Tumor associated macrophages as key contributors and targets in current and future therapies for melanoma.

INTRODUCTION: Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis. AREAS COVERED: We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov. EXPERT OPINION: Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

Inside "Operation Change Agent": Mallinckrodt's Plan for Capturing the Opioid Market.

CONTEXT: The United States is deeply entangled in an opioid crisis that began with the overuse of prescription painkillers. At the height of the prescription opioid crisis (2006-2012), Mallinckrodt Pharmaceuticals was the largest opioid manufacturer. This study explores Mallinckrodt strategies to expand its market share by promoting a new opioid. METHODS: Using the Opioids Industry Document Archive, we analyzed the incentive structures, sales contests, and rhetorical strategy behind Mallinckrodt's "Operation Change Agent," a campaign to switch patients from OxyContin to Mallinckrodt-branded painkillers. A structured search of the archive in October 2022 retrieved 464 documents dated between 2010 and 2020. FINDINGS: We identified a range of sales force motivational techniques, including hypertargeting high-decile prescribers, the provision of free trial kits, using emotion-based language to connect with prescribers, and strategies to oppose prescriber resistance. Throughout, managers used specific incentivization metaphors to frame strategies through sport and ultramarathons. CONCLUSIONS: This research on internal corporate strategy adds to growing challenges to industry claims that opioid sales teams simply educated providers and helped fill existing demand for their products. Moreover, this research has important implications for regulatory policy and consumer protections that can better protect health in the face of competitive market forces.

B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma.

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

Anti-cancer pro-inflammatory effects of an IgE antibody targeting the melanoma-associated antigen chondroitin sulfate proteoglycan 4.

Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence of the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal IgE antibody with human constant domains recognizing CSPG4 to target melanoma. CSPG4 IgE binds to human melanomas including metastases, mediates tumoricidal antibody-dependent cellular cytotoxicity and stimulates human IgE Fc-receptor-expressing monocytes towards pro-inflammatory phenotypes. IgE demonstrates anti-tumor activity in human melanoma xenograft models engrafted with human effector cells and is associated with enhanced macrophage infiltration, enriched monocyte and macrophage gene signatures and pro-inflammatory signaling pathways in the tumor microenvironment. IgE prolongs the survival of patient-derived xenograft-bearing mice reconstituted with autologous immune cells. No ex vivo activation of basophils in patient blood is measured in the presence of CSPG4 IgE. Our findings support a promising IgE-based immunotherapy for melanoma.

The opioid industry document archive: New directions in research on corporate political strategy.

The opioid crisis in the United States has resulted in more than 500,000 deaths since 1999, and recent estimates suggest that attributable deaths could reach 842,000 by 2032. While heroin and synthetic products such as fentanyl now account for the majority of opioid overdoses, the prescription opioid crisis that emerged in the mid-1990s was the primary antecedent to the current situation. Recent settlements in litigation against opioid producers, suppliers and retailers has resulted in the release of almost 2.5 million previously confidential internal documents that have been made publicly accessible via the online Opioid Industry Documents Archive, a collaboration between the University of California, San Francisco and Johns Hopkins University. These corporate records provide critical insights into the operations and strategies of manufacturers and other actors in the opioid supply chain. This article describes the provenance of the opioid documents and their potential value as a research resource. It then outlines methodological approaches to their analysis, drawing on comparisons in conducting research using the Truth Tobacco Industry Documents. The Opioid Industry Documents Archive is a new and important addition to existing industry document collections that enable scrutiny and analysis of the role of corporate actors in determining health outcomes. Beyond their immediate application to researching the corporate and regulatory foundations of the current opioid crisis, the opioid document collections will contribute to a greater understanding of the commercial determinants of public health by providing means to better locate the causes of public health crises, identify politically acceptable solutions to their resolution, and inform strategies for preventing future corporate-driven epidemics.

Pesticide exposure and poisoning in Brazil: Outcome severity, clinical manifestations and management of cases reported to a poison control center.

