Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial.

BACKGROUND: Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment. METHODS: This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete. FINDINGS: Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. INTERPRETATION: These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients. FUNDING: AbbVie.

Cognitive telerehabilitation: an expert consensus paper on current evidence and future perspective.

The progressive improvement of the living conditions and medical care of the population in industrialized countries has led to improvement in healthcare interventions, including rehabilitation. From this perspective, Telerehabilitation (TR) plays an important role. TR consists of the application of telemedicine to rehabilitation to offer remote rehabilitation services to the population unable to reach healthcare. TR integrates therapy-recovery-assistance, with continuity of treatments, aimed at neurological and psychological recovery, involving the patient in a family environment, with an active role also of the caregivers. This leads to reduced healthcare costs and improves the continuity of specialist care, as well as showing efficacy for the treatment of cognitive disorders, and leading to advantages for patients and their families, such as avoiding travel, reducing associated costs, improving the frequency, continuity, and comfort of performing the rehabilitation in its own spaces, times and arrangements. The aim of this consensus paper is to investigate the current evidence on the use and effectiveness of TR in the cognitive field, trying to also suggest some recommendations and future perspectives. To the best of our knowledge, this is the first consensus paper among multiple expert researchers that comprehensively examines TR in different neurological diseases. Our results supported the efficacy and feasibility of TR with good adherence and no adverse events among patients. Our consensus summarizes the current evidence for the application of cognitive TR in neurological populations, highlighting the potential of this tool, but also the limitations that need to be explored further.

The Effect of Viscous Drag on the Maximum Residual Stresses Achievable in High-Yield-Strength Materials in Laser Shock Processing.

In this paper, the experimentally observed significant increase in yield stress for strain rates beyond 104 s-1 (viscous regime) is explicitly considered in laser shock processing (LSP) simulations. First, a detailed review of the most common high-strain-rate deformation models is presented, highlighting the expected strain rates in materials subject to LSP for a wide range of treatment conditions. Second, the abrupt yield stress increase presented beyond 104 s-1 is explicitly considered in the material model of a titanium alloy subject to LSP. A combined numerical-analytical approach is used to predict the time evolution of the plastic strain. Finally, extended areas are irradiated covering a squared area of 25 × 25 mm2 for numerical-experimental validation. The in-depth experimental residual stress profiles are obtained by means of the hole drilling method. Near-surface-temperature gradients are explicitly considered in simulations. In summary, the conventionally accepted strain rate range in LSP (106-107 s-1) is challenged in this paper. Results show that the conventional high-strain-rate hardening models widely used in LSP simulations (i.e., Johnson Cook model) clearly overestimate the induced compressive residual stresses. Additionally, pressure decay, whose importance is usually neglected, has been found to play a significant role in the total plastic strain achieved by LSP treatments.

Collaborative cytometric inter-laboratory ring test for probiotics quantification.

Introduction: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. From this definition, accurate enumeration of probiotic products is a necessity. Nonetheless, this definition does not specify the methods for assessing such viability. Colony forming units is the de facto gold standard for enumerating viable in probiotic products. The notion of microbial viability has been anchored in the concept of cultivability, which refers to a cell's capacity to replicate and form colonies on agar media. However, there is a growing consensus that the term "viability" should not be exclusively tied to the ability to cultivate cells. For example, bacterial cells can exist in a Viable But Non-Culturable (VBNC) state, characterized by the maintenance of characteristics such as membrane integrity, enzymatic activity, pH gradients, and elevated levels of rRNA, despite losing the ability to form colonies. Methods: Herein we present the results of a collaborative inter-laboratory ring test for cytometric bacterial quantification. Specifically, membrane integrity fluorescence flow cytometry (FFC) method and the newer impedance flow cytometry (IFC) method have been used. Both methods interrogate single cells in solution for the presence of intact membranes. FFC exploits fluorochromes that reflect the presence or absence of an intact membrane. IFC probes membrane integrity in a label-free approach by detecting membrane-induced hindrances to the propagation of electricity. Results: A performance ring-test and comparison design on the FFC method showed that the method is robust against the exchange of equipment, procedures, materials, and operators. After initial method optimization with assessments of rehydration medium, wake-up duration, and phase shift gating on the individual strains, the IFC method showed good agreement with the FFC results. Specifically, we tested 6 distinct species of probiotic bacteria (3 Lactobacillus and 3 Bifidobacterium strains) finding good agreement between FFC and IFC results in terms of total and live cells. Discussion: Together, these results demonstrate that flow cytometry is a reliable, precise, and user-friendly culture-independent method for bacterial enumeration.

