An Intersectional Analysis of Child and Adolescent Inclusion in Local Participation Processes

Educational and social initiatives promoting participation among children and adolescents struggle with the widely‐held notion that non‐adult stages of life are merely transitory and that, therefore, non‐adults' views on public life are of less value. Apart from this hurdle of adult‐centrism, there are other obstacles to the full participation of this segment of the population. The present study analyses the inbuilt structures that help or hinder children and adolescents' participation in the local arena. Being ascribed to one or other of the social categories (gender, origins, racialisation, economic status, functional diversity, physical and mental health, gender identity), in addition to being a child or adolescent, involves a further difficulty in exercising one's rights in general and the right of participation in particular, and this weakens young people's social inclusion and exercise of citizenship, deepening their social vulnerability. This is where the intersectional approach can help us avoid the exclusion of children and adolescents with added social barriers. In this article, we survey 191 local youth workers to determine their perceptions of inclusivity in child participation bodies in their municipality. The specific measures in place are also discussed. Lastly, we identify the challenges to children's inclusion in local participation processes and some strategies for advancing towards the creation of more diverse and inclusive arenas of participation

Large T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance

Large T cell; Immune checkpoints; Multiple myelomaCèl·lules T grans; Punts de control immunitari; Mieloma múltipleCélulas T grandes; Puntos de control inmunitario; Mieloma múltipleTumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27− and CD27+ T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations.This work was supported by grants from the Instituto de Salud Carlos III/Subdireccion General de Investigacion Sanitaria and co-financed by FEDER funds (CB16/12/00233, CB16/12/00369, PI17/01243, PI19/00818 and PI20/00048), and together with Fundación Científica de la Asociación Española Contra el Cáncer (FCAECC) for iMMunocell Transcan-2 (AC17/00101), FCAECC Predoctoral Grant Junta Provincial Navarra, the Cancer Research UK (C355/A26819), FCAECC and Italian Association for Cancer Research (AIRC) under the Accelerator Award Program (EDITOR), 2017 Multiple Myeloma Research Foundation Immunotherapy Networks of Excellence, Black Swan Research Initiative of the International Myeloma Foundation, European Hematology Association nonclinical advanced research grant (3680644), European Research Council 2015 Starting Grant (MYELOMANEXT grant 680200), the Cancer Research Innovation in Science Cancer Foundation (PR_EX_2020-02), the Leukemia Lymphoma Society, unrestricted grants from Bristol-Myers Squibb/Celgene and Takeda, Roche imCORE program (NAV-4 and NAV-15), Fondazione Regionale per la Ricerca Biomedica (Regione Lombardia) (Project ID 065 JTC 2016), ERA-NET TRANSCAN-2, and by My First AIRC Grant 2020 (n. 24534, 2021/2026), and by the Riney Family Multiple Myeloma Research Program Fund

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Mieloma; Assajos controlats aleatorisMieloma; Ensayos controlados aleatoriosMyeloma; Randomized controlled trialsAlthough case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene

Presence of Ceramidase Activity in Electronegative LDL

Electronegative low-density lipoprotein (LDL(−)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them is increased bioactive lipid mediator content, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC), and sphingomyelinase (SMase), in LDL(−). However, these enzymes' activities do not explain the increased Sph content, which typically derives from Cer degradation. In the present study, we analyzed the putative presence of ceramidase (CDase) activity, which could explain the increased Sph content. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph, and NEFA spontaneously increased in LDL(−) incubated alone at 37 °C, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in turn, increased Cer content in LDL(−). In addition, LDL(−) efficiently degraded fluorescently labeled Cer (NBD-Cer) to form Sph and NEFA. These observations defend the existence of the CDase-like activity's association with LDL(−). However, neither the proteomic analysis nor the Western blot detected the presence of an enzyme with known CDase activity. Further studies are thus warranted to define the origin of the CDase-like activity detected in LDL(−)

