HLA molecular mismatches and induced donor-specific tolerance in combined living donor kidney and hematopoietic stem cell transplantation.

Introduction: We investigated the potential role of HLA molecular mismatches (MM) in achieving stable chimerism, allowing for donor-specific tolerance in patients undergoing combined living donor kidney and hematopoietic stem cell transplantation (HSCT). Methods: All patients with available DNA samples (N=32) who participated in a phase 2 clinical trial (NCT00498160) where they received an HLA mismatched co-transplantation of living donor kidney and facilitating cell-enriched HSCT were included in this study. High-resolution HLA genotyping data were used to calculate HLA amino acid mismatches (AAMM), Eplet MM, three-dimensional electrostatic mismatch scores (EMS-3D), PIRCHE scores, HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence MM, and KIR ligands MM between the donor and recipient in both directions. HLA MM were analyzed to test for correlation with the development of chimerism, graft vs. host disease (GvHD), de novo DSA, and graft rejection. Results: Follow-up time of this cohort was 6-13.5 years. Of the 32 patients, 26 developed high-level donor or mixed stable chimerism, followed by complete withdrawal of immunosuppression (IS) in 25 patients. The remaining six of the 32 patients had transient chimerism or no engraftment and were maintained on IS (On-IS). In host versus graft direction, a trend toward higher median number of HLA-DRB1 MM scores was seen in patients On-IS compared to patients with high-level donor/mixed chimerism, using any of the HLA MM modalities; however, initial statistical significance was observed only for the EMS-3D score (0.45 [IQR, 0.30-0.61] vs. 0.24 [IQR, 0.18-0.36], respectively; p=0.036), which was lost when applying the Bonferroni correction. No statistically significant differences between the two groups were observed for AAMM, EMS-3D, Eplet MM, and PIRCHE-II scores calculated in graft versus host direction. No associations were found between development of chimerism and GvHD and non-permissive HLA-DPB1 T-cell epitope group MM, HLA-B leader sequence, and KIR ligands MM. Conclusion: Our results suggest an association between HLA-DRB1 molecular mismatches and achieving stable chimerism, particularly when electrostatic quality of the mismatch is considered. The non-permissive HLA-DPB1 T-cell epitope group, HLA-B leader sequence, and KIR ligands MM do not predict chimerism and GvHD in this combined kidney/HSCT transplant patient cohort. Further work is needed to validate our findings. Clinical trial registration: https://clinicaltrials.gov/study/NCT00498160, identifier NCT00498160.

Impact of platelet activation on the release of cell-free mitochondria and circulating mitochondrial DNA.

BACKGROUND: Research on circulating mitochondrial DNA (cir-mtDNA) based diagnostic is insufficient, as to its function, origin, structural features, and particularly its standardization of isolation. To date, plasma preparation performed in previous studies do not take into consideration the potential bias resulting from the release of mitochondria by activated platelets. METHODS: To tackle this, we compared the mtDNA amount determined by a standard plasma preparation method or a method optimally avoiding platelet activation. MtDNA extracted from the plasma of seven healthy individuals was quantified by Q-PCR in the course of the process of both methods submitted to filtration, freezing or differential centrifugation. RESULTS: 98.7 to 99.4% of plasma mtDNA corresponded to extracellular mitochondria, either free or into large extracellular vesicles. Without platelet activation, the proportion of both types of entities remained preponderant (76-80%), but the amount of detected mtDNA decreased 67-fold. CONCLUSION: We show the high capacity of platelets to release free mitochondria in "in vitro" conditions. This represents a potent confounding factor when extracting mtDNA for cir-mtDNA investigation. Platelet activation during pre-analytical conditions should therefore be avoided when studying cir-mtDNA. Our findings lead to a profound revision of the assumptions previously made by most works in this field. Overall, our data suggest the need to characterize or isolate mtDNA associated various structural forms, as well as to standardize plasma preparation, to better circumscribe cir-mtDNA's diagnostic capacity.

Circulating DNA reveals a specific and higher fragmentation of the Y chromosome.

