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The combination of visual assessment of whole body [18F]FDG PET images and evaluation of bone marrow samples by Multiparameter Flow Cytometry (MFC) or Next-Generation Sequencing (NGS) is currently the most common clinical practice for the detection of Measurable Residual Disease (MRD) in Multiple Myeloma (MM) patients. In this study, radiomic features extracted from the bone marrow biopsy locations are analyzed and compared to those extracted from the whole bone marrow in order to study the representativeness of these biopsy locations in the image-based MRD assessment. Whole body [18F]FDG PET of 39 patients with newly diagnosed MM were included in the database, and visually evaluated by experts in nuclear medicine. A methodology for the segmentation of biopsy sites from PET images, including sternum and posterior iliac crest, and their subsequent quantification is proposed. First, starting from the bone marrow segmentation, a segmentation of the biopsy sites is performed. Then, segmentations are quantified extracting SUV metrics and radiomic features from the [18F]FDG PET images and are evaluated by Mann–Whitney U-tests as valuable features differentiating PET+/PET− and MFC+ /MFC− groups. Moreover, correlation between whole bone marrow and biopsy sites is studied by Spearman ρ rank. Classification performance of the radiomics features is evaluated applying seven machine learning algorithms. Statistical analyses reveal that some images features are significant in PET+/PET− differentiation, such as SUVmax, Gray Level Non-Uniformity or Entropy, especially with a balanced database where 16 of the features show a p value 18F]FDG PET images in MRD assessment in MM patients.

Multiple myeloma (MM) is characterized by an immunosuppressive microenvironment that enables tumor development. One of the mechanisms of immune evasion used by MM cells is the inhibition of natural killer (NK) cell effector functions; thus, the restoration of NK cell antitumor activity represents a key goal to increase tumor cell recognition, avoid tumor escape and potentially enhancing the effect of other drugs. In this study, we evaluated the ability of the investigational medicine NKTR-255, an IL-15 receptor agonist, to engage the IL-15 pathway and stimulate NK cells against MM cells. We observed that incubation with NKTR-255 was able to tilt the balance toward an activated phenotype in NK cells isolated from peripheral blood mononuclear cells of patients with MM, with increased expression of activating receptors on the surface of treated NK cells. This resulted in an enhanced degranulation, cytokine release, and anti-tumor cytotoxicity when the NK cells were exposed to both MM cell lines and primary MM cells. We further evaluated the in vivo effect of NKTR-255 in fully humanized immunocompetent mice subcutaneously engrafted with H929 MM cells. Compared with placebo, weekly injection of the mice with NKTR-255 increased the number of circulating NK cells in peripheral blood and delayed tumor growth. Finally, we observed that combination of NKTR-255 with the anti-CD38 antibody, daratumumab, was effective against MM cells in vitro and in vivo. Taken together, our data suggest a significant impact of NKTR-255 in inducing NK cell function against MM cells with important translational implications.

Impacts of climate warming on forests vigour are forecasted to increase in magnitude. Yet it remains unclear how stand characteristics and competition modulate the relationship between tree growth and gross primary production with drought. Here, we studied how the spatial variation in stand density, basal area and height modulates tree growth (Basal Area Increment, BAI and stand growth), summer NDVI, as well as their responses to drought (Standardized Precipitation-Evapotranspiration Index, SPEI) in 56 Aleppo pine (Pinus halepensis Mill.) planted forests located in Northeast Spain. Long-term BAI responses to SPEI were strongly determined by stand density, suggesting that competition modulates Aleppo pine growth responses to drought. Along this, summer NDVI also displayed strong associations with SPEI. NDVI was mostly related with stand growth, suggesting canopy densification drives NDVI pattern and trends. Short-term BAI and NDVI responses to severe droughts were mainly independent of stand characteristics. In the studied region, drought is a universal factor limiting Aleppo pine secondary growth and canopy greening. However, the results suggest that stand density modulates Aleppo pine growth responses to drought on the long-term, reducing the growth in densest stands. Denser stands with larger trees are the ones that present higher NDVI values, suggesting that canopy activity depends more on stand canopy coverage than on secondary growth rate and its response to drought. In these Mediterranean pines, canopy activity and secondary growth are temporally coupled but spatially decoupled.

Purpose: Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Experimental Design: We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusions: Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.

In the current era, 5%-10% of Fontan patients die or need a transplant in childhood, and approximately 50% will experience the same fate by age 40 years. Heart transplant (HTx) can be successful for selected children and adults with Fontan circulatory failure of any mechanism, with a 1-year post-transplant survival rate approaching 90% in children and 80% in the largest single-centre adult Fontan HTx experience. Protein-losing enteropathy and plastic bronchitis can be expected to resolve post-transplant, and limited data suggest patients with Fontan-associated liver disease who survive HTx can expect improvement in liver health. Early Fontan failure, within 12 months of Fontan completion, is not easily rescued by HTx, and late referrals and failure to refer adult patients remain problematic. Very little is known about the numbers of patients who are not referred, are turned down following assessment for HTx, or die on the waiting list-numbers that are needed to understand the complete picture of HTx in the Fontan population and to identify where best to focus quality-improvement efforts. Recent revisions to listing prioritization in Canada with considerations specific to the Fontan population aim to mitigate the fact that the status-listing criteria are not tailored to the congenital heart population. Transplanting high-risk children prior to Fontan completion, developing adult congenital heart disease transplant centres with expertise that can also offer combined heart-liver transplant when appropriate, and improving single-ventricle mechanical support options and criteria for both adults and children may help mitigate the early post-listing mortality.

