Molecular mechanisms controlling age-associated B cells in autoimmunity.

Age-associated B cells (ABCs) have emerged as critical components of immune responses. Their inappropriate expansion and differentiation have increasingly been linked to the pathogenesis of autoimmune disorders, aging-associated diseases, and infections. ABCs exhibit a distinctive phenotype and, in addition to classical B cell markers, often express the transcription factor T-bet and myeloid markers like CD11c; hence, these cells are also commonly known as CD11c+ T-bet+ B cells. Formation of ABCs is promoted by distinctive combinations of innate and adaptive signals. In addition to producing antibodies, these cells display antigen-presenting and proinflammatory capabilities. It is becoming increasingly appreciated that the ABC compartment exhibits a high degree of heterogeneity, plasticity, and sex-specific regulation and that ABCs can differentiate into effector progeny via several routes particularly in autoimmune settings. In this review, we will discuss the initial insights that have been obtained on the molecular machinery that controls ABCs and we will highlight some of the unique aspects of this control system that may enable ABCs to fulfill their distinctive role in immune responses. Given the expanding array of autoimmune disorders and pathophysiological settings in which ABCs are being implicated, a deeper understanding of this machinery could have important and broad therapeutic implications for the successful, albeit daunting, task of targeting these cells.

The academic point-of-care anti-CD19 chimeric antigen receptor T-cell product varnimcabtagene autoleucel (ARI-0001 cells) shows efficacy and safety in the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma.

Varnimcabtagene autoleucel (var-cel) is an academic anti-CD19 chimeric antigen receptor (CAR) product used for the treatment of non-Hodgkin lymphoma (NHL) in the CART19-BE-01 trial. Here we report updated outcomes of patients with NHL treated with var-cel. B-cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty-five patients with NHL were treated. Cytokine release syndrome (any grade) occurred in 84% of patients (4% grade ≥3) and neurotoxicity in 7% (2% grade ≥3). The objective response rate was 73% at Day +100, and the 3-year duration of response was 56%. The 3-year progression-free and overall survival were 40% and 52% respectively. High lactate dehydrogenase was the only covariate with an impact on progression-free survival. The 3-year incidence of B-cell recovery was lower in patients with NHL compared to ALL (25% vs. 60%). In conclusion, in patients with NHL, the toxicity of var-cel was manageable, while B-cell recovery was significantly prolonged compared to ALL. This trial was registered as NCT03144583.

Stochastic processes and changes in evolutionary rate are associated with diversification in a lineage of tropical hard pines (Pinus).

The study of the patterns of polymorphism and molecular evolution among closely related species is key to understanding the evolutionary forces involved in the diversification of lineages. This point is a big challenge in species with slow evolutionary rates, long life cycles, and ancient, shared polymorphisms such as conifers. Under the premise of divergence in a stepwise migration process, we expect clinal geographical patterns of purifying selection efficiency, and genetic structure related to latitude or longitude. If migration is accompanied by changes in the environment, we could further expect a role of positive selection in driving species divergence. Here, we infer patterns of polymorphism, efficiency of purifying selection, and molecular evolution using a dataset of 161 nuclear genes (∼71 Kb) in a lineage of hard pines from North America, the Caribbean, Mexico, and Central America presumed to have migrated from North America toward lower latitudes with tropical conditions. Under the premise of differences in selective pressures, we also look for possible signals of positive selection. To test our hypothesis, first we estimated different indices to infer patterns of polymorphism and efficiency of purifying selection (Ka, Ks, Ka/Ks, dN, dS, dN/dS, and dxy) and compared these metrics across five clades. Also, we investigated possible clinal patterns in these indices and morphological traits (needle length and cone length). Then we inferred genetic structure and environmental differences among species to test for possible signals of positive selection using phylogenetic methods in specific clades. We found differences among clades using Ka, Ks, and Ka/Ks with a relaxation of purifying selection, especially in the Elliotti and Patula clades. We also found environmental differences related to geographic distance, and among clades suggesting differences in selective pressures. The indices Ks, dxy, and needle length had relationships with geography but not ovulate cone length. Finally, we found that most analyzed genes are under purifying selection, but there was an exception of faster evolutionary rate in some pine species, suggesting the possible action of positive selection in divergence. Our study indicated that stochastic processes have played a key role in the diversification of the group, with a possible input of positive selection in pines from Mexico and Central America.