This work aimed to identify variables associated with increased risk of outcome severity as well as to describe clinical manifestations/symptoms and management of pesticide-related cases reported to a poison center in Brazil. An increased risk of more severe outcomes was observed when exposures occurred in rural areas, involved suicide attempts and moderately to extremely hazardous pesticides. Clinical manifestations with higher frequencies included vomiting, nausea, sialorrhea, headache, miosis and sweating. From the treatment initially applied to the patient, 51.91% encompassed gastric lavage, but this procedure was only recommended in 20.01% of cases by the CIATox. Identifying risk factors associated with poor outcome, describing clinical manifestations, and contrasting initial treatment measures adopted against those recommended by the Poison Center can help determine diagnosis, prognosis and ensure appropriate clinical interventions are used in cases of pesticide poisoning.

Attitudes towards the 'Shisha No Thanks' campaign video: Content analysis of Facebook comments.

INTRODUCTION: While social media are commonly used in public health campaigns, there is a gap in our understanding of what happens after the campaign is seen by the target audience. This study aims to understand how the Shisha No Thanks campaign video was received by the Facebook audience by analyzing Facebook comments posted to it. Specifically, this study aims to determine whether the Facebook audience accepted or rejected the campaign's message. METHODS: A sample of the Facebook comments was extracted, and the study team, which included cultural support workers, developed content categories consistent with the research question. Each comment was then coded by three team members, and only assigned a category if there was agreement by at least two members. RESULTS: Of the 4990 comments that were sampled, 9.1% (456) accepted the campaign message, 22.9% (1144) rejected the message, 21.8% (1089) were unclear, and 46.1% (2301) contained only tagged names. Of the sample, 2.8% (138) indicated the commenter took on board the campaign message by expressing an intention to stop smoking shisha, or asking a friend to stop smoking shisha. Of the comments that showed rejection of the campaign, the majority were people dismissing the campaign by laughing at it or expressing pro-shisha sentiments. CONCLUSIONS: This study demonstrates that conducting content analyses of social media comments can provide important insight into how a campaign message is received by a social media audience.

Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies.

The application of monoclonal antibodies (mAbs) for the treatment of melanoma has significantly improved the clinical management of this malignancy over the last decade. Currently approved mAbs for melanoma enhance T cell effector immune responses by blocking immune checkpoint molecules PD-L1/PD-1 and CTLA-4. However, more than half of patients do not benefit from treatment. Targeting the prominent myeloid compartment within the tumor microenvironment, and in particular the ever-abundant tumor-associated macrophages (TAMs), may be a promising strategy to complement existing therapies and enhance treatment success. TAMs are a highly diverse and plastic subset of cells whose pro-tumor properties can support melanoma growth, angiogenesis and invasion. Understanding of their diversity, plasticity and multifaceted roles in cancer forms the basis for new promising TAM-centered treatment strategies. There are multiple mechanisms by which macrophages can be targeted with antibodies in a therapeutic setting, including by depletion, inhibition of specific pro-tumor properties, differential polarization to pro-inflammatory states and enhancement of antitumor immune functions. Here, we discuss TAMs in melanoma, their interactions with checkpoint inhibitor antibodies and emerging mAbs targeting different aspects of TAM biology and their potential to be translated to the clinic.

Enriched circulating and tumor-resident TGF-ß+ regulatory B cells in patients with melanoma promote FOXP3+ Tregs.

