P/M Macromolecular Switch Based on Conformational Control Exerted by an Achiral Side Chain within an Axially Chiral Locked Pendant.

Molecular switches, supramolecular chemistry, and polymers can be combined to create stimuli-responsive multichiral materials. Therefore, by acting on the extended/bent conformational composition of an achiral arm, it is possible to create a macromolecular gear, where different supramolecular interactions can be activated/deactivated to control the helical sense of a polymer containing up to five different chiral axial motifs. For this, a chiral allene with a flexible achiral arm was introduced as a pendant in poly(phenylacetylene). Through flexible arm control between extended and bent conformations, it is possible to selectively induce either a P or M helical sense in the polymer, while the relative spatial distribution of the substituents in the allene remains unaltered in two perpendicular planes (configurationally locked). These results show that complex dynamic multichiral materials can be obtained by the polymerization of appropriate monomers that combine chirality, switching properties, and the ability to generate chiral supramolecular assemblies.

Polymyalgia rheumatica.

Polymyalgia rheumatica is an inflammatory disease producing pain and stiffness, mainly in the shoulders and pelvic girdle, in people older than 50 years. Elevation of acute phase reactants is common due to the inflammatory nature of the disease. Since there are no specific diagnostic tests, diagnosis requires the exclusion of other diseases with similar presentations. Imaging has helped to identify the pathological substrate of polymyalgia rheumatica and it is increasingly used to support clinical diagnosis or to detect coexistent giant cell arteritis. Although polymyalgia rheumatica does not clearly impair survival or organ function, it can have a detrimental effect on quality of life. Glucocorticoids at 12·5-25·0 mg prednisone per day are effective in inducing remission in most individuals but, when tapered, relapses occur in 40-60% of those affected and side-effects are common. Assessment of disease activity can be difficult because pain related to common comorbidities such as osteoarthritis and tendinopathies, can return when glucocorticoids are reduced, and acute phase reactants are increased less during flares in individuals undergoing treatment or might increase for other reasons. The role of imaging in assessing disease activity is not yet completely defined. In the search for more efficient and safer therapies, tocilizumab and sarilumab have shown efficacy in randomised controlled trials and additional targeted therapies are emerging. However, judicious risk-benefit balance is essential in applying therapeutic innovations to people with polymyalgia rheumatica.

Significance of clinical-immunological patterns and diagnostic yield of biopsies in microscopic polyangiitis and granulomatosis with polyangiitis.

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.

Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVES: To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). METHODS: A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously. RESULTS: Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment. CONCLUSION: These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

BACKGROUND: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.

Single-cell transcriptomic profiling reveals a pathogenic role of cytotoxic CD4+ T cells in giant cell arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4+ T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4+ T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4+ T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4+ T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4+ T cells in GCA and suggest targeting CTLs as a potential therapeutic option.

miR-146a and miR-146b regulate the expression of ICAM-1 in giant cell arteritis.

Giant cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries. MiRNAs are small, non-coding RNAs that inhibit gene expression at post-transcriptional level. Several miRNAs have been shown to be dysregulated in temporal artery biopsies (TABs) from GCA patients, but their role is unknown. The aims of the present work were: to gain insight into the link between inflammation and miRNA up-regulation in GCA; to identify the role of miR-146a and miR-146b. Primary cultures from TABs were treated with IL-1ß, IL-6, soluble IL-6R (sIL6R), IL-17, IL-22, IFNγ, LPS and PolyIC. Correlations between cytokine mRNA and miRNA levels were determined in inflamed TABs. Primary cultures from TABs, human aortic endothelial and smooth muscle cells and ex-vivo TAB sections were transfected with synthetic miR-146a and miR-146b to mimic miRNA activities. Cell viability, target gene expression, cytokine levels in culture supernatants were assayed. Treatment of primary cultures from TABs with IL-1ß and IL-17 increased miR-146a expression while IL-1ß, IL-6+sIL6R and IFNγ increased miR-146b expression. IFNγ and IL-1ß mRNA levels correlated with miR-146a/b levels. Following transfection, cell viability decreased only in primary cultures from TABs. Moreover, transfection of miR-146a/b mimics increased ICAM-1 gene expression and production of the soluble form of ICAM-1 by primary cultures from TABs and by ex-vivo TABs. ICAM-1 expression was higher in inflamed than normal TABs and ICAM-1 levels correlated with miR-146a/b levels. Expression of miR-146a and miR-146b in GCA appeared to be driven by inflammatory cytokines (e.g. IL-1ß, IFNγ). miR-146a and miR-146b seem responsible for the increase of soluble ICAM-1.