Chromosome stability is a key point in genome evolution, particularly that of the Y chromosome. The Y chromosome loss in blood and tumor cells is well established. Through processes that are common to other chromosomes too, the Y chromosome undergoes degradation and fragmentation in the blood stream before elimination. This process gives rise to circulating DNA (cirDNA) fragments, whose examination may provide potential insight into the role of DNA fragmentation in blood for the Y chromosome elimination. In this study, we employed shallow whole genome sequencing (sWGS) to comprehensively assess the total cirDNA and the individual chromosome fragment size profiles in the plasma of healthy male individuals. Here, we show that (i) the fragment size profiles of total circulating DNA (cirDNA) and DNA fragments originating from autosomes and the X chromosome in blood plasma are homogeneous, and have a remarkably low variability (mean CV = 7%) among healthy individuals, (ii) the Y chromosome has a distinct fragment size profile with the accumulation of the fragment < 145 bp and depletion of the dinucleosome-associated fragments (290-390 bp), and its fragment fraction in blood decreases with age. These results indicate a higher fragmentation of the Y chromosome compared to other chromosomes and this in turn might be due to its increased susceptibility to degradation. Our findings pave the way for an elucidation of the impact of chromosomal origin on DNA degradation and the Y chromosome biology.

Ecological determinants of obesity risk in Mexican infants: a scoping review.

BACKGROUND: Childhood obesity is a multifactorial disease. Most of these factors start to develop before birth and worsen throughout life. Therefore, prevention efforts should begin in the first 1000 days of life. This study aimed to quantify published studies on risk factors according to the Six-Cs model of childhood obesity (cell, child, clan, culture, community, and country) and determine which of them have been related to anthropometric indicators of overweight or obesity in children under 2 years of age in Mexico. METHODS: A systematic scoping review (PRISMA-ScR) was performed. PubMed, Scopus, and EBSCOhost databases were reviewed. RESULTS: We found that 88% of the studies were observational. The child and family spheres were the most studied, individually and as a whole. The least studied were community, culture, and country. The main risk factors related to obesity indicators were high birth weight, birth by cesarean section, and inadequate feeding practices, in addition to mothers with obesity and those who underestimate their child's weight, stressful parenting style, and food insecurity in the home, together with living in urban areas, family income, and beliefs about preference for ultra-processed products. CONCLUSION: In Mexico, the study of obesity in early childhood is emerging at the research level. However, further efforts are required to close the knowledge gap at the socioecological level to design evidence-based interventions and reduce early obesity.

INTRODUCCIÓN: La obesidad infantil es una enfermedad multifactorial en la que varios factores comienzan a desarrollarse antes del nacimiento y se agravan a lo largo de la vida. Por ello, los esfuerzos de prevención para evitar su desarrollo deben comenzar durante los primeros 1000 días de vida. Los objetivos de este estudio fueron cuantificar los estudios publicados sobre factores de riesgo según el modelo de obesidad infantil de las 6-Cs (célula, niño, familia, cultura, comunidad y país) y determinar cuáles de ellos se han relacionado con indicadores de sobrepeso u obesidad en niños menores de 2 años en México. MÉTODOS: Se realizó una revisión sistemática de alcance (PRISMA-ScR). Se revisaron las bases de datos de PubMed, Scopus y EBSCOhost. RESULTADOS: Se encontró que el 88% de los estudios fueron de tipo observacional. La esfera niño y familia fueron las más abordadas, tanto individual como en conjunto. Las menos estudiadas fueron comunidad, cultura y país. Los principales factores de riesgo relacionados con indicadores de obesidad fueron alto peso al nacer, nacer por vía cesárea y prácticas inadecuadas de alimentación; además, madres con obesidad y que subestiman el peso del hijo, estilo de crianza presionante e inseguridad alimentaria en el hogar, aunado el vivir en zonas urbanas, ingreso económico-familiar y creencias sobre la preferencia por productos ultraprocesados. CONCLUSIONES: En México, el estudio de obesidad durante los primeros 1000 días es emergente a nivel de investigación, pero se requiere continuar con el esfuerzo para cerrar la brecha de conocimiento a nivel socio-ecológico, diseñar intervenciones basadas en la evidencia y disminuir la obesidad temprana.