B cells are emerging as key players of anti-tumor adaptive immune responses. We investigated regulatory and pro-inflammatory cytokine-expressing B cells in patients with melanoma by flow cytometric intracellular cytokine, CyTOF, transcriptomic, immunofluorescence, single-cell RNA-seq, and B:T cell co-culture analyses. We found enhanced circulating regulatory (TGF-ß+ and PD-L1+) and reduced pro-inflammatory TNF-α+ B cell populations in patients compared with healthy volunteers (HVs), including lower IFN-γ+:IL-4+ and higher TGF-ß+:TNF-α+ B cell ratios in patients. TGF-ß-expressing B cells in the melanoma tumor microenvironment assembled in clusters and interacted with T cells via lymphoid recruitment (SELL, CXCL13, CCL4, CD74) signals and with Tregs via CD47:SIRP-γ, and FOXP3-promoting Galectin-9:CD44. While reduced in tumors compared to blood, TNF-α-expressing B cells engaged in crosstalk with Tregs via TNF-α signaling and the ICOS/ICOSL axis. Patient-derived B cells promoted FOXP3+ Treg differentiation in a TGF-ß-dependent manner, while sustaining expression of IFN-γ and TNF-α by autologous T-helper cells and promoting T-helper cell proliferation ex vivo, an effect further enhanced with anti-PD-1 checkpoint blockade. Our findings reveal cytokine-expressing B cell compartments skewed toward regulatory phenotypes in patient circulation and melanoma lesions, intratumor spatial localization, and bidirectional crosstalk between B and T cell subsets with immunosuppressive attributes.

Therapeutic Value of Sentinel Lymph Node Biopsy in Patients With Melanoma: A Randomized Clinical Trial.

Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, Setting, and Participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main Outcomes and Measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and Relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00297895.

Health-related quality of life trajectories in melanoma patients after electrochemotherapy: real-world insights from the InspECT register.

BACKGROUND: Electrochemotherapy (ECT) effectively controls skin metastases from cutaneous melanoma. OBJECTIVES: This study aimed to evaluate health-related quality of life (HRQoL) in melanoma patients pre-/post-ECT and its effect on treatment outcome. METHODS: The analysis included prospective data from the International Network for Sharing Practices of ECT register. Following the Standard Operating Procedures, patients received intravenous or intratumoural bleomycin (15,000 IU/m2 ; 1000 IU mL/cm3 ) followed by 100-microsecond, 1000-V/cm electric pulses. Endpoints included response (RECIST v3.0), local progression-free survival (LPFS), toxicity (CTCAE v5.0), and patient-reported HRQoL at baseline, one, two, four and ten months (EuroQol [EQ-5D-3L], including 5-item utility score [EQ-5D] and visual analogue scale for self-reported health state [EQ-VAS]). Comparisons within/between subgroups were made for statistical and minimal important differences (MID). HRQoL scores and clinical covariates were analysed to identify predictors of response in multivariate analysis. RESULTS: Median tumour size was 2 cm. Complete response rate, G3 toxicity and one-year LPFS in 378 patients (76% of the melanoma cohort) were 47%, 5%, and 78%. At baseline, age-paired HRQoL did not differ from the general European population. Following ECT, both EQ-5D and EQ-VAS scores remained within MID boundaries, particularly among complete responders. A subanalysis of the EQ-5D items revealed a statistically significant deterioration in pain/discomfort and mobility (restored within four months), and self-care and usual activities (throughout the follow-up) domains. Concomitant checkpoint inhibition correlated with better EQ-5D and EQ-VAS trajectories. Baseline EQ-5D was the exclusive independent predictor for complete response (RR 14.76, p=0.001). CONCLUSIONS: HRQoL of ECT melanoma patients parallels the general population and is preserved in complete responders. Transient deterioration in pain/discomfort and mobility and persistent decline in self-care and usual activities may warrant targeted support interventions. Combination with checkpoint inhibitors is associated with better QoL outcomes. Baseline HRQoL provides predictive information which can help identify patients most likely to respond.

Diagnostic accuracy of an automated artificial intelligence derived right ventricular to left ventricular diameter ratio tool on CT pulmonary angiography to predict pulmonary hypertension at right heart catheterisation.