DNA promoter methylation of a subset of proteasome subunit genes. Heatmap comparing methylation pattern of 35 MM patients and 30 PBMC samples. The methylation degree is given by a color code: red – methylated state, blue – unmethylated state. Each line represents an individual sample, each column a single CpG. The methylation degree is encoded by color with blue for an unmethylated and red for a methylated state. Artificially methylated controls were included. For PSMD5, hypermethylation was only present in MM cells, not in PBMCs. For PSMC2, hypermethylation occurred in both, MM cells and PBMCs, indicating a physiological state probably independent of disease development and progression. In the remaining proteasome subunit genes, no aberrant promoter methylation was detected.

Patient-derived mutations impair PI response to Carfilzomib and Ixazomib. Cytotoxicity assay and IC50 values of RPMI-8226 MM cell lines harboring two different stably expressed patient-derived mutations in proteasome subunits. The mutants were more resistant to the proteasome inhibitors Carfilzomib and Ixazomib compared to the controls (*) harboring lentivirally-encoded WT sequence of PSMC6/PSMD1. Shown are the means and standard deviations of three independent experiments (biological replicates) and three technical replicates in each experiment. The PSMC6 and PSMD1 expression levels were equivalent for the mutants and the controls.

Genetic variants in the Würzburg dataset.

Cell survival of DNMTi pretreated KMS11 cells under BTZ exposure. AlamarBlue assay after 72 hours of incubation with varying concentrations of BTZ (0.5 nM to 4 nM) on DNMTi pretreated cells (48 h 500 nM Aza, 72 h 100 nM Dec) and PI naïve KMS11. No resensitizing effect to PI treatment was observed.

Primers used for luciferase reporter assay.

Primers used for DBS.

Purpose:Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored.Experimental Design:We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents.Results:We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles.Conclusions:Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.

Quality check of DBS assays with artificially methylated standard DNAs. DNA standards of 0%, 25%, 50%, 75% and 100% methylation were sequenced with the PSMB5, PSMC2, PSMC5, PSMC6, PSMD1 and PSMD5 DBS assays to confirm assay sensitivity. Results for all investigated DBS amplicons correlated well with the expected curves (P < 0.001) (A). The sequencing depths of the PSMD5 DBS assay was 10-3 (B).

Raw data measurements of the dual-luciferase reporter assay in the L363 cell line. All measurements were performed in duplicates on 20.000 cells.

Human mobility has become an extremely complex phenomenon in Mexico, especially the undocumented transit of people from Central American countries to the United States, due to changes in patterns, dynamics of flows and the response of the State. The objective of this article is to describe the main state policies of border and migration control in Mexico that have been consolidated in the last ten years. With a highly restrictive component, these policies have been based on securitization, displacing the relevance of human security. A critical analysis of the influences of the national security paradigm over the representation of migration as a threat in the context of the COVID-19 pandemic is presented. It is concluded that the pandemic allowed to justify the state’s indifference to people in an irregular situation in the country, but also to continue implementing immigration containment measures. La movilidad humana en México, y especialmente el tránsito indocumentado de personas de origen centroamericano rumbo a Estados Unidos, se ha vuelto un fenómeno complejo, por los cambios en los patrones, las dinámicas de los flujos y la respuesta del Estado. El objetivo de este artículo es describir las principales políticas estatales de control fronterizo y migratorio que se han consolidado en México en los últimos diez años. Con un componente muy restrictivo, estas tienen como fundamento a la securitización, que desplaza a la seguridad humana. Se presenta un análisis crítico de la influencia del paradigma de seguridad nacional sobre la representación de la migración como amenaza en el contexto de la pandemia de COVID-19. Se concluye que la pandemia permitió justificar la indiferencia estatal frente a las personas en situación irregular en el país, y continuar implementando medidas de contención migratoria. Abstract Human mobility has become an extremely complex phenomenon in Mexico, especially the undocumented transit of people from Central American countries to the United States, due to changes in patterns, dynamics of flows and the response of the State. The objective of this article is to describe the main state policies of border and migration control in Mexico that have been consolidated in the last ten years. With a highly restrictive component, these policies have been based on securitization, displacing the relevance of human security. A critical analysis of the influences of the national security paradigm over the representation of migration as a threat in the context of the COVID-19 pandemic is presented. It is concluded that the pandemic allowed to justify the state’s indifference to people in an irregular situation in the country, but also to continue implementing immigration containment measures. O fenômeno da mobilidade humana no México, especialmente o trânsito rumo aos Estados Unidos de forma irregular, tornou-se extremamente complexo por mudanças nos padrões, dinâmicas e problemáticas diversas. Neste artigo descrevemos de forma geral as principais políticas estatais de controlo fronteiriço e migratório no México que se consolidaram nos últimos dez anos como postas em marcha de políticas migratórias altamente restritivas, As quais tiveram como fundamento a securitização, deslocando a relevância da segurança humana. Mais do que um estudo conceitual ou teórico sobre migração, este texto pretende ser uma análise contextual e crítica de como o paradigma de segurança nacional influencia de maneira sobre a representação da migração como forma de ameaça no contexto de uma pandemia de COVID-19. Por último, concluímos que a pandemia se traduziu no pretexto perfeito para justificar a indiferença estatal face às pessoas em situação irregular no país, mas também para continuar a implementar medidas de contenção migratória.