Ecological determinants of obesity risk in Mexican infants: a scoping review / Determinantes ecológicos de riesgo de obesidad en lactantes mexicanos: una revisión de alcance

Abstract Background: Childhood obesity is a multifactorial disease. Most of these factors start to develop before birth and worsen throughout life. Therefore, prevention efforts should begin in the first 1000 days of life. This study aimed to quantify published studies on risk factors according to the Six-Cs model of childhood obesity (cell, child, clan, culture, community, and country) and determine which of them have been related to anthropometric indicators of overweight or obesity in children under 2 years of age in Mexico. Methods: A systematic scoping review (PRISMA-ScR) was performed. PubMed, Scopus, and EBSCOhost databases were reviewed. Results: We found that 88% of the studies were observational. The child and family spheres were the most studied, individually and as a whole. The least studied were community, culture, and country. The main risk factors related to obesity indicators were high birth weight, birth by cesarean section, and inadequate feeding practices, in addition to mothers with obesity and those who underestimate their child's weight, stressful parenting style, and food insecurity in the home, together with living in urban areas, family income, and beliefs about preference for ultra-processed products. Conclusion: In Mexico, the study of obesity in early childhood is emerging at the research level. However, further efforts are required to close the knowledge gap at the socioecological level to design evidence-based interventions and reduce early obesity.

Resumen Introducción: La obesidad infantil es una enfermedad multifactorial en la que varios factores comienzan a desarrollarse antes del nacimiento y se agravan a lo largo de la vida. Por ello, los esfuerzos de prevención para evitar su desarrollo deben comenzar durante los primeros 1000 días de vida. Los objetivos de este estudio fueron cuantificar los estudios publicados sobre factores de riesgo según el modelo de obesidad infantil de las 6-Cs (célula, niño, familia, cultura, comunidad y país) y determinar cuáles de ellos se han relacionado con indicadores de sobrepeso u obesidad en niños menores de 2 años en México. Métodos: Se realizó una revisión sistemática de alcance (PRISMA-ScR). Se revisaron las bases de datos de PubMed, Scopus y EBSCOhost. Resultados: Se encontró que el 88% de los estudios fueron de tipo observacional. La esfera niño y familia fueron las más abordadas, tanto individual como en conjunto. Las menos estudiadas fueron comunidad, cultura y país. Los principales factores de riesgo relacionados con indicadores de obesidad fueron alto peso al nacer, nacer por vía cesárea y prácticas inadecuadas de alimentación; además, madres con obesidad y que subestiman el peso del hijo, estilo de crianza presionante e inseguridad alimentaria en el hogar, aunado el vivir en zonas urbanas, ingreso económico-familiar y creencias sobre la preferencia por productos ultraprocesados. Conclusiones: En México, el estudio de obesidad durante los primeros 1000 días es emergente a nivel de investigación, pero se requiere continuar con el esfuerzo para cerrar la brecha de conocimiento a nivel socio-ecológico, diseñar intervenciones basadas en la evidencia y disminuir la obesidad temprana.

Comparison of the structures and topologies of plasma extracted circulating nuclear and mitochondrial cell-free DNA.