AIM: To determine the diagnostic accuracy of an automated artificial intelligence derived right ventricle/left ventricle diameter ratio (RV/LV) computed tomography pulmonary angiography (CTPA) analysis tool to detect pulmonary hypertension (PH) in patients with suspected PH referred to a specialist centre. MATERIALS AND METHODS: The present study was a retrospective analysis of a prospectively maintained database of 202 consecutive patients with suspected PH, who underwent CTPA within 12 months of right heart catheterisation (RHC). Automated ventricular segmentation and RV/LV calculation (Imbio LLC, Minneapolis, MN, USA) was undertaken on the CTPA images. PH diagnosis was made using the RHC reference standard. RESULTS: The automated RV/LV correlated more strongly with RHC metrics than main pulmonary artery (MPA) diameter and MPA to ascending aorta diameter ratio (MPA/AA) measured manually (mean pulmonary arterial pressure [mPAP] r=0.535, R2 = 0.287 p<0.001; pulmonary vascular resistance [PVR] r=0.607, R2 = 0.369 p<0.001). In the derivation cohort (n=100), the area under the receiver-operating curve for automated RV/LV discriminating PH was 0.752 (95% confidence interval [CI] 0.677-0.827, p<0.001). Using an optimised Youden's Index of ≥1.12 classified from derivation, automated RV/LV ratio analysis was more sensitive for the detection of PH with higher positive predictive value (PPV) when compared with manual MPA and MPA/AA in the validation cohort (n=102). Automated RV/LV compromise (1.12) and specific (1.335) thresholds were strongly predictive of mortality (log-rank 7.401, p=0.007 and log-rank 16.075, p<0.001 respectively). CONCLUSION: In suspected PH, automated RV/LV diameter thresholds have high sensitivity for PH, outperform manual MPA and MPA/AA and can predict survival.

Autoimmunity Is a Significant Feature of Idiopathic Pulmonary Arterial Hypertension.

Rationale: Autoimmunity is believed to play a role in idiopathic pulmonary arterial hypertension (IPAH). It is not clear whether this is causative or a bystander of disease and if it carries any prognostic or treatment significance. Objectives: To study autoimmunity in IPAH using a large cross-sectional cohort. Methods: Assessment of the circulating immune cell phenotype was undertaken using flow cytometry, and the profile of serum immunoglobulins was generated using a standardized multiplex array of 19 clinically validated autoantibodies in 473 cases and 946 control subjects. Additional glutathione S-transferase fusion array and ELISA data were used to identify a serum autoantibody to BMPR2 (bone morphogenetic protein receptor type 2). Clustering analyses and clinical correlations were used to determine associations between immunogenicity and clinical outcomes. Measurements and Main Results: Flow cytometric immune profiling demonstrates that IPAH is associated with an altered humoral immune response in addition to raised IgG3. Multiplexed autoantibodies were significantly raised in IPAH, and clustering demonstrated three distinct clusters: "high autoantibody," "low autoantibody," and a small "intermediate" cluster exhibiting high concentrations of ribonucleic protein complex. The high-autoantibody cluster had worse hemodynamics but improved survival. A small subset of patients demonstrated immunoglobulin reactivity to BMPR2. Conclusions: This study establishes aberrant immune regulation and presence of autoantibodies as key features in the profile of a significant proportion of patients with IPAH and is associated with clinical outcomes.

Evaluation of 'Shisha No Thanks' - a co-design social marketing campaign on the harms of waterpipe smoking.