Circular polarized 3D-printed cylindrical DRA using parasitic dielectric helix.

This article presents a 3D-printed cylindrical dielectric resonator antenna operating at 5.8 GHz that achieves circular polarization by integrating a fully dielectric parasitic helix with a higher permittivity than the cylindrical resonator. The antenna polarization can be right-handed or left-handed depending on the turning sense of the helix. An extensive parametric study was done for the helix design to evaluate the effects of the dimensions and dielectric constant of the helix over the matching and axial ratio of the antenna. The manufacturing is made using low-loss dielectric filaments and a low-cost 3D printer. Simulation and measurement results show that both antennas are well-matched and operate with the corresponding circular polarization, with an axial ratio bandwidth compatible with UAV applications.

Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy.

Despite its often low efficacy and high toxicity, the standard treatment for acute myeloid leukemia (AML) is induction chemotherapy with cytarabine and idarubicin. Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.

Using Impedance Flow Cytometry for Rapid Viability Classification of Heat-Treated Bacteria.

In the future, rapid electrical characterization of cells with impedance flow cytometry promises to be a fast and accurate method for the evaluation of cell properties. In this paper, we investigate how the conductivity of the suspending medium along with the heat exposure time affects the viability classification of heat-treated E. coli. Using a theoretical model, we show that perforation of the bacteria membrane during heat exposure changes the impedance of the bacterial cell from effectively less conducting than the suspension medium to effectively more conducting. Consequently, this results in a shift in the differential argument of the complex electrical current that can be measured with impedance flow cytometry. We observe this shift experimentally through measurements on E. coli samples with varying medium conductivity and heat exposure times. We show that increased exposure time and lower medium conductivity results in improved classification between untreated and heat-treated bacteria. The best classification was achieved with a medium conductivity of 0.045 S/m after 30 min of heat exposure.

Systematic Evaluation of Antigenic Stimulation in Chronic Lymphocytic Leukemia: Humoral Immunity as Biomarkers for Disease Evolution.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Studies of CLL antibody reactivity have shown differential targets to autoantigens and antimicrobial molecular motifs that support the current hypothesis of CLL pathogenesis. METHODS: In this study, we conducted a quantitative serum analysis of 7 immunoglobulins in CLL and monoclonal B-cell lymphocytosis (MBL) patients (bead-suspension protein arrays) and a serological profile (IgG and IgM) study of autoantibodies and antimicrobial antigens (protein microarrays). RESULTS: Significant differences in the IgA levels were observed according to disease progression and evolution as well as significant alterations in IgG1 according to IGHV mutational status. More representative IgG autoantibodies in the cohort were against nonmutagenic proteins and IgM autoantibodies were against vesicle proteins. Antimicrobial IgG and IgM were detected against microbes associated with respiratory tract infections. CONCLUSIONS: Quantitative differences in immunoglobulin serum levels could be potential biomarkers for disease progression. In the top 5 tumoral antigens, we detected autoantibodies (IgM and IgG) against proteins related to cell homeostasis and metabolism in the studied cohort. The top 5 microbial antigens were associated with respiratory and gastrointestinal infections; moreover, the subsets with better prognostics were characterized by a reactivation of Cytomegalovirus. The viral humoral response could be a potential prognosis biomarker for disease progression.

Single-Cell DNA Sequencing and Immunophenotypic Profiling to Track Clonal Evolution in an Acute Myeloid Leukemia Patient.

Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an NPM1-mutated AML patient with an initial low ratio of FLT3-ITD (low-risk ELN-2017), treated with midostaurin combined with standard chemotherapy as front-line treatment, and with salvage therapy plus gilteritinib following allogenic stem cell transplantation after relapse. Simultaneous single-cell DNA sequencing and cell-surface immunophenotyping was used in diagnostic and relapse samples to understand the clinical scenario of this patient and to reconstruct the clonal composition of both tumors. Four independent clones were present before treatment: DNMT3A/DNMT3A/NPM1 (63.9%), DNMT3A/DNMT3A (13.9%), DNMT3A/DNMT3A/NPM1/FLT3 (13.8%), as well as a wild-type clone (8.3%), but only the minor clone with FLT3-ITD survived and expanded after therapy, being the most represented one (58.6%) at relapse. FLT3-ITD was subclonal and was found only in the myeloid blast population (CD38/CD117/CD123). Our study shows the usefulness of this approach to reveal the clonal architecture of the leukemia and the identification of small subclones at diagnosis and relapse that may explain how the neoplastic cells can escape from the activity of different treatments in a stepwise process that impedes the disease cure despite different stages of complete remission.

Regulatory Evolution of the phoH Ancestral Gene in Salmonella enterica Serovar Typhimurium.

One important event for the divergence of Salmonella from Escherichia coli was the acquisition by horizontal transfer of the Salmonella pathogenicity island 1 (SPI-1), containing genes required for the invasion of host cells by Salmonella. HilD is an AraC-like transcriptional regulator in SPI-1 that induces the expression of the SPI-1 and many other acquired virulence genes located in other genomic regions of Salmonella. Additionally, HilD has been shown to positively control the expression of some ancestral genes (also present in E. coli and other bacteria), including phoH. In this study, we determined that both the gain of HilD and cis-regulatory evolution led to the integration of the phoH gene into the HilD regulon. Our results indicate that a HilD-binding sequence was generated in the regulatory region of the S. enterica serovar Typhimurium phoH gene, which mediates the activation of promoter 1 of this gene under SPI-1-inducing conditions. Furthermore, we found that repression by H-NS, a histone-like protein, was also adapted on the S. Typhimurium phoH gene and that HilD activates the expression of this gene in part by antagonizing H-NS. Additionally, our results revealed that the expression of the S. Typhmurium phoH gene is also activated in response to low phosphate but independently of the PhoB/R two-component system, known to regulate the E. coli phoH gene in response to low phosphate. Thus, our results indicate that cis-regulatory evolution has played a role in the expansion of the HilD regulon and illustrate the phenomenon of differential regulation of ortholog genes. IMPORTANCE Two mechanisms mediating differentiation of bacteria are well known: acquisition of genes by horizontal transfer events and mutations in coding DNA sequences. In this study, we found that the phoH ancestral gene is differentially regulated between Salmonella Typhimurium and Escherichia coli, two closely related bacterial species. Our results indicate that this differential regulation was generated by mutations in the regulatory sequence of the S. Typhimurium phoH gene and by the acquisition by S. Typhimurium of foreign DNA encoding the transcriptional regulator HilD. Thus, our results, together with those from an increasing number of studies, indicate that cis-regulatory evolution can lead to the rewiring and reprogramming of transcriptional regulation, which also plays an important role in the divergence of bacteria through time.

Should we Help our Children with Homework? A Meta-Analysis Using PISA Data.

