Clinical Utility of the Molecular Microscope Diagnostic System in a Real-World Transplant Cohort: Moving Towards a New Paradigm.

Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.

The DNA methyltransferase inhibitor decitabine blunts the response to a high animal fat and protein diet in mice.

Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis, i.e., that the DNA methyltransferase inhibitor decitabine (Dec) ameliorates the metabolic profile of mice fed a moderately high-animal fat and protein diet (HAFPD), a proxy of cardiovascular risk-associated Western-type diet. HAFPD-fed mice were exposed to Dec or vehicle for eight weeks (8W set, 4-32/group). To assess any memory of past exposure to Dec, we surveyed a second mice set treated as 8W but HAFPD-fed for further eight weeks without any Dec (16W set, 4-20/group). In 8W, Dec markedly reduced HAFPD-induced body weight gain in females, but marginally in males. Characterization of females revealed that Dec augmented skeletal muscle lipid content, while decreasing liver fat content and increasing plasma non-esterified fatty acids, adipose insulin resistance, and -although marginally- whole blood acylcarnitines, compared to HAFPD alone. Skeletal muscle mitochondrial DNA copy number was higher in 8W mice exposed to HAFPD and Dec, or in 16W mice fed HAFPD only, relative to 8W mice fed HAFPD only, but Dec induced a transcriptional profile indicative of ameliorated mitochondrial function. Memory of past Dec exposure was tissue-specific and sensitive to both duration of exposure to HAFPD and age. In conclusion, Dec redirected HAFPD-induced lipid accumulation towards the skeletal muscle, likely due to augmented mitochondrial functionality and increased lipid demand. As caveat, Dec induced adipose insulin resistance. Our findings may help identifying strategies for prevention and treatment of lipid dysmetabolism.

Labeled dataset for training despeckling filters for SAR imagery.

When training Artificial Intelligence and Deep Learning models, especially by using Supervised Learning techniques, a labeled dataset is required to have an input with data and its corresponding labeled output data. In the case of images, for classification, segmentation, or other processing tasks, a pair of images is required in the same sense, one image as an input (the noisy image) and the desired (the denoised image) one as an output. For SAR despeckling applications, the common approach is to have a set of optical images that then are corrupted with synthetic noise, since there is no ground truth available. The corrupted image is considered the input and the optical one is the noiseless one (ground truth). In this paper, we provide a dataset based on actual SAR images. The ground truth was obtained from SAR images of Sentinel 1 of the same region in different instants of time and then they were processed and merged into one single image that serves as the output of the dataset. Every SAR image (noisy and ground truth) was split into 1600 images of 512 × 512 pixels, so a total of 3200 images were obtained. The dataset was also split into 3000 for training and 200 for validation, all of them available in four labeled folders.

Circulating microRNAs associated with prediabetes and geographic location in Latinos.

BACKGROUND: Globally, type 2 diabetes is highly prevalent in individuals of Latino ancestry. The reasons underlying this high prevalence are not well understood, but both genetic and lifestyle factors are contributors. Circulating microRNAs are readily detectable in blood and are promising biomarkers to characterize biological responses (i.e., changes in gene expression) to lifestyle factors. Prior studies identified relationships between circulating microRNAs and risk for type 2 diabetes, but Latinos have largely been under-represented in these study samples. AIMS/HYPOTHESIS: The aim of this study was to assess for differences in expression levels of three candidate microRNAs (miR-126, miR-146, miR-15) between individuals who had prediabetes compared to normal glycemic status and between individuals who self-identified with Latino ancestry in the United States (US) and native Mexicans living in or near Leon, Mexico. METHODS: This was a cross-sectional study that included 45 Mexicans and 21 Latino participants from the US. Prediabetes was defined as fasting glucose 100-125 mg/dL or 2-h post-glucose challenge between 140 and 199 mg/dL. Expression levels of microRNAs from plasma were measured by qPCR. Linear and logistic regression models were used to assess relationships between individual microRNAs and glycemic status or geographic site. RESULTS: None of the three microRNAs was associated with risk for type 2 diabetes. MiR-146a and miR-15 were significantly lower in the study sample from Mexico compared to the US. There was a significant interaction between miR-146a and BMI associated with fasting blood glucose. CONCLUSIONS/INTERPRETATION: This study did not replicate in Latinos prior observations from other racial groups of associations between miR-126, miR-146a, and miR-15 and risk for type 2 diabetes. Future studies should consider other microRNAs related to different biological pathways as possible biomarkers for type 2 diabetes in Latinos.