A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

Modular Synthesis of PEG-Dendritic Block Copolymers by Thermal Azide-Alkyne Cycloaddition with Internal Alkynes and Evaluation of their Self-Assembly for Drug Delivery Applications.

Linear-dendritic block copolymers assemble in solution due to differences in the solubility or charge properties of the blocks. The monodispersity and multivalency of the dendritic block provide unparalleled control for the design of drug delivery systems when incorporating poly(ethylene glycol) (PEG) as a linear block. An accelerated synthesis of PEG-dendritic block copolymers based on the click and green chemistry pillars is described. The tandem composed of the thermal azide-alkyne cycloaddition with internal alkynes and azide substitution is revealed as a flexible, reliable, atom-economical, and user-friendly strategy for the synthesis and functionalization of biodegradable (polyester) PEG-dendritic block copolymers. The high orthogonality of the sequence has been exploited for the preparation of heterolayered copolymers with terminal alkenes and alkynes, which are amenable for subsequent functionalization by thiol-ene and thiol-yne click reactions. Copolymers with tunable solubility and charge were so obtained for the preparation of various types of nanoassemblies with promising applications in drug delivery.

Foliar mycobiome remains unaltered under urban air-pollution but differentially express stress-related genes.

Air pollution caused by tropospheric ozone contributes to the decline of forest ecosystems; for instance, sacred fir, Abies religiosa (Kunth) Schltdl. & Cham. forests in the peri-urban region of Mexico City. Individual trees within these forests exhibit variation in their response to ozone exposure, including the severity of visible symptoms in needles. Using RNA-Seq metatranscriptomic data and ITS2 metabarcoding, we investigated whether symptom variation correlates with the taxonomic and functional composition of fungal mycobiomes from needles collected in this highly polluted area in the surroundings of Mexico City. Our findings indicate that ozone-related symptoms do not significantly correlate with changes in the taxonomic composition of fungal mycobiomes. However, genes coding for 30 putative proteins were differentially expressed in the mycobiome of asymptomatic needles, including eight genes previously associated with resistance to oxidative stress. These results suggest that fungal communities likely play a role in mitigating the oxidative burst caused by tropospheric ozone in sacred fir. Our study illustrates the feasibility of using RNA-Seq data, accessible from global sequence repositories, for the characterization of fungal communities associated with plant tissues, including their gene expression.

Whoever wants better healthcare simply pays more: citizens' perception about voluntary private health insurance in Colombia.

OBJECTIVES: To explore the perceptions that Colombians have about voluntary private health insurance plans (VPHI) in the health system to identify the tensions that exist between the public and private systems. METHODS: A qualitative case study approach with 46 semi structured interviews of patients, healthcare workers, healthcare administrators, decision-makers, and citizens. Interviews were recorded, transcribed, anonymized, digitally stored, and analyzed following grounded theory guidelines. RESULTS: We developed a paradigmatic matrix that explores how, in a context mediated by both the commodification of health and social stratification, perceptions about the failures in the public health system related to lack of timely care, extensive administrative procedures, and the search for privileged care led to positioning VPHI as a solution to these failures. The interviewees identified three consequences of using VPHI: first, the worsening of problems of timely access to care in the public system; second, higher costs for citizens translated into double payment for technologies and services to which they are entitled; third, the widening of inequity gaps in access to health services between people with similar needs but different payment capacities. CONCLUSIONS: These findings can help decision makers to understand citizens´ perceptions about the implications that VPHI may have in worsening equity gaps in the Colombian health system. It also shows, how VPHI is perceived as a double payment for services covered within social security plans and suggests that the perceived lack of timely access to care in the public systems and the fear that citizens have for themselves or their family members when using suboptimal healthcare are important drivers to purchase these private insurances.