OBJECTIVES Studies concerning factors associated with long-term outcomes in adult congenital heart disease (ACHD) patients after infective endocarditis (IE) are scarce, while IE-related mortality in these patients remains a burden. We evaluated the factors associated with long-term survival in ACHD patients admitted for IE. METHODS We performed a retrospective single-centre study of all ACHD patients admitted for IE to a tertiary cardiothoracic centre between 1999 and 2015. Underlying ACHD, detailed echocardiographic and clinical data, surgical treatment and long-term follow-up were analysed. RESULTS We identified 151 ACHD patients admitted due to 176 episodes IE with 30-day, 6-month and 1-, 5- and 10-year survival of 95.4%, 92.7%, 92.7%, 84.7% and 75.6%, respectively. In a multivariable analysis, adjusted estimated probability of death was consistently higher after an IE episode among patients with complex as compared to simple/moderate ACHD: 10.6% vs 2.4% at 30 days, 15.0% vs 3.4% at 6 months and 1 year, 30.4% vs 7.8% at 5 years and 44.9% vs 13.1% at 10 years. Risk of death was higher among patients with prosthetic valve in comparison with those without (risk ratios 1.73–1.92). Surgical treatment was required in 76 (43.2%) episodes with 30-day mortality of 3.9%. Risk of death appeared to be lower than in the conservatively treated subgroup (risk ratios 0.71–0.78). CONCLUSIONS We demonstrated satisfactory long-term survival in ACHD patients who were treated for IE in a tertiary cardiothoracic centre. Early mortality tended to be lower in the surgically treated subgroup. Factors negatively associated with long-term survival were complex ACHD and presence of prosthetic valve.

Background: Survival in multiple myeloma has improved significantly in recent years, especially in young patients. This is due to the introduction of new drugs with new mechanisms of action. We reviewed the evolution of the survival of patients with MM between 1999 and 2020 at our 12 de Octubre Hospitalinstitution. Then, to confirm our results, we used data from TriNetx, a global health research platform that includes patients from Europe and US. Methods: Using the H120 cohort, with 703 patients, we compared survival time since MM diagnosis in three groups based on age at MM diagnosis over three time periods. Comparator cohorts included 62,572 patients from US Collaborative Network and 6,377 patients from EMEA Collaborative Network. Finally, we analysed differences in the patterns of treatment between networks across the world. Kaplan‒Meier analysis was used to estimate survival probabilities,and between-group differences were tested using the log-rank test and hazard ratio. Results: For patients from H12O, the median OS was 35.61 (28.38-42.84, 95% CI), 55.59 (40.20-70.98, 95%) and 68.67 (54.92-82.42, 95%) months for the 1999-2009, 2010-2014 and 2015-2020 cohorts, respectively (p=0.0001). Among all patients included in the EMEA network, the median OS was 20.32 months vs. 34.75 months from 1999-2009 vs. 2010-2014. The median OS from the 2010-2014 vs. 2015-2020 time cohorts was 34.75 months vs. 54.43 months, respectively. In relation to the US cohort, the median OS from before 2010 vs. 2010-2014 wasnot reached in either time cohort and neither when comparing the 2010-2014 vs. 2015-2019 time cohorts. Bortezomib is the most commonly used drug in the EMEA cohort, while lenalidomide is the most commonly used drug in the US cohort. Conclusions: This large-scale study based on real-world data confirms the previous finding that MM patients have increased their survival in the last two decades.