Decoding CD4+ T cell transcriptome in giant cell arteritis: Novel pathways and altered cross-talk with monocytes.

BACKGROUND: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis. METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes. RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA. CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.

Neointimal myofibroblasts contribute to maintaining Th1/Tc1 and Th17/Tc17 inflammation in giant cell arteritis.

Vascular smooth muscle cells (VSMCs) have been shown to play a role in the pathogenesis of giant cell arteritis (GCA) through their capacity to produce chemokines recruiting T cells and monocytes in the arterial wall and their ability to migrate and proliferate in the neointima where they acquire a myofibroblast (MF) phenotype, leading to vascular stenosis. This study aimed to investigate if MFs could also impact T-cell polarization. Confocal microscopy was used to analyze fresh fragments of temporal artery biopsies (TABs). Healthy TAB sections were cultured to obtain MFs, which were then treated or not with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) and analyzed by immunofluorescence and RT-PCR. After peripheral blood mononuclear cells and MFs were co-cultured for seven days, T-cell polarization was analyzed by flow cytometry. In the neointima of GCA arteries, we observed a phenotypic heterogeneity among VSMCs that was consistent with a MF phenotype (α-SMA+CD90+desmin+MYH11+) with a high level of STAT1 phosphorylation. Co-culture experiments showed that MFs sustain Th1/Tc1 and Th17/Tc17 polarizations. The increased Th1 and Tc1 polarization was further enhanced following the stimulation of MFs with IFN-γ and TNF-α, which induced STAT1 phosphorylation in MFs. These findings correlated with increases in the production of IL-1ß, IL-6, IL-12 and IL-23 by MFs. Our study showed that MFs play an additional role in the pathogenesis of GCA through their ability to maintain Th17/Tc17 and Th1/Tc1 polarizations, the latter being further enhanced in case of stimulation of MF with IFN-γ and TNF-α.

Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis.

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are rare systemic inflammatory disorders with overlapping symptoms, elevated eosinophil counts, and heterogenous clinical presentations. Although progress has been made in recent years, there are substantial gaps in our understanding of the pathologic mechanisms involved in these diseases, as well as numerous unmet needs relating to both diagnosis and patient management. For example, in most cases of HES, the underlying cause of hypereosinophilia is unknown, while in EGPA, although a polygenic genetic susceptibility has been found, understanding of the pathogenic mechanisms remains largely elusive. Delineating differences between certain disease variants may be challenging, and there are no reliable predictive markers of disease course. In addition, the current diagnostic criteria for HES and classification criteria for EGPA are not easy to implement in a nonspecialist setting, and specialist referral pathways need to be signposted more clearly. Furthermore, disease-specific activity scores need to be developed to aid the assessment of treatment effects, and improved biomarkers are needed to aid with treatment stratification. In this review, we outline the limitations of our current understanding of HES and EGPA and highlight areas for future work, which ultimately should help improve patient management and outcomes.

Nursing students' attitude toward euthanasia following its legalization in Spain.