RESUMEN: OBJETIVOS: Explorar las percepciones que tienen los colombianos sobre los planes de seguro de salud privados voluntarios (VPHI) en el sistema de salud para identificar las tensiones que existen entre los sistemas público y privado. MéTODOS: Un estudio cualitativo de caso con 46 entrevistas semiestructuradas a pacientes, trabajadores de la salud, administradores de salud, tomadores de decisiones y ciudadanos. Las entrevistas se grabaron, transcribieron y almacenaron de manera anónima. El análisis se hizo siguiendo conceptos de la teoría fundamentada. RESULTADOS: Desarrollamos una matriz paradigmática que explora cómo, en un contexto mediado tanto por la mercantilización de la salud como por la estratificación social, las percepciones sobre las fallas en el sistema de salud público relacionadas con la falta de atención oportuna, procedimientos administrativos extensos y la búsqueda de atención privilegiada llevaron a posicionar los VPHI como una solución a estas fallas. Los entrevistados identificaron tres consecuencias del uso de los VPHI: primero, el empeoramiento de los problemas de acceso oportuno a la atención en el sistema público; segundo, mayores costos para los ciudadanos, traducidos en un pago doble por tecnologías y servicios a los que tienen derecho; tercero, el aumento de las brechas de equidad en el acceso a los servicios de salud entre personas con necesidades similares pero diferentes capacidades de pago. CONCLUSIONES: Estos hallazgos pueden ayudar a los tomadores de decisiones a comprender las percepciones de los ciudadanos sobre las implicaciones que el VPHI puede tener en el empeoramiento de las brechas de equidad en el sistema de salud colombiano. También muestra cómo el VPHI se percibe como un pago doble por servicios cubiertos dentro de los planes de seguridad social y sugiere que la falta percibida de acceso oportuno a la atención en los sistemas públicos y el miedo que los ciudadanos tienen por sí mismos o por sus familiares cuando utilizan una atención sanitaria subóptima son factores importantes para adquirir estos seguros privados.

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia.

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

Current outcomes of SARS-CoV-2 Omicron variant infection in high-risk haematological patients treated early with antivirals.

OBJECTIVES: We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals. METHODS: We conducted a prospective observational study on high-risk haematological patients admitted in our hospital between December 2021 and March 2022. We performed detection techniques on viral subgenomic mRNAs until negative results were obtained to document active, prolonged viral replication. RESULTS: This analysis included 60 consecutive adults with high-risk haematological malignancies and COVID-19. All of these patients underwent early treatment with remdesivir. Thirty-two (53%) patients received combined antiviral strategies, with sotrovimab or hyperimmune plasma being added to remdesivir. The median length of viral replication-as measured by real-time RT-PCR and/or subgenomic RNA detection-was 20 (IQR 14-28) days. Prolonged viral replication (6 weeks after diagnosis) was documented in six (10%) patients. Only two patients had prolonged infection for more than 2 months. Overall mortality was 5%, whereas COVID-19-related mortality was 0%. CONCLUSIONS: Current outcomes of high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predminance are good with the use of early antiviral strategies. Persistent viral shedding is uncommon.

The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

Evaluating pollution-related damage and restoration success in urban forests with participatory monitoring and digital tools.

Peri-urban forest monitoring requires indicators of vegetation damage. An example is the sacred fir (Abies religiosa) forests surrounding Mexico City, which have been heavily exposed to tropospheric ozone, a harmful pollutant, for over 4 decades. We developed a participatory monitoring system with which local community members and scientists generated data on ozone tree damage. Santa Rosa Xochiac rangers (13) used the digital tool KoboToolBox to record ozone damage to trees, tree height, tree ages, tree condition, tree position, and whether the tree had been planted. Thirty-five percent of the trees (n = 1765) had ozone damage. Younger trees had a lower percentage of foliage damaged by ozone than older trees (p < 0.0001), and asymptomatic trees tended to be younger (p < 0.0001). Symptomatic trees were taller than asymptomatic trees of the same age (R2 c  = 0.43, R2 m  = 0.27). Involving local communities facilitated forest monitoring and using digital technology improved data quality. This participatory system can be used to monitor forest condition change over time and thus aids restoration efforts driven by government or local communities' interests, facilitating local decision-making.