Introduction: The function, origin and structural features of circulating nuclear DNA (cir-nDNA) and mitochondrial DNA (cir-mtDNA) are poorly known, even though they have been investigated in numerous clinical studies, and are involved in a number of routine clinical applications. Based on our previous report disproving the conventional plasma isolation used for cirDNA analysis, this work enables a direct topological comparison of the circulating structures associated with nuclear DNA and mitochondrial cell-free DNA. Materials and methods: We used a Q-PCR and low-pass whole genome sequencing (LP-WGS) combination approach of cir-nDNA and cir-mtDNA, extracted using a procedure that eliminates platelet activation during the plasma isolation process to prevent mitochondria release in the extracellular milieu. Various physical procedures, such as filtration and differential centrifugation, were employed to infer their circulating structures. Results: DSP-S cir-mtDNA mean size profiles distributed on a slightly shorter range than SSP-S. SSP-S detected 40-fold more low-sized cir-mtDNA fragments (<90 bp/nt) and three-fold less long-sized fragments (>200 bp/nt) than DSP-S. The ratio of the fragment number below 90 bp over the fragment number above 200 bp was very homogenous among both DSP-S and SSP-S profiles, being 134-fold lower with DSP-S than with SSP-S. Cir-mtDNA and cir-nDNA DSP-S and SSP-S mean size profiles of healthy individuals ranged in different intervals with periodic sub-peaks only detectable with cir-nDNA. The very low amount of cir-mtDNA fragments of short size observed suggested that most of the cir-mtDNA is poorly fragmented and appearing longer than ∼1,000 bp, the readout limit of this LP-WGS method. Data suggested that cir-nDNA is, among DNA extracted in plasma, associated with ∼8.6% of large structures (apoptotic bodies, large extracellular vesicles (EVs), cell debris…), ∼27.7% in chromatin and small EVs and ∼63.7% mainly in oligo- and mono-nucleosomes. By contrast, cir-mtDNA appeared to be preponderantly (75.7%) associated with extracellular mitochondria, either in its free form or with large EVs; to a lesser extent, it was also associated with other structures: small EVs (∼18.4%), and exosomes or protein complexes (∼5.9%). Conclusion: This is the first study to directly compare the structural features of cir-nDNA and cir-mtDNA. The significant differences revealed between both are due to the DNA topological structure contained in the nucleus (chromatin) and in the mitochondria (plasmid) that determine their biological stability in blood. Although cir-nDNA and cir-mtDNA are principally associated with mono-nucleosomes and cell-free mitochondria, our study highlights the diversity of the circulating structures associated with cell-free DNA. They consequently have different pharmacokinetics as well as physiological functions. Thus, any accurate evaluation of their biological or diagnostic individual properties must relies on appropriate pre-analytics, and optimally on the isolation or enrichment of one category of their cirDNA associated structures.

Propiedades psicométricas del Children Eating Behavior Questionnaire en niños mexicanos menores de 3 años / Psychometric properties of the Children's Eating Behavior Questionnaire in Mexican children under 3 years of age

Resumen Objetivo: México es uno de los países con mayor prevalencia de obesidad infantil a nivel mundial. Se requieren de instrumentos de valoración integrales válidos para el abordaje del problema. El Children Eating Behavior Questionnaire. (CEBQ) permite evaluar las conductas alimentarias de los niños relacionadas con el riesgo de obesidad, por lo que se planteó el siguiente objetivo evaluar las propiedades psicométricas de la versión original del CEBQ en niños mexicanos de 1 a 3 años. Material y Métodos: 201 madres residentes del noreste de México completaron el CEBQ en centros de salud comunitarios. Se realizó un análisis factorial confirmatorio (AFC) a través de componentes principales y fiabilidad (consistencia interna) con alfa de Cronbach (α). Resultados: Se identificó un modelo con siete factores y 24 ítems, los índices de bondad de ajuste del modelo propuesto fueron adecuados: índice de ajuste comparativo (CFI= 0.90), y error cuadrático medio de aproximación (RMSEA= 0.06). Los factores que integran el CEBQ tienen aceptable confiabilidad internaα > 0.70. Conclusión: El CEBQ en niños mexicanos de 1 a 3 años tiene propiedades psicométricas que lo hace una medida confiable y válida para evaluar comportamientos alimentarios relacionados con el riesgo de obesidad. Se recomienda contrastar este modelo en poblaciones similares.

Abstract Objective: Mexico is one of the countries with the highest prevalence of childhood obesity worldwide. Valid comprehensive assessment instruments are required to address the problem. The Child Eating Behavior Questionnaire(CEBQ) allows the assessment of children's eating behaviors related to obesity risk, so the following objective was to evaluate the psychometric properties of the original version of the CEBQ in Mexican children aged 1 to 3 years. Material and Methods: 201 mothers residing in northeastern Mexico completed the CEBQ in community health centers. A confirmatory factor analysis (CFA) was performed through principal components and reliability (internal consistency) with Cronbach's alpha (α). Results: A model with seven factors and 24 items was identified, the goodness-of-fit indices of the proposed model were adequate: comparative fit index (CFI=0.90), and root mean square error of approximation (RMSEA= 0.06). The factors that make up the CEBQ have acceptable internal reliability α > 0.70. Conclusion: The CEBQ in Mexican children aged 1 to 3 years has psychometric properties that make it a reliable and valid measure to assess eating behaviors related to obesity risk. It is recommended to contrast this model in similar populations.

