Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Large-scale real-life analysis of survival and usage of therapies in multiple myeloma.

Survival in multiple myeloma has improved significantly in recent years, especially in young patients. We reviewed the evolution of the survival of patients with MM in three groups based on age at MM diagnosis over three time periods between 1999 and 2020 at our 12 de Octubre Hospital institution (H12O). Then, to confirm our results, we used data from TriNetx, a global health research platform that includes patients from Europe to US. 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. For patients from H12O, the median OS was 35.61, 55.59 and 68.67 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 versus 34.75 months from 1999-2009 versus 2010-2014. The median OS from the 2010-2014 versus 2015-2020 time cohorts was 34.75 months versus 54.43 months, respectively. In relation to the US cohort, the median OS from before 2010 versus 2010-2014 was not reached in either time cohort and neither when comparing the 2010-2014 versus 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. 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.

Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1.

Whereas total loss of Lis1 is lethal, disruption of one allele of the Lis1 gene results in brain abnormalities, indicating that developing neurons are particularly sensitive to a reduction in Lis1 dosage. Here we show that Lis1 is enriched in neurons relative to levels in other cell types, and that Lis1 interacts with the microtubule motor cytoplasmic dynein. Production of more Lis1 in non-neuronal cells increases retrograde movement of cytoplasmic dynein and leads to peripheral accumulation of microtubules. These changes may reflect neuron-like dynein behaviours induced by abundant Lis1. Lis1 deficiency produces the opposite phenotype. Our results indicate that abundance of Lis1 in neurons may stimulate specific dynein functions that function in neuronal migration and axon growth.

Impact of COVID-19 in patients with multiple myeloma based on a global data network.

The COVID-19 pandemic has represented a major cause of morbidity/mortality worldwide, overstressing health systems. Multiple myeloma (MM) patients show an increased risk for infections and they are expected to be particularly vulnerable to SARS-CoV-2 infection. Here we have obtained a comprehensive picture of the impact of COVID-19 in MM patients on a local and a global scale using a federated data research network (TriNetX) that provided access to Electronic Medical Records (EMR) from Health Care Organizations (HCO) all over the world. Through propensity score matched analyses we found that the number of new diagnoses of MM was reduced in 2020 compared to 2019 (RR 0.86, 95%CI 0.76-0.96) and the survival of newly diagnosed MM cases decreased similarly (HR 0.61, 0.38-0.81). MM patients showed higher risk of SARS-CoV-2 infection (RR 2.09, 1.58-2.76) and a higher excess mortality in 2020 (difference in excess mortality 9%, 4.4-13.2) than non-MM patients. By interrogating large EMR datasets from HCO in Europe and globally, we confirmed that MM patients have been more severely impacted by COVID-19 pandemic than non-MM patients. This study highlights the necessity of extending preventive measures worlwide to protect vulnerable patients from SARS-CoV-2 infection by promoting social distancing and an intensive vaccination strategies.

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

Room temperature reversible hydrogen storage in polyaniline (PANI) nanofibers.

We report for the first time the reversible hydrogen storage behavior at room temperature in polyaniline nanofibers. The rate of hydrogen sorption during the initial run was very rapid and an extended plateau pressure of about 30 bars was obtained from the pressure-composition isotherm profiles of these polyaniline nanofibers. The reversible cycling capacity of approximately 3-4 wt% was demonstrated at room temperature and has been attributed to the unique nanofibrous microstructural and surface properties.

Aortic stenosis prognosis in older patients: frailty is a strong marker of early congestive heart failure admissions : Influence of frailty in aortic stenosis.

PURPOSE: Degenerative aortic stenosis has become a new valvular epidemic in the last few decades due to its high prevalence in the geriatric population. We sought to analyse factors that could influence earlier hospitalization for congestive heart failure in geriatric patients with moderate-severe degenerative aortic stenosis. METHODS: This investigation was an ambispective cohort study of 104 patients aged 70 years or older with moderate-severe aortic stenosis. Epidemiological, geriatric, clinical, echocardiographic and electrocardiographic variables were collected. During the follow-up, the number of admissions for congestive heart failure and the time elapsed from diagnosis to first admission were recorded. RESULTS: A total of 45.2% of the patients were admitted for congestive heart failure, with a median time to first admission of 3 years (95% CI 1.88-4.25). For patients aged 85 years or older, this median was 8.07 months (95% CI 0.05-1.99). The first admission for congestive heart failure was independently related to frailty (HR 4.46, 95% CI: 1.38-14.41), atrial fibrillation (HR 2.19, 95% CI: 1.01-4.73), a high EuroSCORE (HR 1.03, 95% CI: 1.00-1.05), the affected valvular area (HR 0.11, 95% CI: 0.02-0.47), age (HR 1.11, 95% CI: 1.04-1.18) and renal failure (HR 4.13, 95% CI: 1.46-11.63). The median time to admission for frail patients was 1.08 years (95% CI 0.30-1.86). CONCLUSIONS: In geriatric patients with moderate-severe degenerative aortic stenosis, frailty is an independent marker of early congestive heart failure admission with a powerful and important association.

NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein.

Disruption of one allele of the LIS1 gene causes a severe developmental brain abnormality, type I lissencephaly. In Aspergillus nidulans, the LIS1 homolog, NUDF, and cytoplasmic dynein are genetically linked and regulate nuclear movements during hyphal growth. Recently, we demonstrated that mammalian LIS1 regulates dynein functions. Here we characterize NUDEL, a novel LIS1-interacting protein with sequence homology to gene products also implicated in nuclear distribution in fungi. Like LIS1, NUDEL is robustly expressed in brain, enriched at centrosomes and neuronal growth cones, and interacts with cytoplasmic dynein. Furthermore, NUDEL is a substrate of Cdk5, a kinase known to be critical during neuronal migration. Inhibition of Cdk5 modifies NUDEL distribution in neurons and affects neuritic morphology. Our findings point to cross-talk between two prominent pathways that regulate neuronal migration.

A Validation and Reliability Study of the Physical Activity and Healthy Food Efficacy Scale for Children (PAHFE).

The purpose of this study was to obtain validity evidence for the Physical Activity and Healthy Food Efficacy Scale for Children (PAHFE). Construct validity evidence identifies four subscales: Goal-Setting for Physical Activity, Goal-Setting for Healthy Food Choices, Decision-Making for Physical Activity, and Decision-Making for Healthy Food Choices. The scores on each of these subscales show a moderate to high degree of internal consistency (0.59

A Comparative Evaluation of Kernel Equating and Test Characteristic Curve Equating.

This study compares the kernel equating (KE) and test characteristic curve (TCC) equating methods using the nonequivalent anchor test equating design. In this Monte Carlo study, four independent variables were examined: sample size, test length, average form discrimination, anchor test reliability, and the percentage of anchor items. For each condition, there were 100 replications. To assess the performance of TCC equating and KE, the differences between the examinee parametric true scores and the equated estimated expected true scores were examined. The equated scores were based on the average across replications for each condition. Generally speaking, both KE and TCC equating produced accurate results, although KE tended to perform better than TCC on the parametric true score scale across conditions. Past research and the current study's results seem to indicate that KE should be strongly considered for most equating situations, particularly in light of its flexibility.

[Actinomycotic infective endocarditis of the mitral valve. Anatomoclinical case and review of literature]. / Endocarditis infecciosa actinomicótica de la válvula mitral. Caso de autopsia y revisión de la literatura.

Actinomycotic infections of the heart is an uncommon disease, especially if the infection affects the valvular endocardium as primary focus. Just a few cases have been reported previously. We report a case of primary endocarditis of the mitral valve caused by Actinomyces sp diagnosed at necropsy in a 34 year-old man with history of chronic rheumatic disease presenting as a usual case of infective endocarditis.

An introduction to mixture item response theory models.

Mixture item response theory (IRT) allows one to address situations that involve a mixture of latent subpopulations that are qualitatively different but within which a measurement model based on a continuous latent variable holds. In this modeling framework, one can characterize students by both their location on a continuous latent variable as well as by their latent class membership. For example, in a study of risky youth behavior this approach would make it possible to estimate an individual's propensity to engage in risky youth behavior (i.e., on a continuous scale) and to use these estimates to identify youth who might be at the greatest risk given their class membership. Mixture IRT can be used with binary response data (e.g., true/false, agree/disagree, endorsement/not endorsement, correct/incorrect, presence/absence of a behavior), Likert response scales, partial correct scoring, nominal scales, or rating scales. In the following, we present mixture IRT modeling and two examples of its use. Data needed to reproduce analyses in this article are available as supplemental online materials at http://dx.doi.org/10.1016/j.jsp.2016.01.002.

Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats.

The increase in the elderly population has generated concern to meet health demands. The research efforts to elucidate the mechanisms of damage associated with aging have also been significantly increased, especially in order to avoid the reduction of the cognitive abilities in geriatric patients, resulting from the damage generated mainly at the level of the hippocampus during old age. At present, many studies describe resveratrol as an antiaging component. There are reports that it can activate the Sirt1 gene related to antiaging, emulating the effects obtained by caloric restriction in rodents. The aim of the study was to evaluate the effect of chronic administration of resveratrol (10 mg/kg) on cognitive performance in behavioral tests after 8 months of treatment and on the preservation of cerebral integrity in the cytoarchitecture of regions CA1 and CA2. Results showed that the cytoarchitecture of the CA1 and CA2 regions in the hippocampus retained their integrity over time in rats treated with resveratrol, and the behavioral test performed revealed that chronic resveratrol administration for 8 months showed improvements in cognitive performance. The results indicate that resveratrol may exhibit therapeutic potential for age-related conditions.

Familial dilated cardiomyopathy: A multidisciplinary entity, from basic screening to novel circulating biomarkers.