BACKGROUND: Euthanasia is a controversial practice in many countries. Since Spain's Euthanasia Law came into effect on March 24, 2021, healthcare providers have faced a new challenge since they must inform patients, provide care, accompany them, and implement the law. It also represents a new stumbling block at universities, which must adapt to regulatory changes and educate future professionals accordingly. Little is known about the attitude of nursing students in Spain toward euthanasia since this law was implemented. OBJECTIVE: This study aims to answer the following research questions: What is the attitude of nursing students toward euthanasia? What factors influence this attitude? RESEARCH DESIGN: A cross-sectional study was conducted using an online questionnaire. PARTICIPANTS AND RESEARCH CONTEXT: The study population comprised all nursing students at a public university in Barcelona (n = 444), Spain, during the 2022-2023 academic year. The validated Spanish version of the Euthanasia Attitude Scale was employed. A bivariate analysis was performed. ETHICAL CONSIDERATIONS: The university Ethics Committee (CEEAH 6247) approved this study. All participating students signed an informed consent form. Participation was voluntary, and data anonymity and confidentiality were guaranteed. RESULTS: Two hundred and forty-four nursing students responded to the questionnaire. The mean total score was 79.64. Participants with religious beliefs presented lower scores, indicating a more negative attitude toward euthanasia. Participants in their second, third, or fourth year of the nursing degree scored higher, demonstrating a more positive attitude. CONCLUSIONS: The attitude of nursing students toward euthanasia was remarkably positive. Working on ethical content during the degree course and clinical practice are factors that help to develop a more positive attitude. In addition, nursing education should encourage professional aspects to prevail over religious beliefs in euthanasia situations.

Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing.

OBJECTIVES: The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. METHODS: Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. RESULTS: Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. CONCLUSIONS: We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis.

EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the use of imaging modalities in primary large vessel vasculitis (LVV). METHODS: A systematic literature review update was performed to retrieve new evidence on ultrasound, MRI, CT and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) for diagnosis, monitoring and outcome prediction in LVV. The task force consisted of 24 physicians, health professionals and patients from 14 countries. The recommendations were updated based on evidence and expert opinion, iterating until voting indicated consensus. The level of agreement was determined by anonymous votes. RESULTS: Three overarching principles and eight recommendations were agreed. Compared to the 2018 version, ultrasound is now recommended as first-line imaging test in all patients with suspected giant cell arteritis, and axillary arteries should be included in the standard examination. As an alternative to ultrasound, cranial and extracranial arteries can be examined by FDG-PET or MRI. For Takayasu arteritis, MRI is the preferred imaging modality; FDG-PET, CT or ultrasound are alternatives. Although imaging is not routinely recommended for follow-up, ultrasound, FDG-PET or MRI may be used for assessing vessel abnormalities in LVV patients with suspected relapse, particularly when laboratory markers of inflammation are unreliable. MR-angiography, CT-angiography or ultrasound may be used for long-term monitoring of structural damage, particularly at sites of preceding vascular inflammation. CONCLUSIONS: The 2023 EULAR recommendations provide up-to-date guidance for the role of imaging in the diagnosis and assessment of patients with LVV.

Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism.

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [ß (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [ß (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [ß (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]. CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses.

The plethora of immunomodulatory drugs: opportunities for immune-mediated kidney diseases.

In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future.

Cost-effectiveness of omalizumab for the treatment of severe pediatric allergic asthma-Results of a real-life study in Spain.

BACKGROUND: Severe pediatric allergic asthma (SPAA) induces a huge economic burden in terms of direct, indirect, and intangible costs. The use of omalizumab for the treatment of these patients has produced a significant improvement in several clinical outcomes, but at the same time, the cost for the management of the disease has also increased. The aim of this report was to evaluate whether the use of omalizumab is cost-effective. METHODS: A sample of 426 children with SPAA from the ANCHORS (Asthma iN CHildren: Omalizumab in Real-life in Spain) study was used to calculate the incremental cost-effectiveness ratio (ICER) for the avoidance of moderate-to-severe exacerbations (MSE) and also for the improvement in childhood Asthma Control Test (c-ACT) or the Asthma Control Questionnaire (ACQ5). We retrospectively collected data on health encounters and drug consumption before and up to 6 years after the beginning of the treatment with omalizumab. RESULTS: The ICER per avoided MSE was €2107 after 1 year, and it consistently decreased to €656 in those followed up to 6 years. Similarly, the ICER for the minimally important difference in control tests showed a decrease from €2059 to €380 per each 0.5 points of improvement in ACQ5 and from €3141 to €2322 per each 3 points improvement in c-ACT, at years 1 and 6, respectively. CONCLUSION: The use of OMZ is a cost-effective option for most children with uncontrolled SPAA, especially those who have frequent exacerbations; the costs are progressively reduced in successive years of treatment.