12 páginas, 7 figuras, 1 tabla, Lung ultrasound (LUS) allows for the detection of a series of manifestations of COVID-19, such as B-lines and consolidations. The objective of this work was to study the inter-rater reliability (IRR) when detecting signs associated with COVID-19 in the LUS, as well as the performance of the test in a longitudinal or transverse orientation. Thirty-three physicians with advanced experience in LUS independently evaluated ultrasound videos previously acquired using the ULTRACOV system on 20 patients with confirmed COVID-19. For each patient, 24 videos of 3 s were acquired (using 12 positions with the probe in longitudinal and transverse orientations). The physicians had no information about the patients or other previous evaluations. The score assigned to each acquisition followed the convention applied in previous studies. A substantial IRR was found in the cases of normal LUS (κ = 0.74), with only a fair IRR for the presence of individual B-lines (κ = 0.36) and for confluent B-lines occupying < 50% (κ = 0.26) and a moderate IRR in consolidations and B-lines > 50% (κ = 0.50). No statistically significant differences between the longitudinal and transverse scans were found. The IRR for LUS of COVID-19 patients may benefit from more standardized clinical protocols., This research was partially funded by CDTI (Spanish acronym: Centre for Industrial Tech- nological Development), funding number COI-20201153. Partially supported by the Google Cloud Research Credits program with the funding number GCP19980904, by the project RTI2018-099118- A-I00 founded by MCIU/AEI/FEDER UE and by the European Commission–NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global).

Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.

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Belantamab mafodotin (BM) is a new anti-BCMA antibody-drug conjugate, recently approved for triple-class relapsed and refractory multiple myeloma (RRMM). We assessed real-world outcomes with BM in patients under the Spanish Expanded Access Program (EAP).We conducted an observational, retrospective, multicenter study including RRMM patients who received ≥ 1 dose of BM (Nov 2019 to Jun 2021). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs).Thirty-three patients were included with a median of 70 years of age (range, 46-79 years). Median time from diagnosis was 71 months (range, 10-858 months). Median prior lines was 5 (range, 3-8 lines); 90% of patients were triple-/quad-/penta-refractory; 48% showed high-risk cytogenetics. Median BM doses was 3 (range 1-16 doses), with a median follow-up of 11 months (6-15 months). ORR was 42.2% (≥ VGPR, 18.2%). Median PFS was 3 months (95% CI 0.92-5.08) in the overall population, and 11 months (HR 0.26; 95% CI 0.10-0.68) for patients who achieved ≥ PR. PFS was not significantly different according to age, cytogenetic risk, and prior therapy lines. OS was 424 days (95% CI 107-740). Non-hematological TEAEs (57.6% of patients; 30.3% ≥ G3) included keratopathy (51.5%; 21.2% ≥ G3) and patient-reported vision-related symptoms (45.5%). Keratopathy was resolved in 70.6% of patients. G3 hematological TEAEs was 18.2%, thrombocytopenia (21.2%). Dose reductions due to TEAEs: 30.3%; delays: 36.4%. Treatment discontinuation causes: progression (54.5%), toxicity (non-ocular; 6%/ocular; 6% /ocular + non-ocular toxicity; 3%), death (6%), and patient's decision (3%).BM showed relevant anti-myeloma activity in RRMM with a manageable safety profile. These results corroborate those observed in the BM pivotal trial.

Polymers are essential materials in our daily life. The synthesis of value-added polymers is mainly performed from fossil fuel-derived monomers. However, the adoption of the circular economy model based on the bioeconomy will reduce the dependence on fossil fuels. In this context, biorefineries have emerged to convert biomass into bioenergy and produce high value-added products, including molecules that can be further used as building blocks for the synthesis of biopolymers and bioplastics. The achievement of catalytic systems able to polymerize the natural monomer counterparts, such as terpenes or terpenoids, is still a challenge in the development of polymers with good mechanical, thermal, and chemical properties. This review describes the most common types of bioplastics and biopolymers and focuses specifically on the polymerization of terpenes and terpenoids, which represent a source of promising monomers to create bio-based polymers and copolymers.

Adults with congenital heart disease represent a highly diverse, ever-growing population. Optimal approaches to management of problems such as arrhythmia, sudden cardiac death, heart failure, transplant, application of advanced therapies and unrepaired shunt lesions are incompletely established. Efforts to strengthen our understanding of these complex clinical challenges and inform evidence-based practices are ongoing.This narrative review summarizes evidence underpinning current approaches to congenital heart disease management while highlighting areas requiring further investigation. A search of literature published in 'Medline,' 'EMBASE,' and 'PubMed' using search terms 'congenital heart disease,' 'arrhythmia,' 'sudden cardiac death,' 'heart failure,' 'heart transplant,' 'advanced heart failure therapy,' 'ventricular assist device (VAD),' 'mechanical circulatory support (MSC),' 'intracardiac shunt' and combinations thereof was undertaken.Application of novel technologies in the diagnosis and management of arrhythmia has and will continue to improve outcomes in this population. Sudden death remains a prevalent problem with many persistent unknowns. Heart failure is a leading cause of morbidity and mortality. Improved access to specialist care, advanced therapies and cardiac transplant is needed. The emerging field of cardio-obstetrics will continue to define state-of-the-art care for the reproductive health of women with heart disease.