Presence of Ceramidase Activity in Electronegative LDL

Ceramide; SphingomyelinaseCeramida; EsfingomielinasaCeramida; EsfingomielinasaElectronegative low-density lipoprotein (LDL(−)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them is increased bioactive lipid mediator content, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC), and sphingomyelinase (SMase), in LDL(−). However, these enzymes’ activities do not explain the increased Sph content, which typically derives from Cer degradation. In the present study, we analyzed the putative presence of ceramidase (CDase) activity, which could explain the increased Sph content. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph, and NEFA spontaneously increased in LDL(−) incubated alone at 37 °C, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in turn, increased Cer content in LDL(−). In addition, LDL(−) efficiently degraded fluorescently labeled Cer (NBD-Cer) to form Sph and NEFA. These observations defend the existence of the CDase-like activity’s association with LDL(−). However, neither the proteomic analysis nor the Western blot detected the presence of an enzyme with known CDase activity. Further studies are thus warranted to define the origin of the CDase-like activity detected in LDL(−).This research was funded by grants PI13/00364, PI16/00471, FIS PI019/00421, and PI20/00334 from the Instituto de Salud Carlos III, Spanish Ministry of Health (co-financed by the European Regional Development Fund). N.P. is the recipient of FI20/00252 from Instituto de Salud Carlos III. This research was supported by CIBER (Consorcio Centro de Investigación Biomédica en Red) (CB07/08/0016), Instituto de Salud Carlos III, and Ministerio de Ciencia e Innovación and Unión Europea—European Regional Development Fund. CIBERDEM (CB07/08/0016) and CIBERCV (CB16/11/00257) are Instituto de Salud Carlos III Projects. A.A.-S. is member of RETICS INVICTUS PLUS (RD16/0019/0010, the Instituto de Salud Carlos III project). N.P., S.B., N.R., and J.L.S.-Q. are members of the Quality Research Group 2017-SGR-1149 from Generalitat de Catalunya and the Group of Vascular Biology of the Spanish Society of Atherosclerosis

The prognostic value of multiparameter flow cytometry minimal residual disease assessment in relapsed multiple myeloma

Letter to the editor.-- et al.This study was supported by the Cooperative Research Thematic Network grants RD12/0036/0058 of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III, Spain, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370; G03/136; Sara Borrell: CD13/00340); and Asociación Española Contra el Cáncer (GCB120981SAN), Spain. The study was also supported internationally by the International Myeloma Foundation Junior Grant Proposal and the Multiple Myeloma Research Foundation research fellow award.Peer Reviewe

Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma

In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal residual disease (flow-MRD) in bone marrow (BM), for improved assessment of response to therapy and prognostication. However, disturbing levels of variability exist regarding the specific protocols and antibody panels used in individual laboratories. Overall, consensus exists about the utility of combined assessment of CD38 and CD138 for the identification of BM plasma cells (PC); in contrast, more heterogeneous lists of markers are used to further distinguish between normal/reactive PCs and myeloma PCs in the MRD settings. Among the later markers, CD19, CD45, CD27, and CD81, together with CD56, CD117, CD200, and CD307, have emerged as particularly informative; however, no single marker provides enough specificity for clear discrimination between clonal PCs and normal PCs. Accordingly, multivariate analyses of single PCs from large series of normal/reactive vs. myeloma BM samples have shown that combined assessment of CD138 and CD38, together with CD45, CD19, CD56, CD27, CD81, and CD117 would be ideally suited for MRD monitoring in virtually every MM patient. However, the specific antibody clones, fluorochrome conjugates and sources of the individual markers determines its optimal (vs. suboptimal or poor) performance in an eight-color staining. Assessment of clonality, via additional cytoplasmic immunoglobulin (CyIg) κ vs. CyIgλ evaluation, may contribute to further establish the normal/reactive vs. clonal nature of small suspicious PC populations at high sensitivity levels, provided that enough cells are evaluatedGrant sponsor: Red Tematica de Investigacion Cooperativa en Cancer (RTICC) of the Instituto de Salud Carlos III (Ministry of Economy and Competitivity, Madrid, Spain) – FEDER; Grant number: RD12/0036/0048; Grant sponsors: EuroFlow Consortium; the International Myeloma Foundation-Black Swan Research Initiative.Peer Reviewe

The capacity of apob-depleted plasma in inducing atp-binding cassette a1/g1-mediated macrophage cholesterol efflux-but not gut microbial-derived metabolites-is independently associated with mortality in patients with st-segment elevation myocardial infarction