Association of the 3'UTR polymorphism (rs11665896) in the FGF21 gene with metabolic status and nutrient intake in children with obesity.

Background Fibroblast growth factor 21 (FGF21) is considered an important regulator of lipid and glucose metabolism. However, the role of FGF21 in macronutrient intake and metabolic disease, particularly in pediatric population, still needs further clarification. This study aimed to evaluate the association of rs11665896 in the FGF21 gene with metabolic status and macronutrient intake in a cohort of Mexican children with obesity. Methods Eighty-four lean children and 113 children with obesity, from 8 to 11 years of age, were recruited. FGF21 rs11665896 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Somatometric evaluations, nutrient intake, glucose, lipids, insulin and FGF21 serum levels were measured in the obesity group. Results The T allele of rs11665896 in the FGF21 gene was associated with obesity (odds ratio [OR] = 1.99, 95% confidence interval [CI] = 1.14-3.46; p = 0.0151). Subjects with obesity carrying the TT genotype consumed less lipids and more carbohydrates compared to other genotypes. Circulating FGF21 levels correlated negatively with carbohydrate intake (r = -0.232, p = 0.022) and positively with body weight (r = 0.269, p = 0.007), waist (r = 0.242, p = 0.016) and hip girth (r = 0.204, p = 0.042). FGF21 levels were lower in carriers of at least one T allele. Conclusions Genetic variants in FGF21 could influence metabolic status, food preferences and qualitative changes in nutritional behavior in children.

Riesgo de desnutrición prequirúrgico como factor causal de estancia hospitalaria prolongada en cirugía gastrointestinal / Risk of pre-surgical malnutrition as a causal factor of prolonged hospital stay in gastro intestinal surgery

Resumen Introducción La desnutrición corresponde al déficit de energía y nutrimentos. Contribuye con mayor número y gravedad de complicaciones en diversas enfermedades. En procedimientos quirúrgicos, la desnutrición se ha relacionado con infecciones intrahospitalarias e incremento en mortalidad. Se ha postulado que una valoración nutricional adecuada identifica de forma oportuna el riesgo de desarrollar complicaciones. Objetivo Identificar la frecuencia de riesgo de desnutrición preoperatoria y sus efectos en pacientes sometidos a intervención quirúrgica por patología gastrointestinal. Material y métodos Estudio clínico observacional, descriptivo y retrospectivo, que incluye la totalidad de expedientes de pacientes que fueron intervenidos por cirugía gastrointestinal de enero a diciembre de 2016. La asociación entre variables con el desenlace primario se realizó mediante análisis de regresión logística. Resultados Se incluyeron 138 expedientes. La frecuencia de riesgo de desnutrición preoperatoria fue del 4%. El grupo con riesgo de desnutrición tuvo una mediana de estancia hospitalaria de cinco vs dos días en el grupo sin riesgo (p = 0.014). No se observaron diferencias estadísticas en complicaciones postquirúrgicas. La hipoproteinemia es el principal factor sérico relacionado con la existencia de desnutrición preoperatoria (OR 5.91, IC 95% 1.12-31.1, p = 0.036). Finalmente, la presencia de riesgo de desnutrición preoperatoria se asoció con estancia hospitalaria prolongada (OR 1.33, IC 95% 1.07-1.64, p = 0.008) Conclusiones La existencia de riesgo de desnutrición preoperatoria se relaciona con estancia hospitalaria prolongada en pacientes intervenidos por cirugía gastrointestinal. Estudios subsecuentes deberán enfocarse en implementar estrategias nutricionales que incidan en menor tiempo de estancia en hospital.