30 Pág. Centro de Investigación Forestal (CIFOR), Understorey evaluation is essential in wildlife habitat management, biomass storage and wildfire suppression, among other areas. The lack of a standardised methodology in the field measurements, and in their subsequent analysis, forces researchers to look for procedures that effectively extract understorey data to make management decisions corresponding to actual stand conditions. In this sense, when analysing the understorey characteristics from LiDAR data, it is very usual to ask: “what value should we set the understorey height range to?” It is also usual to answer by setting a numeric value on the basis of previous research. Against that background, this research aims to identify the optimal height to canopy base (HCB) filter–LiDAR metric relationship for estimating understorey height (UH) and understorey cover (UC) using LiDAR data in the Pokupsko Basin lowland forest complex (Croatia). First, several HCB values per plot were obtained from field data (measured HCBi—HCBM-i, where i ɛ (minimum, maximum, mean, percentiles)), and then they were modelled based on LiDAR metrics (estimated HCBi—HCBE-i). These thresholds, measured and estimated HCBi per plot, were used as point cloud filters to estimate understorey parameters directly on the point cloud located under the canopy layer. In this way, it was possible to predict the UH with errors (RMSE) between 0.90 and 2.50 m and the UC with errors (RMSE) between 8.8 and 18.6 in cover percentage. Finally, the sensitivity analysis showed the HCB filter (the upper threshold to select the understorey LiDAR points) is the most important factor affecting the UH estimates, while this factor and the LiDAR metric are the most important factors affecting the UC estimates., This research was funded by the Department of Economy, Industry and Competitiveness, Spanish Government (DI-16-08446, Saray Martín-García), by the European Commission through the project ‘My Sustainable Forest’ (H2020-EO-2017; 776045) and by the Croatian Science Foundation under the project IP-2016-06-7686 “Retrieval of Information from Different Optical 3D Remote Sensing Sources for use in Forest Inventory (3D-FORINVENT)”. The work of doctoral student Luka Jurjevi´c has been fully supported by the “Young researchers” career development project—training of doctoral students” of the Croatian Science Foundation funded by the European Union from the European Social Fund.

Belantamab-mafodotin (belamaf) is a novel antibody-drug conjugate targeting B-cell maturation antigen that showed anti-myeloma activity in patients with relapsed and refractory multiple myeloma (RRMM). We performed an observational, retrospective, and multicenter study aimed to assess the efficacy and safety of single-agent belamaf in 156 Spanish patients with RRMM. The median number of prior therapy lines was 5 (range, 1–10), and 88% of patients were triple-class refractory. Median follow-up was 10.9 months (range, 1–28.6). The overall response rate was 41.8% (≥CR 13.5%, VGPR 9%, PR 17.3%, MR 2%). The median progression-free survival was 3.61 months (95% CI, 2.1–5.1) and 14.47 months (95% CI, 7.91–21.04) in patients achieving at least MR (p < 0.001). Median overall survival in the entire cohort and in patients with MR or better was 11.05 months (95% CI, 8.7–13.3) and 23.35 (NA-NA) months, respectively (p < 0.001). Corneal events (87.9%; grade ≥ 3, 33.7%) were the most commonly adverse events, while thrombocytopenia and infections occurred in 15.4% and 15% of patients, respectively. Two (1.3%) patients discontinued treatment permanently due to ocular toxicity. Belamaf showed a noticeably anti-myeloma activity in this real-life series of patients, particularly among those achieving MR or better. The safety profile was manageable and consistent with prior studies.

Sensitive and specific genotyping of human papillomaviruses (HPVs) is critical for the surveillance and monitoring of the vaccine effectiveness. Here, HPV genotypes were identified in 137 cervical samples with different histology (79 ≤CIN1 and 58 CIN3+) using Nested-PCR followed by Next-Generation sequencing (NGS) and relative proportions for each genotype in multiple infections were computed. All samples had been previously genotyped by PCR-Reverse Blotting Hybridization (PCR-RBH) thus allowing for a concordance analysis between both techniques. Multiple infections were present in 85% of ≤CIN1 cases compared to only 41% in CIN3+ cases (p

En un contexto de inusitados cambios en las dinámicas migratorias en México, la frontera sur se ha convertido en un espacio de encuentros y desencuentros, de tensiones, pero también de muestras de solidaridad entre la población local y la extranjera proveniente de regiones como África, Asia, el Caribe, Sudamérica y, por supuesto, Centroamérica. A partir de contextualizar el origen del que huye la población desplazada, enfatizamos en las experiencias de vida que se desprenden de habitar temporalmente en una ciudad fronteriza como Tapachula, que históricamente ha tenido una dinámica de flujos laborales con la región centroamericana. Reflexionamos en torno a los impactos que ha tenido la pandemia en el control de la movilidad de las personas, generando una condición de inmovilidad que arrastra consigo una persistente vulnerabilidad, y con ello, el fortalecimiento de enfoques para la gestión migratoria altamente restrictivos, ahora justificados por motivos sanitarios.