Evaluación del daño relacionado a la contaminación y del éxito de la restauración de los bosques urbanos con un monitoreo participativo y herramientas digitales Resumen El monitoreo de los bosques periurbanos requiere indicadores de daños en la vegetación. Un ejemplo son los bosques de abeto (Abies religiosa) que rodean la Ciudad de México, pues desde hace más de 4 décadas han estado expuestos al ozono troposférico, un contaminante nocivo. Desarrollamos un sistema de monitoreo participativo con el que miembros de la comunidad local y científicos generaron datos sobre los daños causados por el ozono en los árboles. Los guardabosques de Santa Rosa Xochiac (133) utilizaron la herramienta digital KoboToolBox para registrar los daños causados por el ozono en los árboles, su altura, edad, estado, posición y si eran árboles plantados. El 35% de los árboles (n = 1,765) presentó daños por ozono. Los árboles más jóvenes tenían un menor porcentaje de follaje dañado por el ozono que los árboles más viejos (p<0.0001), y los árboles asintomáticos tendían a ser más jóvenes (p<0.0001). Los árboles sintomáticos eran más altos que los asintomáticos de la misma edad (R2 c = 0.43, R2 m = 0.27). La participación de las comunidades locales facilitó el monitoreo forestal y el uso de tecnología digital mejoró la calidad de los datos. Este sistema participativo puede utilizarse para monitorear los cambios en el estado de los bosques a lo largo del tiempo y contribuir a los esfuerzos de restauración impulsados por el gobierno o las comunidades locales, facilitando la toma de decisiones a nivel local.

[Validation of a new strategy for the identification of SARS-CoV-2 variants by sequencing the spike gene by Sanger]. / Validación de una nueva estrategia para la identificación de variantes de SARS-CoV-2 mediante secuenciación del gen espiga por Sanger.

Introduction: The emergence of multiple variants of SARS-CoV-2 during the COVID-19 pandemic is of great world concern. Until now, their analysis has mainly focused on next-generation sequencing. However, this technique is expensive and requires sophisticated equipment, long processing times, and highly qualified technical personnel with experience in bioinformatics. To contribute to the analysis of variants of interest and variants of concern, increase the diagnostic capacity, and process samples to carry out genomic surveillance, we propose a quick and easy methodology to apply, based on Sanger sequencing of 3 gene fragments that code for protein spike. Methods: Fifteen positive samples for SARS-CoV-2 with a cycle threshold below 25 were sequenced by Sanger and next-generation sequencing methodologies. The data obtained were analyzed on the Nextstrain and PANGO Lineages platforms. Results: Both methodologies allowed the identification of the variants of interest reported by the WHO. Two samples were identified as Alpha, 3 Gamma, one Delta, 3 Mu, one Omicron, and 5 strains were close to the initial Wuhan-Hu-1 virus isolate. According to in silico analysis, key mutations can also be detected to identify and classify other variants not evaluated in the study. Conclusion: The different SARS-CoV-2 lineages of interest and concern are classified quickly, agilely, and reliably with the Sanger sequencing methodology.

Novel Speech Recognition Systems Applied to Forensics within Child Exploitation: Wav2vec2.0 vs. Whisper.

The growth in online child exploitation material is a significant challenge for European Law Enforcement Agencies (LEAs). One of the most important sources of such online information corresponds to audio material that needs to be analyzed to find evidence in a timely and practical manner. That is why LEAs require a next-generation AI-powered platform to process audio data from online sources. We propose the use of speech recognition and keyword spotting to transcribe audiovisual data and to detect the presence of keywords related to child abuse. The considered models are based on two of the most accurate neural-based architectures to date: Wav2vec2.0 and Whisper. The systems were tested under an extensive set of scenarios in different languages. Additionally, keeping in mind that obtaining data from LEAs are very sensitive, we explore the use of federated learning to provide more robust systems for the addressed application, while maintaining the privacy of the data from LEAs. The considered models achieved a word error rate between 11% and 25%, depending on the language. In addition, the systems are able to recognize a set of spotted words with true-positive rates between 82% and 98%, depending on the language. Finally, federated learning strategies show that they can maintain and even improve the performance of the systems when compared to centralized trained models. The proposed systems set the basis for an AI-powered platform for automatic analysis of audio in the context of forensic applications of child abuse. The use of federated learning is also promising for the addressed scenario, where data privacy is an important issue to be managed.

Filtering the NMR Spectra of Mixtures by Coordination to Paramagnetic Cu2.