A straightforward method to quantify circulating mRNAs as biomarkers of colorectal cancer.

Optimizing the biomarker combination to be analyzed in liquid biopsies should improve personalized medicine. We developed a method to purify circulating cell-free mRNAs from plasma samples and to quantify them by RT-qPCR. We selected three candidate colorectal cancer biomarkers (B2M, TIMP-1, and CLU). Their mRNA levels were significantly higher in plasma of patients with metastatic colorectal cancer patients (mCRC) (n = 107) than in healthy individuals (HI) (n = 53). To increase the discriminating performance of our method, we analyzed the sum of the three mRNA levels (BTC index). The area under the ROC curve (AUC) to estimate the BTC index capacity to discriminate between mCRC and HI plasma was 0.903. We also determined the optimal BTC index cut-off to distinguish between plasma samples, with 82% of sensitivity and 93% of specificity. By using mRNA as a novel liquid biopsy analytical parameter, our method has the potential to facilitate rapid screening of CRCm.

Nursing Staff Mortality During the Covid-19 Pandemic, Scoping Review.

Introduction: In a pandemic, the risk of infection and mortality for nurses can increase substantially. This study analyzes the information reported on the mortality of nursing personnel from different countries due to COVID-19. Methods: We performed a scoping review by searching information available in PubMed, Scielo, and Google Scholar databases using concepts related to nursing, mortality, COVID-19, etc. The studies were searched from September 1 to October 30, 2021. This review included 12 articles were selected among 73 identified for the scope search because they included nurses. Results: Nursing personnel presented a high mortality rate after physicians and health personnel. The average age of the deceased nurses was 43 years, being higher in men than in women. Higher mortality rates were reported in services attending COVID-19, nursing homes, and psychiatric centers. Conclusion: Contagion and deaths are attributed to lack of planning and inadequate personal protective equipment.

Association of neutrophil extracellular traps with the production of circulating DNA in patients with colorectal cancer.

We postulate that a significant part of circulating DNA (cirDNA) originates in the degradation of neutrophil extracellular traps (NETs). In this study, we examined the plasma level of two markers of NETs (myeloperoxidase (MPO) and neutrophil elastase (NE)), as well as cirDNA levels in 219 patients with a metastatic colorectal cancer (mCRC), and in 114 healthy individuals (HI). We found that in patients with mCRC the content of these analytes was (i) highly correlated, and (ii) all statistically different (p < 0.0001) than in HI (N = 114). These three NETs markers may readily distinguish between patients with mCRC from HI, (0.88, 0.86, 0.84, and 0.95 AUC values for NE, MPO, cirDNA, and NE + MPO + cirDNA, respectively). Concomitant analysis of anti-phospholipid (anti-cardiolipin), NE, MPO, and cirDNA plasma concentrations in patients with mCRC might have value for thrombosis prevention, and suggested that NETosis may be a critical factor in the immunological response/phenomena linked to tumor progression.

Impact of SIRPα polymorphism on transplant outcomes in HLA-identical living donor kidney transplantation.

Signal-regulatory protein α (SIRPα), a polymorphic inhibitory membrane-bound receptor, and its ligand CD47 have recently been implicated in the modulation of innate immune allorecognition in murine models. Here, we investigate the potential impact of SIRPα donor-recipient mismatches on graft outcomes in human kidney transplantation. To eliminate the specific role of HLA-matching in alloresponse, we genotyped the two most common variants of SIRPα in a cohort of 55 HLA-identical, biologically-related, donor-recipient pairs. 69% of pairs were SIRPα identical. No significant differences were found between donor-recipient SIRPα-mismatch status and T cell-mediated rejection/borderline changes (25.8% vs. 25%) or slow graft function (15.8% vs. 17.6%). A trend towards more graft failure (GF) (23.5% vs. 5.3%, P = .06), interstitial inflammation (50% vs. 23%, P = .06) and significant changes in peritubular capillaritis (ptc) (25% vs. 0%, P = .02) were observed in the SIRPα-mismatched group. Unexpectedly, graft-versus-host (GVH) SIRPα-mismatched pairs exhibited higher rates of GF and tubulitis (38% vs. 5%, P = .031 and .61 ± .88 vs. 0, P = .019; respectively). Whether the higher prevalence of ptc in SIRPα-mismatched recipients and the higher rates of GF in GVH SIRPα-mismatched pairs represent a potential role for SIRPα in linking innate immunity and alloimmune rejection requires further investigation in larger cohorts.