The last few years have been crucial in defining the most appropriate way to quantitatively assess [Whole body [Quantitative analysis for PET+/PET- differentiating demonstrated to be significant for most of the variables assessed with Mann-Whitney U-test such as Variance, Energy, and Entropy (p-value = 0.001). Moreover, the quantitative analysis with a balanced database evaluated by Mann-Whitney U-test revealed in even better results with 19 features with p-values0.001. On the other hand, radiomics analysis for MFC+/MFC- differentiating demonstrated the necessity of combining MFC evaluation with [A proof-of-concept for the extraction and evaluation of bone marrow radiomics features of [

BACKGROUND AND AIMS Telemonitoring (RM), applied in automated peritoneal dialysis (APD), has shown both clinical and quality of life (QoL) benefits, although current evidence is limited. The aim of this study is to analyse the number of significant interventions in a 3-month period (unscheduled consultations and teleconsultations, ) as well as clinical consequences (hospitalizations) and QoL, measured by the EuroQol-5D questionnaire in cohort of RMAPD patients. METHOD Retrospective multicenter exploratory cohort study analysed three cohorts of patients in RMAPD: incident (3 months in technique) versus prevalent with 6 months to 1 year in technique versus prevalent with more than 1 year in technique. Both the baseline characteristics of the patients and the number of significant interventions in a 3-month period were analysed: (unscheduled consultations and teleconsultations,) as well as clinical consequences (hospitalizations) and QoL, measured by the EuroQol-5D questionnaire. The variables have been expressed as mean and standard deviation, as well as an ANOVA test to make comparisons between variables, as well as non-parametric for non-normal variables. RESULTS Analysis of 100 patients in RMAPD from 10 different Spanish centers, classified as: incident (group 0), prevalent 6 months to 1 year (group 1), prevalent >1 year (group 2), the variables analysed are presented in the form of table (Fig. 1): From the results analysed, no significant differences were found between the variables analysed, except in the number of unscheduled teleconsultations, significantly higher in group 0 compared to group 2 (P Interestingly, the patients manifested a good perceived QoL in all groups (M: 0.88, EUROQol-5D). CONCLUSION Despite the limitations of this study, the results allow us to consider telemonitoring as a useful technique in patients in APD since

BACKGROUND AND AIMS The use of remote monitoring programs in peritoneal dialysis (RMAPD) has been related to favorable clinical events, as well as possible reductions in healthcare costs, although the medical literature is scarce. METHOD Prospective, multicenter, longitudinal 2-year study of cohorts to evaluate the number of significant interventions: face-to-face consultations and unscheduled teleconsultations, number of kilometers (km) saved, as well as clinical consequences (hospitalizations, peritonitis) in a cohort of patients in automated peritoneal dialysis with and without exposure to RMAPD. The data are presented in terms of mean, standard deviation and percentage. RESULTS The results of the first 3 months of analysis are shown, in descriptive terms, of incident patients in RMAPD versus No RMAPD, corresponding to 10 Spanish centers participating in the study. The data are shown in the Tables 1 and 2. CONCLUSION In this first quarterly exploratory analysis, despite its limitations, it is evident: Although these results are promising, they still need to be confirmed during the follow-up of the patients over time and checked whether they are also related to other clinical and therapy parameters: time in therapy, technique abandonment rate, dialysis dose, peritonitis rate, hospitalizations and quality of life of the patient.

Congenital heart disease is the most common congenital abnormality, present in an estimated 8 cases per 1000 live births. This prevalence varies significantly among continents, being higher in Asia with 9.3 per 1000 births (95% confidence interval (CI): 8.9–9.7) compared to Europe with 8.2 per 1000 births (95% CI: 8.1–8.3) or North America with 6.9 per 1000 births (95% CI: 6.7–7.1). Whereas some defects are trivial, for example a septal defect that spontaneously closes during childhood, about 0.6 per 1000 adults will have a severe form of congenital heart disease.

Aim To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. Methods Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was ≥150 mg/dL (≥1.7 mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. Results The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2 mg/dL in global population, 135.7 and 116.0 mg/dL in men, and 108.6 and 95.7 mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity. (OR: 1.9). Conclusions The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity.