Abstract Introduction Malnutrition consists of deficit of energy and nutrients. It can contribute to increase the number and severity of complications of the disease. Among surgical procedures, malnutrition its related with nosocomial infections and higher mortality. It has been postulated that an adequate nutritional assessment reduces the risk of developing complications. Objective To determine the prevalence of preoperative malnutrition and it's effects in patients undergoing surgery for gastrointestinal pathology. Material and methods This is a clinical observational, descriptive and retrospective chart review of patients who underwent gastrointestinal surgery from January 2016 to December 2016. The association between risk factors and main outcome was analyzed with logistic regression analysis. Results Our population consisted of 138 files of patients who underwent gastrointestinal surgery. The prevalence of malnutrition was 4%. The group at risk of preoperative malnutrition had a median hospital length of stay of 5 vs 2 days in the group without risk (p = 0.014). There were non-statistical significant differences in post-surgical complications. Hypoproteinemia is the main serum biomarker related to the existence of preoperative malnutrition (OR 5.91, 95% CI 1.12-31.1, p = 0.036). It was identified that the existence of risk of preoperative malnutrition is related to prolonged hospital stay (OR 1.33, 95% CI 1.07-1.64, p = 0.008) Conclusions The evidence of risk of preoperative malnutrition is related to prolonged hospital stay in patients who underwent gastrointestinal surgery. Subsequent studies should focus on nutritional interventions that could shorten hospital length of stay.

Are cannabinoids an effective treatment for chronic non-cancer pain? / ¿Son los cannabinoides un tratamiento efectivo para el dolor crónico no asociado a cáncer?

The use of cannabinoids has been proposed as an analgesic for different painful conditions, especially for chronic pain refractory to usual treatment. However, its real efficacy and safety remains controversial. We sought to determine whether cannabinoids are an effective treatment for chronic non-cancer pain. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified 37 systematic reviews including 41 studies overall, of which 32 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded it is not clear whether cannabinoids decrease pain in patients with chronic non-cancer pain because the certainty of available evidence is very low. On the other hand, they are associated with significant adverse effects.

El uso de cannabinoides se ha propuesto como analgésico para dolores de diversa índole, en especial para pacientes con dolor crónico refractario al tratamiento habitual. Sin embargo, su real eficacia y seguridad sigue siendo motivo de controversia, por lo que buscamos determinar sus efectos en pacientes con dolor crónico no asociado a cáncer. Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos 37 revisiones sistemáticas que en conjunto incluyen 41 estudios, de los que 32 son ensayos aleatorizados relevantes para nuestra pregunta. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metaanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que no está claro si los cannabinoides disminuyen el dolor en pacientes con dolor crónico no asociado a cáncer porque la certeza de la evidencia disponible es muy baja. Por otra parte, se asocian a efectos adversos importantes.

The AGE-RAGE Axis and Its Relationship to Markers of Cardiovascular Disease in Newly Diagnosed Diabetic Patients.

AIM: The purpose of the study was the simultaneous measurement of all the different components of the AGE-RAGE axis as well as several non-invasive markers of cardiovascular disease (CVD) in a cohort of newly diagnosed diabetic patients. MATERIALS AND METHODS: In 80 newly diagnosed diabetic patients we measured serum carboxymethyllysine (CML), soluble RAGE (sRAGE) and peripheral mononuclear (PMNC) RAGE and AGER1 mRNA together with ICAM-1, VCAM-1, and malondialdehyde (MDA). We also assessed cardiovascular function by measurement of flow-mediated vasodilation (FMD), intima-media thickness (IMT) and arterial stiffness. Univariant correlation analysis was used to determine correlation between the variables in the study and multiple regression analysis was used to examine the association between the AGE-RAGE axis components and FMD, IMT and arterial stiffness. RESULTS: Serum CML correlated positively with sRAGE, PMNC RAGE, HOMA-IR, ICAM-1, VCAM-1 and MDA, but inversely with PMNC AGER1. sRAGE and RAGE was positively correlated with AGER; IMT was positively correlated with HOMA-IR, ICAM-1, VCAM-1, MDA, and sRAGE and arterial stiffness had correlation with HOMA-IR, ICAM-1, VCAM-1, MDA, CML, sRAGE, AGER1 and RAGE. In multivariate analysis we found a significant relationship between CML with PMNC RAGE, HOMA-IR; sRAGE with VCAM-1 and MDA; PMNC RAGE with PMNC AGER1and CML; PMNC AGER1 with PMNC RAGE; FMD with sRAGE, CML and HbA1c; IMT with sRAGE, and arterial stiffness with sRAGE, sCML and AGER1. CONCLUSIONS: We found significant and strong associations between the different components of the AGE-RAGE axis and also found significant association between AGE-RAGE axis markers, especially sRAGE with several noninvasive markers of cardiovascular disease risk. sRAGE, an easily measured parameter in blood, may potentially be used as a surrogate marker of AGEs-RAGE in patients with diabetes.

