Search

BACKGROUND: There is significant heterogeneity in cardiovascular disease (CVD) risk among patients with diabetes mellitus (DM). OBJECTIVES: The purpose of this study was to develop risk scores for total CVD and its components from a contemporary pooled, observational cohort of U.S. adults with DM. METHODS: CVD-free adults with DM aged 40 to 79 years were pooled from 4 U.S. population-based cohorts (CARDIA [Coronary Artery Risk Development in Young Adults], Framingham Offspring, Jackson Heart Study, and the MESA (Multiethnic Study of Atherosclerosis) studied since 2000. Baseline DM-specific and non-DM-specific CVD risk factors were evaluated as predictors. We developed 10-year DM Risk Scores (DMRS) for total CVD, atherosclerotic CVD (ASCVD), coronary heart disease (CHD), heart failure (HF) and stroke. Score performance was validated internally and externally. RESULTS: We included 2,174 adults with DM mean age 59.2 ± 10.5 years, 55.4% female and 47.5% Black followed up to 10 years. Age, sex, HbA1c, creatinine, systolic blood pressure, DM medication, and smoking were the most important predictors. The DMRS had good internal discrimination (c-statistics 0.72, 0.72, 0.72, 0.79 and 0.73 for CVD, ASCVD, CHD, HF, and stroke) and calibration (calibration slopes 0.93, 0.95, 0.93, 0.98, and 0.89 for CVD, ASCVD, CHD, HF, and stroke; Greenwood Nam-DAgostino calibration tests were significant for CHD (P

OBJECTIVE: Higher truncated-to-native apolipoprotein (apo) C-I proteoform ratios (C-I/C-I) are associated with favorable cardiometabolic risk profiles, but their relationship with longitudinal changes in insulin resistance (IR) and incident diabetes is unknown. RESEARCH DESIGN AND METHODS: Plasma apoC-I proteoforms were measured by mass spectrometry immunoassay at baseline in 4,742 nondiabetic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and 524 participants with prediabetes in the Actos Now for Prevention of Diabetes (ACT NOW) study. The primary outcome was incident diabetes (fasting glucose [FG] ≥7.0 mmol/L or hypoglycemic medication use in MESA; FG ≥7.0 mmol/L or 2-h glucose ≥11.1 mmol/L in an oral glucose tolerance test [OGTT] in ACT NOW). Secondary outcomes were changes in FG and HOMA-IR in MESA, and OGTT-glucose area under the curve (AUCglucose) and Matsuda insulin sensitivity index (ISI) in ACT NOW. RESULTS: In MESA, a higher C-I/C-I was associated with lower risk of diabetes (n = 564 events; HR 0.87 [95% CI 0.79, 0.95] per SD; P = 0.0036; median follow-up, 9 years), and smaller increases (follow-up adjusted for baseline) in FG (-0.5%; P < 0.0001) and HOMA-IR (-2.9%; P = 0.011) after adjusting for baseline clinical and demographic covariates, including plasma triglycerides and HDL cholesterol. Total apoC-I concentrations were not associated with changes in FG, HOMA-IR, or incident diabetes. In ACT NOW, higher C-I/C-I was associated with smaller increases in AUCglucose (-1.8%; P = 0.0052), greater increases in ISI (7.2%; P = 0.0095), and lower risk of diabetes (n = 59 events; 0.66 [95% CI 0.48, 0.91]; P = 0.004; median follow-up, 2.5 years) after adjusting for treatment group and diabetes risk factors, including plasma lipids. CONCLUSIONS: Our results indicate that apoC-I truncation may contribute to changes in glucose levels, IR, and risk of diabetes.

BackgroundDietary quality has been linked to better glycemic control, but the precise molecular mechanisms giving rise to these associations are not fully understood.ObjectivesTo examine the association of metabolites associated with the intake of a healthy diet with measures of insulin/glucose homeostasis.MethodsUsing cross-sectional data from 295 United States adults, the associations between 3 diet pattern scores and metabolome-wide metabolites were estimated via linear regression models, which controlled for demographic factors and health behaviors. Subsequently, the associations between the diet-related metabolites with 6 measures of glucose/insulin homeostasis were examined in similar models. A Bonferroni correction was applied to control the family-wise error rate at 5%.ResultsFifty-five metabolites were significantly associated with ≥1 diet score (all P < 1.7∗10-5). When these were summed into each of the 3 diet-specific metabolite summary scores, all 3 aggregate measures showed strong associations with 5 out of 6 measures of glucose/insulin homeostasis (P = 9.7∗10-5-4.1∗10-13).ConclusionsAdherence to a priori-defined "healthy diet" is associated with the plasma metabolites that, in turn, are associated with better glycemia. If the associations between replicated in future studies and examined using large-scale longitudinal data, the identified molecules could yield insights into mechanisms by which diet may support glucose and insulin homeostasis.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P