Monitoring levels of circulating cell-free DNA in patients with metastatic colorectal cancer as a potential biomarker of responses to regorafenib treatment.

Circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which can be obtained from serial liquid biopsies to enable tumor genome analysis throughout the course of treatment. We investigated cfDNA and mutant ctDNA as potential biomarkers to predict the best outcomes of regorafenib-treated metastatic colorectal cancer (mCRC) patients. We analyzed longitudinally collected plasma cfDNA of 43 mCRC patients prospectively enrolled in the phase II TEXCAN trial by IntPlex qPCR. Qualitative (KRAS, NRAS, BRAFV600E mutations) and quantitative (total cfDNA concentration, mutant ctDNA concentration, mutant ctDNA fraction) parameters were correlated with overall survival (OS) and progression-free survival (PFS). When examined as classes or continuous variables, the concentrations of total cfDNA, mutant ctDNA, and, partly, mutant ctDNA fraction prior to regorafenib treatment correlated with OS. Patients with baseline cfDNA > 26 ng·mL-1 had shorter OS than those with cfDNA value below this threshold (4.0 vs 6.9 months; log-rank P = 0.0366). Patients with baseline mutant ctDNA > 2 ng·mL-1 had shorter OS than those with mutant ctDNA below this threshold (log-rank P = 0.0154). We show that pretreatment cfDNA and mutant ctDNA levels may identify mCRC patients that may benefit from regorafenib treatment.

Self-reported executive function, and not performance-based measures, strongly associates with symptoms of premenstrual syndrome/premenstrual dysphoric disorder / Autorreporte de funciones ejecutivas, y no medidas de desempeño, fuertemente se asocia con síntomas de síndrome premenstrual/trastorno disfórico premenstrual

Abstract Introduction Premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD) may be neuropsychologically understood as impairments of executive functions (EF), since these are related to the regulation of complex behavior and cognition. Objective To test the utility of self-report of EF versus performance-based measures, for the understanding of PMS/PMDD, and to analyze interactive effects between symptoms of these pathologies and EF on daily-life functionality. Method Mexican women were recruited through non-probabilistic procedures. The Premenstrual Symptoms Screening Tool (PSST) was used to determine severity of symptoms and functional impairment in daily-life activities, and the Behavioral Rating Inventory of Executive Functions-Adults (BRIEF-A) (short Spanish-translated version) adapted to collect information on EF during luteal versus follicular phases. Performance was evaluated with Stroop, Trail Making Test and Letter-Number Sequencing. Results A total of 157 were analyzed. Three groups were formed: No diagnosis ( n = 78); PMS ( n = 67) and PMDD ( n = 12). Between-group differences were observed for both BRIEF-A-Luteal and BRIEF-A-Follicular. Bivariate correlations between these measures and the PSST were found, with double the magnitude relative to BRIEF-A-Luteal. Only two indicators of performance-based measures were weakly associated to the PSST. The regression model showed high multicollinearity between self-reported EF and PMS/PMDD symptoms, and no interaction was found. Discussion and conclusion Self-report probed a better association than based-performance tests for the assessment of EF in PMS/PMDD. EF deficits and PMS/PMDD symptoms, particularly during luteal phase, may be as closely link as to allow for the consideration of these diagnoses as partial forms of dysexecutive syndrome.