Resumen Objetivo Determinar en la poblacion adulta las tasas de prevalencia brutas y ajustadas por edad y sexo de hipertrigliceridemia (HTG) y valorar su asociacion con factores de riesgo cardiovascular, enfermedad renal cronica y enfermedades cardiovasculares y cardiometabolicas. Metodos Estudio observacional transversal realizado en Atencion Primaria, con 6.588 sujetos de estudio adultos, seleccionados aleatoriamente con base poblacional. Los pacientes tenian HTG si la concentracion de trigliceridos era ≥ 150 mg/dL (≥ 1,7 mmol/L) o estaban en tratamiento hipolipidemiante para reducir los trigliceridos. Se valoraron las asociaciones mediante analisis univariado y multivariante, y se determinaron las prevalencias brutas y ajustadas por edad y sexo. Resultados Las medias aritmeticas y geometricas de las concentraciones de trigliceridos fueron respectivamente 120,5 y 104,2 mg/dL en la poblacion global, 135,7 y 116,0 mg/dL en hombres, y 108,6 y 95,7 mg/dL en mujeres. Las prevalencias brutas de HTG fueron 29,6% en poblacion global, 36,9% en hombres y 23,8% en mujeres. Las prevalencias ajustadas por edad y sexo de HTG fueron 27,0% en poblacion global, 34,6% en hombres y 21,4% en mujeres. Las variables independientes que mas se asociaban con la HTG fueron hipercolesterolemia (OR: 4,6), c-HDL bajo (OR: 4,1), esteatosis hepatica (OR: 2,8), diabetes (OR: 2,0) y obesidad (OR: 1,9). Conclusiones Las medias de trigliceridos y las prevalencias de HTG se encuentran intermedias entre las de otros estudios nacionales e internacionales. La quinta parte de la poblacion adulta femenina y mas de un tercio de la masculina presentaba HTG. Los factores independientes asociados con HTG fueron hipercolesterolemia y c-HDL bajo, y las variables cardiometabolicas diabetes, esteatosis hepatica y obesidad.

BackgroundPatients with Fontan circulation are known to be at high risk for developing atrial tachyarrhythmias (AAs). Our objective was to examine the efficacy and safety of amiodarone in the management of ATs in adult Fontan patients.MethodsPrimary outcomes of this single-centre, retrospective study included freedom from AAs and incidence of adverse effects of amiodarone on Fontan patients. Heart failure (HF) events and composite outcomes of death from any cause, Fontan revision and heart transplantation were evaluated as secondary outcomes. Predictors of HF and discontinuing amiodarone were also evaluated.ResultsA total of 61 patients (mean age 31.6±11.3 years, 40.9% female), who were treated with amiodarone in between 1995 and 2018, were included. AAs free survival at 1, 3 and 5 years were 76.2%, 56.9% and 30.6%, respectively. During a median follow-up of 50.5 months, 34 (55.7%) patients developed side effects, and 20 (32.8%) patients discontinued amiodarone due to side effects. Thyroid dysfunction was the most common side effect (n=26, 76.5%), amiodarone-induced thyrotoxicosis (AIT) (n=16, 27.1%) being most common thyroid dysfunction. Young age (age ConclusionsShort-term efficacy of amiodarone in Fontan physiology is acceptable. However, long-term administration is associated with a reduction of efficacy and a significant prevalence of non-cardiac side effects. AIT is associated with exacerbation of HF. The judicious use of amiodarone administration should be considered in this population.

Objective: The objective of this work was to evaluate the in vitro release performance of metformin hydrochloride formulations (500-mg tablets) using the hydrodynamic environment of the flow-through cell method. Results were compared with those generated by the official dissolution test (USP basket apparatus). Methods: The reference drug product and three generic formulations were tested with phosphate buffer pH 6.8 as dissolution medium. Dissolution profiles were carried out with an automated flow-through cell apparatus using laminar flow at 16 ml/min. Drug was quantified at 233 nm during 45 min. Dissolution profiles were compared with the calculation of f2 similarity factor, mean dissolution time, dissolution efficiency, t50% and t63.2%. Dissolution data were adjusted to several mathematical models such as Makoid-Banakar, Peppas-Sahlin, Weibull and Logistic. Results: With the flow-through cell method and at 45 min less than 60% of metformin hydrochloride dissolved was found, while with the USP basket apparatus, less than 75% of the drug was found. Some generic formulations showed f2>50 with both USP apparatuses, but statistical comparisons of parameters indicated significant differences between their dissolution profiles and reference. Due to variability obtained no dissolution profiles were compared by model-dependent approach. Conclusion: To demonstrate safe interchangeability between metformin hydrochloride generic formulations and reference bioequivalence studies should be performed. It is important post-marketing monitoring of the commercial formulations because health regulatory agencies of each country must ensure drug products with quality, safety, and efficacy at the lowest possible cost.