This study presents a temporal analysis aimed at identifying climatic patterns that influence precipitation behavior in the Middle and Lower Paraguay Basin, part of the Paraná River Basin in Paraguayan territory. This research utilizes satellite-based geospatial technologies to analyze the spatial and temporal variability of precipitation in the region. Satellite precipitation images were used for the period 2001–2023, available on NASA's GIOVANNI platform. The results from the classical exploratory statistical analysis allowed for the identification of data distribution, spatial and temporal variability of precipitation in the basin, areas with the highest accumulations, and drought periods, as well as extreme events associated with the El Niño-Southern Oscillation (ENSO) phenomenon, which impacts southern tropical America, including Paraguay. Through the use of remote sensing data and geomatics techniques, this study supports the goals of GEM24, which focus on applying geospatial technologies to address environmental monitoring challenges. The average monthly precipitation series shows a steady trend, with a decrease in recent years. The lowest average was in August 2004 (5.6 mm), and the highest was in December 2015 (345.22 mm). December is the month with the highest average precipitation, while August records the lowest value. The validation between the precipitation data obtained from the Giovanni platform and conventional weather station data, through correlation and linear regression analysis, revealed a strong and statistically significant relationship, indicating that the satellite model is suitable for predicting precipitation, although not perfect. Additionally, the study of temporal anomalies identified prolonged drought periods (2001–2013 and 2020–2022), with intensification in 2020, and periods of intense rainfall (2014–2019), highlighting the 2015 floods. The spatial precipitation anomalies during El Niño (2015) and La Niña (2020), using IMERG and CHIRPS data, allowed for the identification of precipitation spatial patterns. The areas with the highest precipitation were concentrated in the east and south of the country, while drier areas, such as the Paraguayan Chaco in the basin (west), recorded lower precipitation. This study underscores the role of satellite data and geomatics in environmental monitoring, demonstrating how these technologies can enhance our understanding of climatic patterns and extreme weather events. The findings highlight the importance of geospatial data in global environmental change assessments and the monitoring of regional climatic variability, which are central to the objectives discussed in GEM24.

Abstract: CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562; IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in patients with lymphoma. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of interleukin-6 (IL-6) and related transcripts. Recombinant IL-6 led to resistance. Anti-IL-6 antibody tocilizumab improved the ADC’s cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by a PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous antitumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as Myc Proto-Oncogene (MYC) translocations and TP53 inactivation or R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL-6, PI3Kδ, and BCL2.

Abstract Background Osteoarthritis is a leading cause of pain and retirement in athletic horses. Hydro-expansive functionalized nanogels, acting as Drug Delivery Systems, constitute one of the current therapeutic prospects. These nanogels have the potential to combine mechanical benefits through polymers with the biological effect of prolonged release of bioactive molecules. The purpose of this double-blinded randomized tolerance study versus negative control was to evaluate the response of healthy joints to a single injection of the expected efficient dose (further referred to as the trial dose) and overdose of nanogels composed of chitosan and hyaluronic acid and featuring a type A endothelin receptor antagonist and a type B1 bradykinin receptor antagonist. The metacarpophalangeal joints of 8 healthy horses were randomly injected with 2.4 mL of functionalized nanogels and 2.4 mL of saline as control on the contralateral limb. Injections were repeated twice at one-week intervals, followed by injection of a triple dose of nanogel on week four. Clinical, ultrasonographic and synovial fluid cellular and biochemical follow-ups were performed up to three months following the first injection. Results No change in general clinical parameters, lameness or sensitivity to passive flexion of the fetlocks was noted. Mild to moderate synovitis was noted on the day following injection in the treated group, with a significant difference (p

In this work, we consider the indoor and outdoor microclimatic conditions and the influence of the building on their relationship. Microclimatic indexes are a useful tool to characterize microclimatic environments, and they can be used to compare indoor and outdoor microclimate conditions and to evaluate the influence of the building itself on the microclimate. The case study refers to the ancient building of San Panfilo church in Tornimparte (Italy), preserving an important cycle of frescoes by depicted by Saturnino Gatti from 1491 to 1494. The microclimatic conditions were measured during a dedicated campaign at several sites in the church and two sites outside: one in a near-building position and one in an open-air site. In order to characterize the indoor and outdoor microclimatic conditions, some statistical indexes were applied. The results show the comparison in microclimatic conditions in the different sites in the church and between indoor and outdoor environments, allowing for the detection of the influence of the building in the microclimatic conditions.