BACKGROUND: Waterpipe (shisha) is becoming increasingly popular worldwide, particularly among young people; and in some countries, it is one of the few forms of tobacco use that is increasing. While there is a growing body of evidence of the harms of waterpipe smoke, there is a scarcity of research of interventions to address this form of tobacco consumption. METHODS: The Shisha No Thanks project was a co-design social marketing campaign that aimed to raise awareness of the harms of waterpipe smoking among young people from an Arabic speaking background in Sydney, Australia. The campaign distributed material through social media and community events. We evaluated the project through an SMS community panel using a longitudinal study design. The cohort were sent questions before and after the project asking about their awareness of messages of harms, attitudes, intention to reduce waterpipe smoking, and awareness of support services. Data was analysed as matched pre- post- data. RESULTS: The evaluation recruited 133 people to the panel. There was a significantly greater proportion of people who reported seeing, hearing or reading something about the harms of waterpipe smoking after the campaign (67.5%) compared with before (45.0%) (p=0.003). Post-campaign, there were higher proportions of people who strongly agreed that waterpipe smoking causes damage, and that it contains cancer-causing substances, but these increases were not statistically significant. There was low awareness of waterpipe cessation services at baseline and post campaign (22.5%). CONCLUSIONS: The Shisha No Thanks project increased awareness of messages about the harms of waterpipe smoking. Although this is a small study, the longitudinal evaluation findings have international relevance and make a useful contribution to the understanding of the impact such interventions can have in addressing one of the few forms of tobacco use that is growing in both developed and developing countries.

BRAF inhibitors and their immunological effects in malignant melanoma.

INTRODUCTION: The treatment of cutaneous melanoma has been revolutionized by the development of small-molecule inhibitors targeting the MAPK pathway, including inhibitors of BRAF (BRAFi) and MEK (MEKi), and immune checkpoint blockade antibodies, occurring in tandem. Despite these advances, the 5-year survival rate for patients with advanced melanoma remains only around 50%. Although not designed to alter immune responses within the tumor microenvironment (TME), MAPK pathway inhibitors (MAPKi) exert a range of effects on the host immune compartment that may offer opportunities for therapeutic interventions. AREAS COVERED: We review the effects of MAPKi, especially BRAFi, on the TME, focusing on alterations in inflammatory cytokine secretion, recruitment of immune cells and their functions, both during response to BRAFi treatment and as resistance develops. We outline potential combinations of MAPKi with established and experimental treatments. EXPERT OPINION: MAPKi in combination or in sequence with established treatments such as checkpoint inhibitors, anti-angiogenic agents, or new therapies such as adoptive cell therapies, may augment their immunological effects, reverse tumor-associated immune suppression, and offer the prospect of longer-lived clinical responses. Refining therapeutic tools at our disposal and embracing 'old friends' in the melanoma treatment arsenal, alongside new target identification, may improve the chances of therapeutic success.

Development and equivalence of new faces for inclusion in the Childhood Asthma Control Test (C-ACT) response scale.

BACKGROUND: Accurate symptom monitoring is vital when managing pediatric asthma, providing an opportunity to improve control and relieve associated burden. The CHILDHOOD ASTHMA CONTROL TEST (C-ACT) has been validated for asthma control assessment in children; however, there are concerns that response option images used in the C-ACT are not culturally universal and could be misinterpreted. This cross-sectional, qualitative study developed and evaluated alternative response option images using interviews with children with asthma aged 4-11 years (and their parents/caregivers) in the United States, Spain, Poland, and Argentina. Interviews were conducted in two stages (with expert input) to evaluate the appropriateness, understanding and qualitative equivalence of the alternative images (both on paper and electronically). This included comparing the new images with the original C-ACT response scale, to provide context for equivalence results. RESULTS: Alternative response option images included scale A (simple faces), scale B (circles of decreasing size), and scale C (squares of decreasing quantity). In Stage 1, most children logically ranked images using scales A, B and C (66.7%, 79.0% and 70.6%, respectively). However, some children ranked the images in scales B (26.7%) and C (58.3%) in reverse order. Slightly more children could interpret the images within the context of their asthma in scale B (68.4%) than A (55.6%) and C (47.5%). Based on Stage 1 results, experts recommended scales A (with slight modifications) and B be investigated further. In Stage 2, similar proportions of children logically ranked the images used in modified scales A (69.7%) and B (75.7%). However, a majority of children ranked the images in scale B in the reverse order (60.0%). Slightly more children were able to interpret the images in the context of their asthma using scale B (57.6%) than modified scale A (48.5%). Children and parents/caregivers preferred modified scale A over scale B (78.8% and 90.9%, respectively). Compared with the original C-ACT, most children selected the same response option on items using both scales, supporting equivalency. Following review of Stage 2 results, all five experts agreed modified scale A was the optimal response scale. CONCLUSIONS: This study developed alternative response option images for use in the C-ACT and provides qualitative evidence of the equivalency of these response options to the originals.