Resumen Introducción El síndrome premenstrual/trastorno disfórico premenstrual (SPM/TDPM) pueden entenderse neuropsicológicamente como alteraciones de las funciones ejecutivas (FE), ya que éstas permiten la regulación del comportamiento complejo y la cognición. Objetivo Evaluar la utilidad del autorreporte de las FE versus pruebas de desempeño para comprender el SPM/TDPM, y analizar los efectos interactivos entre los síntomas de estas patologías y las FE sobre el funcionamiento diario. Método Mujeres mexicanas fueron reclutadas por medio de procedimientos no probabilísticos. El Instrumento de Detección de Síntomas Premenstruales (PSST) se utilizó para determinar la gravedad de los síntomas y el deterioro funcional en las actividades de la vida diaria, y el Inventario de Evaluación Conductual de la Función Ejecutiva-Adultos (BRIEF-A) (versión breve traducida al español) para recopilar información sobre EF durante las fases lútea versus folicular. Se emplearon también las pruebas de desempeño: Stroop, Trail Making Test y Secuencia de Letras y Números. Resultados Se analizó un total de 157 participantes. Se formaron tres grupos: sin diagnóstico ( n = 78); SPM ( n = 67) y TDPM ( n = 12). Se observaron diferencias entre los grupos para BRIEF-A-Lútea y BRIEF-A-Folicular. Se encontraron correlaciones bivariadas entre estas medidas y el PSST, con el doble de magnitud en relación con BRIEF-A-Lútea. Solo dos indicadores de medidas basadas en el desempeño mostraron una asociación débil con el PSST. El modelo de regresión mostró alta multicolinealidad entre el autorreporte de FE y SPM/TDPM, y no se encontró la interacción esperada. Discusión y conclusión El autorreporte mostró una mejor asociación que las pruebas de rendimiento para la evaluación de FE en SPM/TDPM. Los déficits de EF y los síntomas de SPM/TDPM, particularmente durante la fase lútea, pueden estar tan estrechamente vinculados como para permitir la consideración de estos diagnósticos como formas parciales de síndrome disejecutivo.

Disproportionate left atrial myopathy in heart failure with preserved ejection fraction among participants of the PROMIS-HFpEF study.

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

Effect of Prolonged-Release Pirfenidone on Renal Function in Septic Acute Kidney Injury Patients: A Double-Blind Placebo-Controlled Clinical Trial.

BACKGROUND: There is no treatment for septic acute kidney injury (sAKI). The anti-inflammatory activity of prolonged-release pirfenidone (PR-PFD) could be beneficial in this clinical setting. METHODS: This study was a double-blind randomized clinical trial in sAKI patients with nephrology consultation at the Civil Hospital of Guadalajara, in addition to the usual treatment of AKI associated with sepsis; patients were randomized to receive either PR-PFD at 1,200 mg/day (group A) or 600 mg/day (group B) or a matched placebo for 7 consecutive days. The primary objective was the decrease in serum creatinine (sCr) and increase in urinary volume (UV); the secondary objectives were changes in serum electrolytes, acid-base status, and mortality. RESULTS: Between August 2016 and August 2017, 88 patients were randomized. The mean age was 54 (17 ± SD) years, and 47% were male. The main site of infection was the lung (39.8%), septic shock was present in 39.1% of the cases, and the mean SOFA score was 8.8 points. 28 patients received PFD 1,200 mg, 30 patients received PFD 600 mg, and 30 patients received placebo. During the study, sCr did not differ among the groups. The reversion rate of sCr, UV, and mortality was not different among the groups (p=0.70, p=0.47, and p=0.38, respectively). Mild adverse events were not different among the groups. CONCLUSION: PR-PFD did not improve the clinical course of sAKI and seemed to be safe in terms of adverse events. This trial is registered with NCT02530359.

Circulating nuclear DNA structural features, origins, and complete size profile revealed by fragmentomics.

To unequivocally address their unresolved intimate structures in blood, we scrutinized the size distribution of circulating cell-free DNA (cfDNA) using whole-genome sequencing (WGS) from both double- and single-strand DNA library preparations (DSP and SSP, n = 7) and using quantitative PCR (Q-PCR, n = 116). The size profile in healthy individuals was remarkably homogenous when using DSP sequencing or SSP sequencing. CfDNA size profile had a characteristic nucleosome fragmentation pattern. Overall, our data indicate that the proportion of cfDNA inserted in mono-nucleosomes, di-nucleosomes, and chromatin of higher molecular size (>1000 bp) can be estimated as 67.5% to 80%, 9.4% to 11.5%, and 8.5% to 21.0%, respectively. Although DNA on single chromatosomes or mono-nucleosomes is detectable, our data revealed that cfDNA is highly nicked (97%-98%) on those structures, which appear to be subjected to continuous nuclease activity in the bloodstream. Fragments analysis allows the distinction of cfDNA of different origins: first, cfDNA size profile analysis may be useful in cfDNA extract quality control; second, subtle but reliable differences between metastatic colorectal cancer patients and healthy individuals vary with the proportion of malignant cell-derived cfDNA in plasma extracts, pointing to a higher degree of cfDNA fragmentation and nuclease activity in samples with high malignant cell cfDNA content.