Influence of initial occlusal severity on time and efficiency of Class I malocclusion treatment carried out with and without premolar extractions.

INTRODUCTION: The aim of this retrospective study was to compare the occlusal outcomes, duration and efficiency of Class I malocclusion treatment carried out with and without premolar extractions in patients with different degrees of initial malocclusion severity. METHODS: Complete records of 111 patients were obtained and divided into two groups: Group 1 consisted of 65 patients at an initial mean age of 13.82 years old treated with four premolar extractions; whereas Group 2 consisted of 46 patients at an initial mean age of 14.01 years old treated without extractions. Two subgroups were obtained from each group (1A, 1B, 2A and 2B) with different degrees of malocclusion severity according to the initial values of PAR index. Compatibility was assessed using chi-square and t-tests. The subgroups were compared by means of Analysis of Variance (ANOVA). The variables that might be related to treatment duration and efficiency were assessed using the multiple linear regression analysis. RESULTS: Initial malocclusion severity was positively related to the amount of occlusal correction and consequently to a higher efficiency index. Moreover, extraction protocol showed a positive relationship with treatment duration and a negative relationship with treatment efficiency. CONCLUSION: Extraction and non-extraction protocols for correction of Class I malocclusion provide similar satisfactory results; however, the extraction protocol increases the overall treatment duration. Orthodontic treatment is more efficient in cases with high initial malocclusion severity treated with a non-extraction protocol.

Influence of initial occlusal severity on time and efficiency of Class I malocclusion treatment carried out with and without premolar extractions

INTRODUCTION: The aim of this retrospective study was to compare the occlusal outcomes, duration and efficiency of Class I malocclusion treatment carried out with and without premolar extractions in patients with different degrees of initial malocclusion severity. METHODS: Complete records of 111 patients were obtained and divided into two groups: Group 1 consisted of 65 patients at an initial mean age of 13.82 years old treated with four premolar extractions; whereas Group 2 consisted of 46 patients at an initial mean age of 14.01 years old treated without extractions. Two subgroups were obtained from each group (1A, 1B, 2A and 2B) with different degrees of malocclusion severity according to the initial values of PAR index. Compatibility was assessed using chi-square and t-tests. The subgroups were compared by means of Analysis of Variance (ANOVA).The variables that might be related to treatment duration and efficiency were assessed using the multiple linear regression analysis. RESULTS: Initial malocclusion severity was positively related to the amount of occlusal correction and consequently to a higher efficiency index. Moreover, extraction protocol showed a positive relationship with treatment duration and a negative relationship with treatment efficiency. CONCLUSION: Extraction and non-extraction protocols for correction of Class I malocclusion provide similar satisfactory results; however, the extraction protocol increases the overall treatment duration. Orthodontic treatment is more efficient in cases with high initial malocclusion severity treated with a non-extraction protocol. .

INTRODUÇÃO: o objetivo desse estudo retrospectivo foi comparar os resultados oclusais, o tempo e o grau de eficiência do tratamento da má oclusão de Classe I realizado com e sem extrações em pacientes que apresentavam diferentes tipos de severidade oclusal inicial. MÉTODOS: a amostra foi composta pelas documentações de 111 pacientes, divididas em dois grupos: Grupo 1 (n = 65), com idade inicial média de 13,82 anos, tratados com extrações; Grupo 2 (n = 46), com idade inicial média de 14,01 anos, tratados sem extrações. De cada grupo, foram obtidos dois subgrupos (1A, 1B, 2A e 2B) com severidades oclusais diferentes (alta e baixa), de acordo aos valores iniciais do índice PAR. A avaliação da compatibilidade foi realizada por meio do teste qui-quadrado e do teste t. Os subgrupos foram comparados por meio da análise de variância (ANOVA) e foi realizada a análise de regressão linear múltipla para avaliação das variáveis que poderiam estar relacionadas com o tempo e com a eficiência do tratamento. RESULTADOS: a severidade oclusal inicial esteve diretamente relacionada à quantidade de sua correção e, consequentemente, à obtenção de um maior índice de eficiência; por outro lado, a utilização do protocolo de extrações de pré-molares mostrou uma relação direta com o tempo de tratamento e inversa com a eficiência do tratamento. CONCLUSÃO: no tratamento da má oclusão de Classe I, podem ser obtidos resultados oclusais satisfatórios com uma maior quantidade de correção das alterações oclusais nos casos com maior severidade inicial, e um maior tempo de tratamento quando o tratamento envolve extrações dentárias. .