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D. METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test. RESULTS: Using a Bonferroni-corrected significance threshold of P

Abstract Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Abstract We present here the K9 lymphoma assay, a novel 31-gene targeted next-generation sequencing panel designed for genomic profiling of canine lymphoid neoplasms. Addressing the growing demand for advanced diagnostics in veterinary oncology, this assay enables sensitive identification of known and actionable mutations specific to canine lymphomas, while evaluating its prognostic potential to facilitate diagnosis and prognosis. Our analysis, spanning several B- and T-cell lymphoma histotypes, unveiled distinct mutational landscapes distinguishing tumors derived from immature versus mature lymphocytes. Clustering analysis revealed a shared genetic origin between diffuse large B-cell lymphoma and marginal zone lymphoma, aligning with findings in human lymphomas, with TRAF3 emerging as the most frequently mutated gene across B-cell lymphoma subtypes. Significantly, TP53 mutations demonstrated universal adverse prognostic implications across B-cell lymphomas. Additionally, SETD2 mutations contributed to shorter time-to-progression, underscoring the role of epigenetic dysregulation in B-cell tumors. In T-cell lymphomas, SATB1 and FBXW7 were frequently mutated, warranting further investigation in larger cohorts. Our findings advocate for tailored therapeutic approaches based on the genetic profile, impacting treatment decisions and outcomes in canine lymphoma management. This study provides pivotal insights bridging veterinary and human oncology, paving the way for comprehensive genomic diagnostics and therapeutic strategies in comparative oncology.

In this article, we explore whether the evaluation instruments used in the teacher selection process in Peru are good predictors of teacher effectiveness. To this end, we estimate teacher value-added (TVA) measures for public primary school teachers and test their relationship with Peru's results of two rounds of the teacher evaluation (i.e., a centralized national stage and a decentralized stage performed at the school level). Our findings indicate that among the instruments that comprise the national stage of the process, the logical reasoning and curricular and pedagogical knowledge subtests have the strongest relationship with the TVA measure, while the weakest relationship is found with the reading comprehension component. Also, we find that the weighted aggregate score has a higher relationship with estimated TVA than the specific subtests. At the school-level stage, we find no significant relationships with our measures of TVA for math, as well as a nonrobust relationship for the classroom observation and interview evaluation instruments for reading. Moreover, we find relationships between our TVA measure and several teacher characteristics: TVA is higher for female teachers and for those at higher salary levels while it is lower for teachers with temporary contracts. These results provide lessons for the design and implementation of evaluation instruments in teacher hiring processes around the world.

Action video-games (AVGs) could improve reading efficiency, enhancing not only visual attention but also phonological processing. Here we tested the AVG effects upon three consolidated language-based predictors of reading development in a sample of 79 pre-readers at-risk and 41 non-at-risk for developmental dyslexia. At-risk children were impaired in either phonemic awareness (i.e., phoneme discrimination task), phonological working memory (i.e., pseudoword repetition task) or rapid automatized naming (i.e., RAN of colours task). At-risk children were assigned to different groups by using an unequal allocation randomization: (1) AVG (n = 43), (2) Serious Non-Action Video Game (n = 11), (3) treatment-as-usual (i.e., speech therapy, n = 11), and (4) waiting list (n = 14). Pre- and post-training comparisons show that only phonemic awareness has a significantly higher improvement in the AVG group compared to the waiting list, the non-AVG, and the treatment-as-usual groups, as well as the combined active groups (n = 22). This cross-modal plastic change: (i) leads to a recovery in phonemic awareness when compared to the not-at-risk pre-readers; (ii) is present in more than 80% of AVG at-risk pre-readers, and; (iii) is maintained at a 6-months follow-up. The present findings indicate that this specific multisensory attentional training positively affects how phonemic awareness develops in pre-readers at risk for developmental dyslexia, paving the way for innovative prevention programs.

While the development of creativity, or creative thinking, in mathematics is considered important by many researchers, there are several difficulties in implementing creative tasks, especially before secondary school. Within the original context of a mathematical escape game, this paper reports two episodes exemplifying the difficulties met by sixth graders in abandoning stereotyped habits and acting with creative insubordination. While in the first episode, the puzzling task does not suffice to prompt creativity, in the second episode we show that an original solution may prompt unexpected mathematical contents. In conclusion, escape games could be useful to prompt creativity even in lower grades than it is now shown in the literature, but attention should be paid to the teacher's role in sustaining such creative activities.