Accurate monitoring of the symptoms associated with pediatric asthma is important when managing the condition. The CHILDHOOD ASTHMA CONTROL TEST (C-ACT) is a questionnaire widely used to measure asthma severity in young children (aged 4­11 years). Each question answered by the child in the C-ACT has four possible answer choices. To help children answer, each choice is presented alongside an image of a male child's face ranging from sad to happy. However, there are concerns that the images used are not culturally universal and could be misinterpreted­due to difficulties translating to electronic formats and a lack of differentiation between the images used. Through interviewing children with asthma, we aimed to address these concerns by developing and testing new images. Alternative image options developed included simpler faces, circles of decreasing size and squares of decreasing quantity. Children aged 4­11 years old were interviewed to test whether they understood the response scale using the new images and if they answered in the same way as with the original images. Interviews were conducted in two stages, with expert guidance at key stages. Results showed that children can interpret and understand the newly developed images and that they answer the questions the same as they would using the original images. These new images have the advantages of being culturally neutral and easier to implement on an electronic device.

Diagnostic test accuracy of artificial intelligence analysis of cross-sectional imaging in pulmonary hypertension: a systematic literature review.

OBJECTIVES: To undertake the first systematic review examining the performance of artificial intelligence (AI) applied to cross-sectional imaging for the diagnosis of acquired pulmonary arterial hypertension (PAH). METHODS: Searches of Medline, Embase and Web of Science were undertaken on 1 July 2020. Original publications studying AI applied to cross-sectional imaging for the diagnosis of acquired PAH in adults were identified through two-staged double-blinded review. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies and Checklist for Artificial Intelligence in Medicine frameworks. Narrative synthesis was undertaken following Synthesis Without Meta-Analysis guidelines. This review received no funding and was registered in the International Prospective Register of Systematic Reviews (ID:CRD42020196295). RESULTS: Searches returned 476 citations. Three retrospective observational studies, published between 2016 and 2020, were selected for data-extraction. Two methods applied to cardiac-MRI demonstrated high diagnostic accuracy, with the best model achieving AUC=0.90 (95% CI: 0.85-0.93), 89% sensitivity and 81% specificity. Stronger results were achieved using cardiac-MRI for classification of idiopathic PAH, achieving AUC=0.97 (95% CI: 0.89-1.0), 96% sensitivity and 87% specificity. One study reporting CT-based AI demonstrated lower accuracy, with 64.6% sensitivity and 97.0% specificity. CONCLUSIONS: Automated methods for identifying PAH on cardiac-MRI are emerging with high diagnostic accuracy. AI applied to cross-sectional imaging may provide non-invasive support to reduce diagnostic delay in PAH. This would be helped by stronger solutions in other modalities. ADVANCES IN KNOWLEDGE: There is a significant shortage of research in this important area. Early detection of PAH would be supported by further research advances on the promising emerging technologies identified.

The Swine Flu Pandemic - Should We Be Concerned?

As I write this review, we are in the midst of the 2009 influenza A (H1N1) pandemic. The extent and impact of this pandemic is still unknown. Although daily reports on confirmed cases and deaths provide a constant stream of detailed information, it is not possible to predict with any degree of precision the impact the outbreak will have in society in general or on the life insurance industry in particular.1 The epidemiology of such disease outbreaks has been likened to a jigsaw puzzle, and we are now at the stage where the picture is intriguing even if we are not sure what we are seeing.2.