BACKGROUND: The role of homework in students' academic performance is a widely debated topic about which there is no definitive answer. The objective of this study was to analyse the importance of parental help with homework in academic achievement, testing its cultural invariance (by country), academic invariance (by subject), and the stability of its effects over time. METHOD: A meta-analysis was performed using the results of PISA evaluations from 2009, 2012, 2015, and 2018 from countries which applied the family PISA questionnaire. We analysed 180 effects and confirmed the fit of the model and the heterogeneity of the effects, performing an analysis of moderators and multimodal inference. RESULTS: Students who had more help with homework had lower academic achievement, with an overall effect (d) = 0.23, 95% CI [0.21, 0.25]. The effects were greater in Europe than in Asia. We did not find differences by subject type, and the results were stable over time. CONCLUSIONS: Family help with homework does not ensure students' academic success, and it is more important how that help is given than how much. This conclusion is valid for different types of subjects and is stable over time, with some variation between cultures.

Análisis de Redes: una Alternativa a los Enfoques Clásicos de Evaluación de los Sistemas Educativos / Network analysis: An alternative to classic approaches for education systems evaluation

Las abundantes investigaciones sobre los sistemas educativos han permitido identificar los factores fundamentales que determinan el éxito educativo del alumnado. Sin embargo, estas investigaciones no han sido muy eficientes a la hora de transferir los resultados a los contextos aplicados en los que se mueven los profesionales y directivos que toman las decisiones sobre los sistemas educativos. La razón principal de este fracaso proviene de la poca familiarización de los profesionales de la educación con la sofisticada metodología estadística y psicométrica utilizada por la mayoría de los investigadores. El objetivo del presente trabajo es analizar los sistemas educativos mediante la metodología de análisis de redes, la cual es muy asequible, clara e intuitiva para profesionales y directivos educativos sin una gran sofisticación metodológica. Se utilizó una muestra de 7,882 estudiantes de segundo curso de la Enseñanza Secundaria Obligatoria. Se evaluó su competencia matemática y se obtuvieron datos relativos al contexto educativo. Se utilizó para los análisis el análisis de redes, calculando indicadores de centralidad, así como de precisión y estabilidad de la red. Los resultados indican que el autoconcepto y las expectativas académicas tienen un importante efecto sobre los resultados en matemáticas. Los hallazgos convergen con los obtenidos previamente con otros enfoques. El acercamiento de análisis de redes ofrece una combinación idónea entre rigor analítico y sencillez interpretativa, lo que le confiere gran potencial para ser empleado en contextos educativos aplicados para la toma de decisiones basadas en datos.

Widespread research on educational systems has made it possible to identify the main factors that define students’ educational success. Nevertheless, these studies have not been very efficient when it comes to transferring their conclusions to the applied contexts where those who teach or make decisions about educational systems move. The main reason for this failure lies on the unfamiliarity of education professionals with the sophisticated statistical and psychometric methodology used by most researchers. The goal of this paper is to analyze educational systems using the Network Analysis methodology, which is very affordable, clear, and intuitive for teachers and educational leaders without a great methodological sophistication. A sample of 7,882 eighth-graders was used. Students’ mathematical skills were evaluated and data were obtained from their educational context. Network Analysis was used calculating indicators of centrality, as well as precision and stability of the network. The results indicate that academic self-concept and academic expectations have an important effect on performance in mathematics. The findings match with those previously obtained with other approaches. The Network Analysis methodology offers an ideal combination of analytical rigor and interpretative simplicity, that provides a great potential to be used in applied educational contexts for evidence-based decision making.

Should we Help our Children with Homework? A Meta-Analysis Using PISA Data / ¿Debemos Ayudar a Nuestros Hijos con los Deberes? un Meta-Análisis con Datos PISA

Background: The role of homework in students’ academic performance is a widely debated topic about which there is no definitive answer. The objective of this study was to analyse the importance of parental help with homework in academic achievement, testing its cultural invariance (by country), academic invariance (by subject), and the stability of its effects over time. Method: A meta-analysis was performed using the results of PISA evaluations from 2009, 2012, 2015, and 2018 from countries which applied the family PISA questionnaire. We analysed 180 effects and confirmed the fit of the model and the heterogeneity of the effects, performing an analysis of moderators and multimodal inference. Results: Students who had more help with homework had lower academic achievement, with an overall effect (d) = 0.23, 95% CI [0.21, 0.25]. The effects were greater in Europe than in Asia. We did not find differences by subject type, and the results were stable over time. Conclusions: Family help with homework does not ensure students’ academic success, and it is more important how that help is given than how much. This conclusion is valid for different types of subjects and is stable over time, with some variation between cultures.