The paramagnetic spin relaxation (PSR) filter allows the selective NMR signal suppression of components in mixtures according to their complexation ability to a paramagnetic ion. It relies on the faster relaxation of nuclei in paramagnetic environments and thus is complementary to classical diffusion and relaxation filters. So far, the PSR filter has established Gd3+ as the sole PSR agent, restricting the paramagnetic filtering repertoire. Herein, we present Cu2+ as a robust PSR agent with characteristic filtering properties. While Gd3+ depends on unspecific ion-pair interactions with anionic components, Cu2+ stands out for filtering species via ordered coordination complexes. An evaluation of the paramagnetic effect of Cu2+ over more than 50 small molecules and polymers has unveiled different sensitivities to Cu2+ (especially high for pyridines, diamines, polyamines, and amino alcohols) and precise filtering conditions for mixtures (1H, COSY, and HMQC) that were challenged with a test bed of commercial drugs. The advantage of integrating Cu2+ and Gd3+ for the stepwise PSR filtering of complex mixtures is also shown.

Demographic modelling helps track the rapid and recent divergence of a conifer species pair from Central Mexico.

Secondary contact of recently diverged species may have several outcomes, ranging from rampant hybridization to reinforced reproductive isolation. In plants, selfing tolerance and disjunct reproductive phenology may lead to reproductive isolation at contact zones. However, they may also evolve under both allopatric or parapatric frameworks and originate from adaptive and/or neutral forces. Inferring the historical demography of diverging taxa is thus a crucial step to identify factors that may have led to putative reproductive isolation. We explored various competing demographypotheses to account for the rapid divergence of a fir species complex (Abies flinckii-A. religiosa) distributed in "sky-islands" across central Mexico (i.e., along the Trans-Mexican Volcanic Belt; TMVB). Despite co-occurring in two independent sympatric regions (west and centre), these taxa rarely interbreed because of disjunct reproductive phenologies. We genotyped 1147 single nucleotide polymorphisms, generated by GBS (genotyping by sequencing), across 23 populations, and compared multiple scenarios based on the geological history of the TMVB. The best-fitting model revealed one of the most rapid and complete speciation cases for a conifer species-pair, dating back to ~1.2 million years ago. Coupled with the lack of support for stepwise colonization, our coalescent inferences point to an early cessation of interspecific gene flow under parapatric speciation; ancestral gene flow during divergence was asymmetrical (mostly from western firs into A. religiosa) and exclusive to the most ancient (i.e., central) contact zone. Factors promoting rapid reproductive isolation should be explored in other slowly evolving species complexes as they may account for the large tropical and subtropical diversity.

Polygenic adaptation and negative selection across traits, years and environments in a long-lived plant species (Pinus pinaster Ait., Pinaceae).

A decade of genetic association studies in multiple organisms suggests that most complex traits are polygenic; that is, they have a genetic architecture determined by numerous loci, each with small effect-size. Thus, determining the degree of polygenicity and its variation across traits, environments and time is crucial to understand the genetic basis of phenotypic variation. We applied multilocus approaches to estimate the degree of polygenicity of fitness-related traits in a long-lived plant (Pinus pinaster Ait., maritime pine) and to analyse this variation across environments and years. We evaluated five categories of fitness-related traits (survival, height, phenology, functional, and biotic-stress response) in a clonal common-garden network planted in contrasted environments (over 20,500 trees). Most of the analysed traits showed evidence of local adaptation based on Qst -Fst comparisons. We further observed a remarkably stable degree of polygenicity, averaging 6% (range of 0%-27%), across traits, environments and years. We detected evidence of negative selection, which could explain, at least partially, the high degree of polygenicity. Because polygenic adaptation can occur rapidly, our results suggest that current predictions on the capacity of natural forest tree populations to adapt to new environments should be revised, especially in the current context of climate change.

First external validation of the FLIPI-L score in a single-center series of patients with follicular lymphoma.

The FLIPI-L has recently been proposed as a novel prognostic index in follicular lymphoma (FL), combining FLIPI and the presence of lymphopenia. In our single-center validation in 381 FL patients, lymphopenia was less frequent than in the original publication and thus the distribution of risk categories was different. Although it was not able to properly predict time to first treatment, FLIPI-L performed slightly better than FLIPI alone in the prediction of response, early relapse, progression-free and overall survival, and histological transformation. This new tool or others encompassing parameters from the microenvironment might improve upon the prognostic ability of classical scores.

Serum soluble CD23 levels are an independent predictor of time to first treatment in chronic lymphocytic leukemia.