ObjectivesAlthough a life-preserving surgery for children with single ventricle physiology, the Fontan palliation is associated with striking morbidity and mortality with advancing age. Our primary objective was to evaluate the impact of non-invasive, external, thoraco-abdominal ventilation on pulmonary blood flow (PBF) and cardiac output (CO) as measured by cardiovascular magnetic resonance (CMR) imaging in adult Fontan subjects.MethodsAdults with a dominant left ventricle post-Fontan palliation (lateral tunnel or extracardiac connections) and healthy controls matched by sex and age were studied. We evaluated vascular flows using phase-contrast CMR imaging during unassisted breathing, negative pressure ventilation (NPV) and biphasic ventilation (BPV). Measurements were made within target vessels (aorta, pulmonary arteries, vena cavae and Fontan circuit) at baseline and during each ventilation mode.ResultsTen Fontan subjects (50% male, 24.5 years (IQR 20.8–34.0)) and 10 matched controls were studied. Changes in PBF and CO, respectively, were greater following BPV as compared with NPV. In subjects during NPV, PBF increased by 8% (Δ0.20 L/min/m2 (0.10–0.53), p=0.011) while CO did not change significantly (Δ0.17 L/min/m2 (−0.11–0.23), p=0.432); during BPV, PBF increased by 25% (Δ0.61 L/min/m2 (0.20–0.84), p=0.002) and CO increased by 16% (Δ0.47 L/min/m2 (0.21–0.71), p=0.010). Following BPV, change in PBF and CO were both significantly higher in subjects versus controls (0.61 L/min/m2 (0.2–0.84) vs −0.27 L/min/m2 (−0.55–0.13), p=0.001; and 0.47 L/min/m2 (0.21–0.71) vs 0.07 L/min/m2 (−0.47–0.33), p=0.034, respectively).ConclusionExternal ventilation acutely augments PBF and CO in adult Fontan subjects. Confirmation of these findings in larger populations with longer duration of ventilation and extended follow-up will be required to determine sustainability of haemodynamic effects.

En la última década hemos sido testigos de hechos inéditos en torno al desplazamiento forzado de personas en varias latitudes del mundo, muchas de las cuales tendrían que acceder a mecanismos de protección en los países a los que llegan. No obstante la existencia de tratados y acuerdos internacionales orientados a preservar la vida de las personas, garantizar su acceso a derechos, así como su inserción e integración en las localidades de acogida, lo que hemos visto es un repliegue en las políticas y acciones que toman los Estados frente a la llegada de personas que buscan protección.

Background: The replacement of the arterio-venous fistula with PTFE prostheses or central tunneled catheters is increasing due to the early exhaustion of autologous native accesses. The percentage of patients with tunneled catheters as vascular access for hemodialysis reaches between 15 to 25%, therefore, it is essential to improve the techniques used to avoid early and late complications, and to look for other possibilities due to early venous exhaustion. The use of tunneled femoral catheters is increasingly frequent due to the impossibility of using accesses of the superior venous axis. In this work we study and analyze the evolution and complications of tunneled catheters, both jugular and femoral, placed in the period from January 1, 2017 to May 30, 2018 in the Interventional Nephrology Unit, Nephrology Department of the Clinical Hospital of Santiago de Compostela. We also compared the evolution of femoral tunneled catheters with tunneled jugular catheters.

Background Pulmonary arterial hypertension (PAH), is a rare and progressive disease with a high morbidity and mortality. Prostanoid pulmonary vasodilators are the most effective treatment for idiopathic and connective tissue associated PAH. Nonetheless, data examining their safety and efficacy in patients with Eisenmenger syndrome the most severe form of PAH, that is, related to cyanotic congenital heart disease (CHD-PAH) remains limited. Aim To evaluate safety and the clinical efficacy of nebulised iloprost in patients with Eisenmenger syndrome who are on maximum background oral PAH therapy. Methods This pilot study was a randomised, double-blind, placebo-controlled, cross-over study. Patients were randomised to receive nebulised placebo or iloprost for 12 weeks and were then crossed over, with a 7–14-day washout. The primary endpoint was a change in 6-minute walk distance (6MWD). Results Sixteen patients (11 females, aged 47.3 ± 9.8 year) were recruited, twelve completed the study. All were in WHO-FC III, with a resting oxygen saturation of 84 [81–87] % and a median 6MWD of 290 [260–300] m. There was no significant difference in the primary endpoint between nebulised iloprost (0[−4–9]m) and placebo (10 [−15–51]m), p = 0.58. There were no safety concerns with nebulised iloprost. Conclusions Our pilot study provides preliminary evidence that the addition of nebulised iloprost to maximum oral PAH therapy did not improve the primary endpoint of 6MWD. Nebulised iloprost was well tolerated with no significant safety concerns in CHD-PAH.

Background Coronary fistula are rare and often present in early adulthood with symptoms of right heart overload from left to right shunting or ischaemia in the distal coronary bed due to coronary steal. Case summary A 73-year-old lady with prior history of supraventricular tachycardia, dyslipidemia and a right coronary artery (RCA) to coronary sinus (CS) fistula, presented with progressive angina. She did not have evidence of ischaemia in the RCA territory on nuclear imaging, and cardiac computed tomography (CT) did not show coronary artery disease but revealed a significantly dilated CS and coronary venous tree. She was found to have CS ostial stenosis and, under transesophageal echocardiographic guidance, underwent successful balloon angioplasty of the CS ostium, with decompression of the coronary venous circulation and resolution of her angina. Discussion Coronary fistula draining to the CS are rare, and association with CS ostial stenosis has been reported very infrequently. CS ostial stenosis can cause elevated coronary venous pressure, leading to decreased global coronary perfusion and symptoms of angina or heart failure. Previous case reports of coronary fistula and CS ostial stenosis were treated with either medical therapy or surgery, and our case is the first to our knowledge to report successful percutaneous treatment.