Antecedentes: el papel de los deberes escolares en el rendimiento académico es un tema ampliamente debatido, no existiendo una respuesta definitiva. El presente trabajo analiza el efecto de la ayuda parental con los deberes sobre los resultados educativos, comprobando la invarianza cultural (por países) y académica (por asignaturas), así como la estabilidad temporal de los efectos. Método: se realizó un meta-análisis con los resultados PISA de los años 2009, 2012, 2015 y 2018, incluyendo los países que aplicaron el cuestionario PISA para las familias. Se analizaron 180 efectos, comprobando el ajuste del modelo y la heterogeneidad de los efectos, y realizando análisis de moderadores y análisis de inferencia con modelos múltiples. Resultados: los estudiantes que reciben más ayuda con los deberes obtienen resultados más bajos: d = 0.23, IC 95% [0.21, 0.25]. Los efectos son mayores en Europa que en Asia. No se encontraron diferencias en función de la asignatura, y los resultados son estables a lo largo del tiempo. Conclusiones: la ayuda familiar con los deberes no garantiza el éxito académico, siendo más importante cómo se hace que el cuánto. Esta conclusión es válida en todas las asignaturas y se muestra estable en el tiempo, observándose variaciones interculturales.

Resiliencia académica: la influencia del esfuerzo, las expectativas y el autoconcepto académico / Academic resilience: The influence of academic effort, expectations, and self-concept

Resumen Introducción: La resiliencia académica consiste en obtener altas calificaciones a pesar de hallarse en una desventaja socioeconómica. En el presente estudio se observó si el esfuerzo, las expectativas y el autoconcepto académicos forman parte de la resiliencia académica o estarían explicando un buen rendimiento académico en general. Método: Los participantes, una población de 7479 adolescentes españoles (M = 13.87; DT = 0.82), fueron divididos en cuatro grupos según el rendimiento académico (Bueno-Malo) y el nivel socioeconómico (Clase alta-Clase baja). Se realizaron análisis de diferencias y regresiones logísticas binarias para detectar cuál de las variables empleadas explicaba el rendimiento académico en los grupos de igual nivel socioeconómico. También se estudió si el sexo influía en la pertenencia a los grupos de buen rendimiento. Resultados: Se observaron diferencias en el esfuerzo, las expectativas y el autoconcepto académicos en función de los cuatro grupos creados; los grupos de buen rendimiento académico obtuvieron puntuaciones más altas independientemente del nivel socioeconómico. Se observó que las expectativas y el autoconcepto académicos explicaban gran parte del rendimiento académico. Se detectó una tasa de mujeres significativamente más alta con relación a la de hombres en los grupos de mayor rendimiento. Conclusiones: Muchas variables, que se han considerado propias de los alumnos académicamente resilientes, explican un buen rendimiento académico, en general, independientemente del nivel socioeconómico.

Abstract Introduction: Academic resilience is defined as getting high marks despite being at a socioeconomic disadvantage. In the present study, it was observed whether Academic Effort, Expectations and Self-Concept are part of academic resilience or would be explaining a good academic performance in general. Method: The participants, a population of 7479 Spanish adolescents (M = 13.87; SD = 0.82), were divided into four groups according to academic performance (Good-Bad) and socioeconomic level (Upper class-Lower class). Analysis of differences and binary logistic regressions were performed to detect which of the variables used explained the academic performance in the groups of the same socioeconomic level. It was also studied whether sex influenced membership in the good performance groups. Results: Differences in Academic Effort, Expectations and Self-concept were found according to the four groups created; the groups with good academic performance obtained higher scores regardless of socioeconomic level. Expectations and academic self-concept were found to explain much of academic performance. A significantly higher rate of women than men was found in higher performance groups. Conclusions: Many variables that have been considered typical of academically resilient students explain good academic performance in general, regardless of socioeconomic status.

