source can be a single, linearly polarized light source that need not necessarily be highly coherent. In this work, the variation in the morphologies produced by this deposition process was evaluated in response to differences in the coherence and relative phase between multiple simultaneous linearly polarized illumination inputs. Specifically, the morphologies of photoelectrodeposits were evaluated when two tandem same-wavelength sources with discrete linear polarizations, both either mutually incoherent or mutually coherent (with defined phase differences), were used. Additionally, morphologies were simulated via computer modeling of the interfacial light scattering and absorption during the photoelectrochemical growth process. The morphologies that were generated using two coherent, in-phase sources were equivalent to those generated using only a single source. In contrast, the use of two coherent, out-of-phase sources produced a range of morphological patterns. For small out-of-phase addition of orthogonal polarization components, lamellar-type patterns were observed. When fully out-of-phase orthogonal sources (circular polarization) were used, an isotropic, mesh-type pattern was instead generated, similar to that observed when unpolarized illumination was utilized. In intermediate cases, anisotropic lamellar-type patterns were superimposed on the isotropic mesh-type patterns, and the relative height between the two structures scaled with the amount of out-of-phase addition of the orthogonal polarization components. Similar results were obtained when two incoherent sources were utilized. In every case, the long axis of the lamellar-type morphology component aligned parallel to the intensity-weighted average polarization orientation. The observations consistently agreed with computer simulations, indicating that the observed morphologies were fully determined by the nature of the illumination utilized during the growth process. The collective data thus indicated that the photoelectrodeposition process exhibits sensitivity toward the coherency, relative phase, and polarization orientations of all optical inputs and that this sensitivity is physically expressed in the morphology of the deposit.

Research in progress: Medical Research Council United Kingdom Refractory Asthma Stratification Programme (RASP-UK).

The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.

Use of the Historical Limits Method to Detect Increases in Primary and Secondary Syphilis, Arizona 2011-2014: An Exploratory Study.

BACKGROUND: Increasing numbers of reported primary and secondary (P&S) syphilis cases in the United States suggest the need for improved surveillance methods. An outbreak detection method using reported syphilis test results, which can be counted before the conclusion of a syphilis case investigation, could lead to timelier outbreak detection. METHODS: The historical limits comparison method was used to compare the number of positive rapid plasma reagin results reported during 2011-2014 with data for the preceding 3 years. An outbreak alert was generated when the monthly count of positive rapid plasma reagin quantitative results was greater than the historical mean plus 2 standard deviations for 2 consecutive months. RESULTS: Three outbreak alerts occurred during 2011-2014. The first alert occurred in December 2012 in Maricopa County (Phoenix area). Primary and secondary cases subsequently increased from 10 in January 2013 to 15 in March followed by 5 months of consecutive increases. A second alert was generated for Maricopa County in May 2014. Primary and secondary cases increased from 29 in May to 42 in July 2014. Reported cases remained elevated for approximately 7 months after the second alert. In December 2013, an outbreak alert occurred for Pima County (Tucson area). The number of reported P&S syphilis cases in Pima County increased from 6 in February to 15 in March. Counts of reported cases remained elevated for approximately 6 months after the alert. CONCLUSIONS: Use of historical limits comparison method based on syphilis laboratory results can provide an outbreak alert before increases in reported cases of P&S syphilis.

Biological clustering supports both "Dutch" and "British" hypotheses of asthma and chronic obstructive pulmonary disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. OBJECTIVE: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. METHODS: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). RESULTS: Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1ß expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. CONCLUSIONS: Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine.

Strategies targeting the IL-4/IL-13 axes in disease.

IL-4 and IL-13 are pleiotropic Th2 cytokines produced by a wide variety of different cell types and responsible for a broad range of biology and functions. Physiologically, Th2 cytokines are known to mediate host defense against parasites but they can also trigger disease if their activities are dysregulated. In this review we discuss the rationale for targeting the IL-4/IL-13 axes in asthma, atopic dermatitis, allergic rhinitis, COPD, cancer, inflammatory bowel disease, autoimmune disease and fibrotic disease as well as evaluating the associated clinical data derived from blocking IL-4, IL-13 or IL-4 and IL-13 together.

Development of a mouse model mimicking key aspects of a viral asthma exacerbation.

Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting ß2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1ß (interleukin-1ß). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1ß were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1ß induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics.

Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma.

RATIONALE: The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.