Serum soluble CD23 (sCD23) levels have been acknowledged as a prognostic factor in patients with chronic lymphocytic leukemia (CLL), but their potential relevance has not been analyzed in recent times. We retrospectively studied 338 CLL, small lymphocytic lymphoma, or CLL-type monoclonal B-cell lymphocytosis patients from a single institution, with available sCD23 levels at diagnosis. Baseline features and outcomes were compared between patients with sCD23 ≤/>1000 UI/L. The 140 patients (41%) who had sCD23 > 1000 UI/L showed adverse-risk clinical and biological characteristics. High sCD23 levels were predictive of a shorter time to first treatment (5-year probability of requiring treatment: 60 vs. 20%, p < 0.0001; hazard ratio (HR) = 1.72, p = 0.003 in a multivariable model also including the CLL International Prognostic Index and the absolute lymphocyte count), and a poorer 5-year overall survival (70 vs. 82%, p = 0.0009). These data suggest the potential of sCD23 to predict treatment-free survival and to shed light on mechanisms of activity and resistance to CD23-directed therapies.

Results of ARI-0001 CART19 cell therapy in patients with relapsed/refractory CD19-positive acute lymphoblastic leukemia with isolated extramedullary disease.

We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with the CD19-directed CAR T cells ARI-0001 in two centers (adult and pediatric), including patients treated in the CART19-BE-01 trial and the consecutive compassionate use program. iEMD was detected by PET-CT in 78% (14/18), and/or by cerebrospinal fluid analysis in 28% (5/18). Patients received cyclophosphamide and fludarabine followed by 1 × 106 ARI-0001 cells/kg, initially as a single dose (first patient) and later split into three fractions (10%, 30%, and 60%). Cytokine release syndrome (CRS) occurred in 50% (9/18) of patients, with no cases of grade ≥3 CRS, and 1 case (6%) of grade 1 neurotoxicity. Tocilizumab was used in 6% of patients (1/18). Procedure-related mortality was 0% at 2 years. Objective responses were seen in 94% (95% confidence interval [CI]: 73%-99%) of patients, with complete responses (CR) seen in 78% (95% CI: 52%-94%) of them. Progression-free and overall survival were 49% (95% CI: 30%-79%) and 61% (95% CI: 40%-92%) at 2 years. In conclusion, the use of ARI-0001 cells in patients with R/R ALL and iEMD was associated with a safety and efficacy profile that is comparable with what is observed in patients with marrow involvement and in line with other CART19 products.

Seroprevalence, spatial distribution, and social determinants of SARS-CoV-2 in three urban centers of Chile.

BACKGROUND: Seroprevalence studies provide an accurate measure of SARS-CoV-2 spread and the presence of asymptomatic cases. They also provide information on the uneven impact of the pandemic, pointing out vulnerable groups to prioritize which is particularly relevant in unequal societies. However, due to their high cost, they provide limited evidence of spatial spread of the pandemic specially in unequal societies. Our objective was to estimate the prevalence of SARS-CoV-2 antibodies in Chile and model its spatial risk distribution. METHODS: During Oct-Nov 2020, we conducted a population-based serosurvey in Santiago, Talca, and Coquimbo-La Serena (2493 individuals). We explored the individual association between positive results and socio-economic and health-related variables by logistic regression for complex surveys. Then, using an Empirical Bayesian Kriging model, we estimated the infection risk spatial distribution using individual and census information, and compared these results with official records. RESULTS: Seroprevalence was 10.4% (95% CI 7.8-13.7%), ranging from 2% (Talca) to 11% (Santiago), almost three times the number officially reported. Approximately 36% of these were asymptomatic, reaching 82% below 15 years old. Seroprevalence was associated with the city of residence, previous COVID-19 diagnosis, contact with confirmed cases (especially at household), and foreign nationality. The spatial model accurately interpolated the distribution of disease risk within the cities finding significant differences in the predicted probabilities of SARS-CoV-2 infection by census zone (IQR 2.5-15.0%), related to population density and education. CONCLUSIONS: Our results underscore the transmission heterogeneity of SARS-CoV-2 within and across three urban centers of Chile. Socio-economic factors and the outcomes of this seroprevalence study enable us to identify priority areas for intervention. Our methodological approach and results can help guide the design of interdisciplinary strategies for urban contexts, not only for SARS-CoV-2 but also for other communicable diseases.