The Hydropathy Index of the HCDR3 Region of the B-Cell Receptor Identifies Two Subgroups of IGHV-Mutated Chronic Lymphocytic Leukemia Patients With Distinct Outcome.

The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and "antigen-experienced" phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations-e.g., del(17p)-together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR.

Teleneurorehabilitation program (virtual reality) for patients with balance disorders: descriptive study.

BACKGROUND: Balance disorders are common in patients with neurological or vestibular diseases. Telerehabilitation program is a treatment to be as safe as conventional treatment. One of the most used methods to perform telerehabilitation is the incorporation of Virtual Reality. In general, rehabilitation programs train predictive postural control, so the patient does not always acquire the necessary autonomy to react to situations of instability. On the other hand, the objective and systematic supervision and measurement of these programs is limited, making it necessary to create clinical protocols with precise and measurable rehabilitation objectives. This study present the training selection methodology and clinical protocol for patients with balance disorders inserted in a Telerehabilitation Program based on Virtual Reality. METHODS: Descriptive study where physiotherapists were trained to use RehaMetrics®. To evaluate their level of agreement in the selection of the exercise clusters developed, the Interobserver Reliability was measured through the kappa statistic. Subsequently, the exercises were applied to a group of patients recruited with sedentary trunk control (Berg Balance Scale = 3 points in item 3), mild or normal cognitive level (Montreal Cognitive Assessment> 21 points), and prescribed for tele-rehabilitation by a doctor. RESULTS: The agreement among the expert physiotherapists irrespective of the cluster exceeds 80%, which indicates a very good strength of agreement, while the novices reached a level of agreement of 45%, which suggests a moderate strength of agreement. All clinical outcomes showed statistically significant differences between the median times, as did the Maximum Width Left Side (MWLS) (cm). The average number of minutes of training was 485.81 (SD 246.49 min), and the number of sessions performed during the 4 weeks of intervention was 17 (SD 7.15 sessions). CONCLUSIONS: This analysis what had excellent interobserver reliability with trained physiotherapists. Regarding the second phase of the study, the results show a statistically significant difference between the initial and final evaluation of the clinical tests, which could result in better performance in aspects such as: balance, gait functionality, meter walked and cognition. Telerehabilitation Program based on Virtual Reality is an excellent alternative to provide continuity of treatment to patients with balance disorders.

Motif WFYY of human PrimPol is crucial to stabilize the incoming 3'-nucleotide during replication fork restart.

PrimPol is the second primase in human cells, the first with the ability to start DNA chains with dNTPs. PrimPol contributes to DNA damage tolerance by restarting DNA synthesis beyond stalling lesions, acting as a TLS primase. Multiple alignment of eukaryotic PrimPols allowed us to identify a highly conserved motif, WxxY near the invariant motif A, which contains two active site metal ligands in all members of the archeo-eukaryotic primase (AEP) superfamily. In vivo and in vitro analysis of single variants of the WFYY motif of human PrimPol demonstrated that the invariant Trp87 and Tyr90 residues are essential for both primase and polymerase activities, mainly due to their crucial role in binding incoming nucleotides. Accordingly, the human variant F88L, altering the WFYY motif, displayed reduced binding of incoming nucleotides, affecting its primase/polymerase activities especially during TLS reactions on UV-damaged DNA. Conversely, the Y89D mutation initially associated with High Myopia did not affect the ability to rescue stalled replication forks in human cells. Collectively, our data suggest that the WFYY motif has a fundamental role in stabilizing the incoming 3'-nucleotide, an essential requisite for both its primase and TLS abilities during replication fork restart.

Impact of measurable residual disease by decentralized flow cytometry: a PETHEMA real-world study in 1076 patients with acute myeloid leukemia.