Idiopathic dilated cardiomyopathy has become one of the most prevalent inherited cardiomyopathies over the past decades. Genetic screening of first-degree relatives has revealed that 30-50% of the cases have a familial origin. Similar to other heart diseases, familial dilated cardiomyopathy is characterized by a high genetic heterogeneity that complicates family studies. Cli'nical screening, 12-lead electrocardiogram and transthoracic echocardiogram are recommended for patients and first-degree family members. Magnetic resonance also needs to be considered. Genetic technologies have become fundamental for the clinical management of this disease. New generation sequencing methods have made genetic testing feasible for extensive panels of genes related to the disease. Recently, new imaging modalities such as speckle-tracking, strain and strain rate or magnetic resonance, and circulating biomarkers such as non-coding RNAs, have emerged as potential strategies to help cardiologists in their clinical practice. Imaging, genetic and blood-based techniques should be considered together in the evaluation and testing of familial dilated cardiomyopathy. Here, we discuss the current procedures and novel approaches for the clinical management of familial dilated cardiomyopathy.

A Begomovirus Isolated from Chlorotic and Stunted Soybean Plants in Mexico is a New Strain of Rhynchosia golden mosaic virus.

Soybean (Glycine max Merr.) is an alternative crop during the summer in Sinaloa, a northern state of Mexico. During the last 4 years, symptoms of yellowing, curled leaves, and stunting have been observed on soybean plantings, and a scrutiny of field samples collected in 2003 identified a begomovirus related to Pepper golden mosaic virus in symptomatic plants (4). A new survey was conducted during the summer of 2004 when the soybean disease was prevalent in the region. Affected plants appeared as patches displaying symptoms ranging from mild to severe yellow mosaic with leaf deformation and stunted growth in several parcels of commercial fields of northern Sinaloa. More than 100 samples from symptomatic soybean plants and weeds growing within the same fields were collected and analyzed for the presence of begomoviruses using DNA hybridization with the coat protein gene of Pepper huasteco yellow vein virus as a probe. Thirty-eight soybean, 12 Rhynchosia sp., and 14 sunflower hybridization-positive samples were subsequently used for polymerase chain reaction (PCR) amplification with the degenerate primers pRep-DGR and pCP70-Mot (1). PCR products were cloned into pGEM-T Easy vector (Promega, Madison, WI) and sequenced. The amplified viral DNA (915 nt) from two soybean plants, Sb1 and Sb2 (GenBank Accession Nos. AY955101 and AY957561, respectively), one isolate from Rhynchosia minima (GenBank Accession No. AY955102), and one from Heliantus annum (GenBank Accession No. AY957560) were sequenced and compared with DNA sequences available at NCBI database using BLAST. The highest sequence similarity was obtained with the two known isolates of Rhynchosia golden mosaic virus, RhGMV [Honduras] (GenBank Accession No. AF239671), and RhGMV [Chiapas] (GenBank Accession No. AF408199), displaying a nucleotide identity of approximately 89% with the Sinaloa isolates. Sequence comparisons of the latter isolates showed that viruses in the weeds were 97% identical to one of the soybean isolates, RhGMV-Sb1, but differed significantly (88% of nucleotide identity) from the second soybean isolate, RhGMV-Sb2. The complete genome A sequence of RhGMV-Sb1 was determined using PCR amplification of viral DNA with four degenerate primers recently described (2), cloning of overlapping PCR products into pGEM-T Easy vector (Promega) and sequencing. The 2,604-bp DNA-A of RhGMV-Sb1 (GenBank Accession No. DQ347950) was compared with the homologous genome of RhGMV [Chiapas] and RhGMV [Honduras] using the CLUSTAL alignment method (MegAlign, DNASTAR software, London) and an overall nucleotide identity of 89.2 and 88.6%, respectively, was determined. Current taxonomic criteria for begomoviruses establish that a DNA-A sequence identity lower than 93% with other isolates of a virus is indicative of a separate strain (3). Therefore, the virus identified in this study is a new strain of RhGMV that is provisionally named Rhynchosia golden mosaic virus-Soybean [Mexico:Sinaloa:2004]. This is the first soybean-infecting begomovirus from the American continent whose genome A has been completely characterized as of today. References: (1) J. T. Ascencio-Ibañez et al. Plant Dis. 86:692, 2002. (2) R. De La Torre-Almaraz et al. Plant Dis. 90:378, 2006. (3) C. Fauquet et al. Arch. Virol. 150:2151, 2005. (4) J. Mendez-Lozano et al. Plant Dis. 90:109, 2006.

Estimating person locations from partial credit data containing missing responses.

Certain assessment situations produce partial credit data. For instance, performance assessment items may utilize a rubric that assigns partial credit for some not completely correct responses. In some cases examinees may choose to not answer each question. This study investigated the effect of various strategies for handling these missing responses for estimating a respondent's location. These methods included ignoring the omitted response, selecting the "midpoint" category score, treating the omitted response as incorrect, hotdecking, and a likelihood-based approach. A simulation study was performed to examine the efficacy of these methods with the partial credit and generalized partial credit models. Expected a posteriori (EAP) ability estimation was used. Results showed that the Midpoint and Likelihood procedures performed the best of methods examined. In contrast, omitted responses should not be treated as incorrect nor ignored when estimating an examinee's proficiency using EAP. Implications for practitioners are discussed.