The Decolonization of Nursing Education.

In the era of COVID-19, coupled with a community in tune to Black lives, the call to action is now. It is now time to stop, listen, and be intentional in efforts to create sustainable policies and programs that shape the ability to deliver culturally competent care to diverse patients, families, professionals, and communities. Our recommendations for how faculty and academia can decolonize nursing education are delineated in this article. All nursing schools and departments should form a diversity, equity, and inclusion (DEI) committee, if they have not already done so. DEI committees can help thread Social Determinants of Health throughout the curriculum, highlight and address microaggressions, and develop formal and informal mentorship programs. As nurses, we must continue the discussion of race with humility but without denial and defensiveness. Subtle racist biases may be unintentionally internalized, and it is our moral and ethical responsibility to recognize these and fight them so that they do not result in prejudicial policy, practice, research, and education. Faculty should celebrate diversity through an exchange of ideas and open communication despite differences in race, gender, sexual orientation, religion, age, social class, or disability.

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

BACKGROUND: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. METHODS: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. RESULTS: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. CONCLUSIONS: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

The shared epitope phenomenon-A potential impediment to virtual crossmatch accuracy.

With the implementation of the new kidney allocation system (KAS), there is increased reliance on a virtual crossmatch/histocompatibility risk assessment (vXM) for evaluating potential presence, as well as strength, of HLA antibodies against a potential donor. The accuracy of such an assessment depends on the precision in the identification of the recipient's antibody profile and the potential donor's HLA typing. While the development of the single antigen bead (SAB) multiplex assay has improved the sensitivity and specificity of HLA antibody detection, several limitations of the assay (specific to certain sensitized patients) can complicate accurate interpretation of results. In this report, we focus on the "shared-epitope" phenomenon, a condition in which antibody strength can be underrepresented, or its presence completely missed, due to binding of the antibody to competing targets on multiple antigens (beads), effectively "diluting" the resulting MFI readout. Here, we provide a relevant background to understand this phenomenon and present a couple of case studies illustrating how it can be investigated, leading to a more accurate histocompatibility consultation.

Manejo ortodóncico de la clase III: presentación de un caso clínico / Orthodontic management of class III: presentation of a clinical case

Introducción: La maloclusión clase III es considerada como severa y en la mayoría de los pacientes la etiología suele estar combinada entre componentes esqueléticos y dentoalveolares. Las posibilidades terapéuticas dependerán de la edad biológica del paciente y del tipo de maloclusión. Conforme va aumentando la edad del paciente va menguando la capacidad de crecimiento y se va asentando la relación de clase III esquelética. Las maloclusiones de clase III esqueléticas se pueden corregir mediante extracciones dentales y cirugía ortognática. Caso clínico: Paciente masculino de 13 años de edad con protrusión mandibular, discrepancia óseo dentaria negativa, convexidad facial disminuida y clase III dental y esqueletal. Resultados: Se resolvió la discrepancia óseo dentaria negativa del paciente, se logró la clase I Molar y canina con una sobremordida adecuada (AU)

Introduction: Class III malocclusion is considered severe and in most patients the etiology is usually combined between skeletal and dentoalveolar components. The therapeutic possibilities depend on the biological age of the patient and the type of malocclusion. As it increases the age of the patient wanes growth capacity and Will settled the relationship skeletal class III. The skeletal class III malocclusion can be corrected by tooth extractions and orthognathic surgery. Case report: Male patient 13 years old with mandibular protrusion, negative tooth bone discrepancy, decreased facial convexity and dental and skeletal class III. Results: Dental patient refusal bone discrepancy was resolved, I molar and canine class and adequate overbite was achieved (AU)