The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P < 0.001) and overall survival (HR: 0.73, P = 0.001), but uncovered the limited prognostic value of MFC based MRD in multivariate and recursive partitioning models including other clinical, genetic and treatment related factors. Virtually all aspects related with methodological, interpretation, and reporting of MFC based MRD testing impacted in its ability to discriminate patients with different CIR. Thus, this study demonstrated that "real-world" assessment of MRD using MFC is prognostic in patients at first remission, and urges greater standardization for improved risk-stratification toward clinical decisions in AML.

Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group. This cooperative nationwide strategy provides advanced molecular diagnostic for acute myeloid leukemia patients of the PETHEMA group.

Experimentación de carga durante los cuidados, principales características a tener en consideración para su intervención: dimensiones negativas, efectos e instrumentos de medición / Workload experimentation during care, main characteristics to take in consideration for your intervention: negative dimensions, effects and measuring instruments / Experimentação de carga durante os cuidados, principais características a ter em consideração para a sua intervenção: dimensões negativas, efeitos e instrumentos de medição

Durante el transcurso de los cuidados y especialmente en los denominados de larga duración, es muy proclive el generarse determinadas situaciones conflictivas a consecuencia de diversos factores tales como, un excesivo volumen de trabajo, elevada responsabilidad, problemas relacionales entre cuidador y persona objeto de cuidados etc. Conllevando a la experimentación de cansancio, estrés y agotamiento principalmente. Todas esas situaciones negativas es lo que muchos autores definen con el concepto de carga o sobrecarga de los cuidados, constituyendo un habitual ámbito de estudio en las investigaciones que versan sobre esta temática. El propósito de este artículo, consiste en llevar a cabo una aproximación conceptual del término de carga, experimentada durante el transcurso de las actividades de cuidados, analizando las dimensiones más relevantes de la misma en primer término, haciendo una distinción entre los conceptos de carga objetiva y subjetiva en segundo término, analizar las principales consecuencias que generan a los cuidadores tales como, percibimiento de sentimientos negativos, problemas de salud física, psíquica, trastornos cardiovasculares e inmunológicos en tercer término, las principales variables asociadas al concepto de carga, y finalmente los principales instrumentos de evaluación de la carga del cuidador

During the provision of cares and, particularly in long-term care, conflictive situations are generated frequently as a consequence of factors such as, excessive workload, high responsibility, relational problems between caregiver and the person subject of care etc., mainly leading to the experimentation of fatigue, stress and exhaustion. All these negative situations are what many authors call burden or overload of care, constituting a common field of study in the research dealing with this subject. The purpose of this article is to frame a conceptual approach to the concept of load experienced during the care, analyzing the most relevant factors contributing to such load, first making a distinction between the concepts of objective and subjective burden, secondly by analyzing the principal consequences for caregivers, such as perceived negative feelings, physical and mental health problems, cardiovascular disorders and immunological problems. Principal variables associated with the concept of burden, and finally the main instruments of evaluation of the caregiver burden are shown

Durante o curso dos cuidados e, especialmente, nos chamados longo prazo, é muito provável que os gerados certas situações de conflito, como resultado de vários fatores, como carga de trabalho excessiva, alta responsabilidade, problemas de relacionamento entre cuidador e pessoa a ser cuidada etc. . Levando à experimentação de fadiga, estresse e exaustão principalmente. Todas estas situações negativas é o que muitos autores definem o conceito de carga ou sobrecarga de atendimento, proporcionando um campo comum de estudo em investigações que lidam com este assunto. O objetivo deste artigo é realizar uma abordagem conceitual da carga prazo experimentaram durante o curso das atividades de atendimento, analisando as dimensões mais relevantes da primeira, fazendo uma distinção entre os conceitos de sobrecarga objetiva e subjetivos em segundo lugar, analisar as principais conseqüências geradas cuidadores, como percibimiento sentimentos negativos, problemas físicos de saúde, transtornos mentais, cardiovasculares e imunológicas terceiro, as principais variáveis associadas com o conceito de carga e, finalmente, principais instrumentos de avaliação do ônus do cuidado