Implementation of web-based respondent driven sampling in epidemiological studies.

BACKGROUND: Respondent-driven sampling (RDS) is a peer chain-recruitment method for populations without a sampling frame or that are hard-to-reach. Although RDS is usually done face-to-face, the online version (WebRDS) has drawn a lot of attention as it has many potential benefits, despite this, to date there is no clear framework for its implementation. This article aims to provide guidance for researchers who want to recruit through a WebRDS. METHODS: Description of the development phase: guidance is provided addressing aspects related to the formative research, the design of the questionnaire, the implementation of the coupon system using a free software and the diffusion plan, using as an example a web-based cross-sectional study conducted in Spain between April and June 2022 describing the working conditions and health status of homecare workers for dependent people. RESULTS: The application of the survey: we discuss about the monitoring strategies throughout the recruitment process and potential problems along with proposed solutions. CONCLUSIONS: Under certain conditions, it is possible to obtain a sample with recruitment performance similar to that of other RDS without the need for monetary incentives and using a free access software, considerably reducing costs and allowing its use to be extended to other research groups.

Emerging roles of MT-MMPs in embryonic development.

Membrane-type matrix metalloproteinases (MT-MMPs) are cell membrane-tethered proteinases that belong to the family of the MMPs. Apart from their roles in degradation of the extracellular milieu, MT-MMPs are able to activate through proteolytic processing at the cell surface distinct molecules such as receptors, growth factors, cytokines, adhesion molecules, and other pericellular proteins. Although most of the information regarding these enzymes comes from cancer studies, our current knowledge about their contribution in distinct developmental processes occurring in the embryo is limited. In this review, we want to summarize the involvement of MT-MMPs in distinct processes during embryonic morphogenesis, including cell migration and proliferation, epithelial-mesenchymal transition, cell polarity and branching, axon growth and navigation, synapse formation, and angiogenesis. We also considered information about MT-MMP functions from studies assessed in pathological conditions and compared these data with those relevant for embryonic development.

Exploring the Decision-Making Process of People Living with HIV Enrolled in Antiretroviral Clinical Trials: A Qualitative Study of Decisions Guided by Trust and Emotions.

The informed consent is an ethical and legal requirement for potential participants to enroll in a study. There is ample of evidence that understanding consent information and enrollment is challenging for participants in clinical trials. On the other hand, the reasoning process behind decision-making in HIV clinical trials remains mostly unexplored. This study aims to examine the decision-making process of people living with HIV currently participating in antiretroviral clinical trials and their understanding of informed consent. We conducted a qualitative socio-constructivist study using semi-structured interviews. Eleven participants were selected by purposive sampling in Argentina until data saturation was reached. A content analysis was performed. The findings highlight the fact that some participants decided to enroll on the spot, while others made the decision a few days later. In all cases, the decision was based on different aspects of trust (in doctors, in the clinical research site, in the clinical trials system) but also on emotions associated with HIV and/or treatment. Moreover, while people living with HIV felt truly informed after the consent dialogue with a researcher, consent forms were unintelligible and unfriendly. The immediacy of patient decision-making has rarely been described before. Enrollment in an HIV clinical trial is mainly a trust-based decision but this does not contradict the ethical values of autonomy, voluntariness, non-manipulation, and non-exploitation. Thus, trust is a key issue to be included in reshaping professional practices to ensure the integrity of the informed consent process.