Human native lipoprotein-induced de novo DNA methylation is associated with repression of inflammatory genes in THP-1 macrophages.

BACKGROUND: We previously showed that a VLDL- and LDL-rich mix of human native lipoproteins induces a set of repressive epigenetic marks, i.e. de novo DNA methylation, histone 4 hypoacetylation and histone 4 lysine 20 (H4K20) hypermethylation in THP-1 macrophages. Here, we: 1) ask what gene expression changes accompany these epigenetic responses; 2) test the involvement of candidate factors mediating the latter. We exploited genome expression arrays to identify target genes for lipoprotein-induced silencing, in addition to RNAi and expression studies to test the involvement of candidate mediating factors. The study was conducted in human THP-1 macrophages. RESULTS: Native lipoprotein-induced de novo DNA methylation was associated with a general repression of various critical genes for macrophage function, including pro-inflammatory genes. Lipoproteins showed differential effects on epigenetic marks, as de novo DNA methylation was induced by VLDL and to a lesser extent by LDL, but not by HDL, and VLDL induced H4K20 hypermethylation, while HDL caused H4 deacetylation. The analysis of candidate factors mediating VLDL-induced DNA hypermethylation revealed that this response was: 1) surprisingly, mediated exclusively by the canonical maintenance DNA methyltransferase DNMT1, and 2) independent of the Dicer/micro-RNA pathway. CONCLUSIONS: Our work provides novel insights into epigenetic gene regulation by native lipoproteins. Furthermore, we provide an example of DNMT1 acting as a de novo DNA methyltransferase independently of canonical de novo enzymes, and show proof of principle that de novo DNA methylation can occur independently of a functional Dicer/micro-RNA pathway in mammals.

Nonextraction treatment of a skeletal Class III malocclusion.

This case report describes the nonsurgical, nonextraction therapy of a 16-year-old boy with a skeletal Class III malocclusion, a prognathic mandible, and a retrusive maxilla. He was initially classified as needing orthognathic surgery, but he and his parents wanted to avoid that. The Class III malocclusion was corrected with a rapid palatal expander and a maxillary protraction mask followed by nonextraction orthodontic treatment with fixed appliances, combined with short Class III and vertical elastics in the anterior area. The height of the maxillary alveolar process and the vertical face height were slightly increased with treatment. Class I molar and canine relationships were achieved, and the facial profile improved substantially.

Long-term stability of Class II malocclusion treated with 2- and 4-premolar extraction protocols.

INTRODUCTION: The objective of this study was to cephalometrically compare the stability of complete Class II malocclusion treatment with 2 or 4 premolar extractions after a mean period of 9.35 years. METHODS: A sample of 57 records from patients with complete Class II malocclusion was selected and divided into 2 groups. Group 1 consisted of 30 patients with an initial mean age of 12.87 years treated with extraction of 2 maxillary premolars. Group 2 consisted of 27 patients with an initial mean age of 13.72 years treated with extraction of 4 premolars. T tests were used to compare the groups' initial cephalometric characteristics and posttreatment changes. Pearson correlation coefficients were calculated to determine the correlation between treatment and posttreatment dental-relationship changes. RESULTS: During the posttreatment period, both groups had similar behavior, except that group 1 had a statistically greater maxillary forward displacement and a greater increase in the apical-base relationship than group 2. On the other hand, group 2 had a statistically greater molar-relationship relapse toward Class II. There were significant positive correlations between the amounts of treatment and posttreatment dentoalveolar-relationship changes. CONCLUSIONS: Treatment of complete Class II malocclusions with 2 maxillary premolar extractions or 4 premolar extractions had similar long-term posttreatment stability.