Altres ajuts: Fundació per a la Bioquímica Clínica i Patologia MolecularImpaired HDL-mediated macrophage cholesterol efflux and higher circulating concentrations of trimethylamine N-oxide (TMAO) levels are independent risk factors for cardiovascular mortality. The TMAO precursors, γ-butyrobetaine (γBB) and Trimethyllysine (TML), have also been recently associated with cardiovascular death, but their interactions with HDL-mediated cholesterol efflux remain unclear. We aimed to determine the associations between APOB depleted plasma-mediated macrophage cholesterol efflux and plasma TMAO, γBB, and TML concentrations and explore their association with two-year follow-up mortality in patients with acute ST-elevation myocardial infarction (STEMI) and unstable angina (UA). Baseline and ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated macrophage cholesterol efflux to APOB-depleted plasma was decreased in patients with STEMI, and the latter was further impaired in those who died during follow-up. Moreover, the circulating concentrations of TMAO, γBB, and TML were higher in the deceased STEMI patients when compared with the STEMI survivors or UA patients. However, after statistical adjustment, only ABCA1/G1-mediated macrophage cholesterol efflux remained significantly associated with mortality. Furthermore, neither the TMAO, γBB, nor TML levels altered the HDL-mediated macrophage cholesterol efflux in vitro. We conclude that impaired ABCA1/G1-mediated macrophage cholesterol efflux is independently associated with mortality at follow-up in STEMI patients

Recovery of polyclonal immunoglobulins during treatment in patients ineligible for autologous stem-cell transplantation is a prognostic marker of longer progression-free survival and overall survival

Immunoparesis is the suppression of normal polyclonal immunoglobulins and is present in most patients with newly diagnosed multiple myeloma (MM). The association of immunoparesis at diagnosis, and particularly its recovery along with treatment, with survival in patients ineligible for autologous stem-cell transplantation (ASCT) has not been well established. This retrospective study evaluated the impact of immunoparesis in 431 patients diagnosed with MM, ineligible for ASCT, with a median overall survival of 36 months [95% confidence interval (CI): 31–40]. Immunoparesis was present in 81.2% of patients at diagnosis and was associated with a trend to a worse overall response rate (ORR: 84.8% vs. 74.9%; OR 1.88 (95% CI: 0.97–3.63), shorter progression-free survival (PFS) [22.0 vs. 18.2 months; hazard ratio (HR) 0.775; 95%CI: 0.590–1.018; p = 0.066], and overall survival (OS) (45.9 vs. 34.2 months; HR 0.746; 95% CI: 0.551–1.010; p = 0.057). Twenty-four per cent of patients who had immunoparesis at diagnosis recovered polyclonal immunoglobulins in the follow-up period. Interestingly, these patients had a better ORR (96.3% vs. 68.2%; OR 12.29 (95% CI: 3.77–40.06), PFS (HR 0.703; 95CI%: 0.526–0.941; p = 0.018) and OS (HR 0.678; 95 CI%: 0.503–0.913; p = 0.011) than patients who did not recover it. In summary, restoring a healthy immune system along with first-line treatment in patients with MM, not receiving ASCT, is associated with better outcomes

Patterns of sedentary behavior in overweight and moderately obese users of the Catalan primary-health care system

Background and objectives Prolonged sitting time (ST) has negative consequences on health. Changing this behavior is paramount in overweight/obese individuals because they are more sedentary than those with normal weight. The aim of the study was to establish the pattern of sedentary behavior and its relationship to health, socio-demographics, occupation, and education level in Catalan overweight/obese individuals. Methods A descriptive study was performed at 25 healthcare centers in Catalonia (Spain) with 464 overweight/moderately obese patients, aged25 to 65 years. Exclusion criteria were chronic diseases which contraindicated physical activity and language barriers. Face-to-face interviews were conducted to collect data on age, gender, educational level, social class, and marital status. Main outcome was ‘sitting time’ (collected by the Marshall questionnaire); chronic diseases and anthropometric measurements were registered. Results 464 patients, 58.4% women, mean age 51.9 years (SD 10.1), 76.1% married, 60% manual workers, and 48.7% had finished secondary education. Daily sitting time was 6.2 hours on working days (374 minutes/day, SD: 190), and about 6 hours on non-working ones (357 minutes/day, SD: 170). 50% of participants were sedentary 6 hours. The most frequent sedentary activities were: working/academic activities around 2 hours (128 minutes, SD: 183), followed by watching television, computer use, and commuting. Men sat longer than women (64 minutes more on working days and 54 minutes on non-working days), and individuals with office jobs (91 minutes), those with higher levels of education (42 minutes), and younger subjects (25 to 35 years) spent more time sitting. Conclusions In our study performed in overweight/moderately obese patients the mean sitting time was around 6 hours which was mainly spent doing work/academic activities and watching television. Men, office workers, individuals with higher education, and younger subjects had longer sitting time. Our results may help design interventions targeted at these sedentary patients to decrease sitting time.