Search Results (123)

Background/Objectives: We aimed to test whether home-based low-intensity interval training (LIIT) could be equally or more effective than traditional continuous walking advice (TWA) in a population hospitalized and healed from severe COVID-19. Methods: This pragmatic nonrandomized controlled trial (NCT04615390) enrolled patients admitted to intensive care units due to COVID-19 who at discharge from the hospital were given a choice between either a home-based LIIT program or TWA. The former received a structured LIIT walking (1:1 walk:rest ratio per 10 times) to be performed at a prescribed progressively increasing speed maintained with a metronome. The latter received TWA according to the guidelines (30 min or moderate intensity activity, 5 days/week). Outcome measures, collected at baseline, at the end of the 3-month training and at the 6-month follow-up, included 6 min walking distance (primary), lower limb strength, quality of life, depression and cognitive status. Results: From a total of 85 enrolled patients, 69 of them (LIIT n = 32; TWA n = 37) completed the study. Home exercise was safely executed with an 82% adherence for the LIIT group and 64% adherence for TWA. After the 3-month program, both groups significantly improved the 6MWD (LIIT: +87 m vs. TWA +42 m; p < 0.001) with a significant difference that was also maintained at follow-up (LIIT: +138 m vs. TWA +69 m; p < 0.001). No other significant between-group differences were noted. However, patients in the LIIT group significantly improved in the majority of the outcomes, while patients of TWA improved in only the primary outcome and the physical component of quality of life. Conclusions: Compared with TWA, LIIT walking was feasible, safe and associated with more favorable multidimensional recovery in COVID-19 survivors after hospitalization for severe pneumonitis. Full article

Major depressive disorder (MDD) is one of the most common diseases, affecting millions of people worldwide. Existing antidepressants do not allow sustainable remission to be achieved in many cases, probably due to insufficient understanding of the etiopathogenesis of MDD. The aim of this study was to identify the key genes, pathways, and master regulators associated with MDD based on a combination of genomic and transcriptomic data analyses. We performed a transcriptome-wide association study (TWAS) to identify the increase and decrease in transcription of particular genes that can be associated with MDD risk, the results of which were used to perform a pathway enrichment analysis that elucidated the pathways and processes associated with MDD. Besides changes in the metabolism of neurotransmitters, the association of some other processes with MDD was revealed, including changes in phospholipid and glycan metabolism, chromatin remodeling, RNA processing and splicing, and cell–extracellular matrix interaction. The transcriptomic analysis performed for brain regions mostly confirmed genome-level findings. The gene expression changes in the brain related to MDD were mostly sex-specific, and the transcription of many genes was changed in the opposite direction in males and females. Finally, master regulators were found, which are the proteins responsible for the transcriptional regulation of the revealed genes and represent the most important proteins contributing to MDD development. Full article

Rapid access to defibrillators, blood products, and time-critical medicines can improve survival, yet urban congestion and fragmented infrastructure delay deliveries. We present and evaluate an end-to-end framework for beyond-visual-line-of-sight (BVLOS) UAV logistics in Essex (UK), integrating (I) strategic depot placement, (II) a hybrid obstacle-aware route planner, and (III) a time-window-aware (TWA) Mixed-Integer Linear Programming (MILP) scheduler coupled to a battery/temperature feasibility model. Four global planners—Ant Colony Optimisation (ACO), Genetic Algorithm (GA), Particle Swarm Optimisation (PSO), and Rapidly Exploring Random Tree* (RRT*)—are paired with lightweight local refiners, Simulated Annealing (SA) and Adaptive Large-Neighbourhood Search (ALNS). Benchmarks over 12 destinations used real Civil Aviation Authority no-fly zones and energy constraints. RRT*-based hybrids delivered the shortest mean paths: RRT* + SA and RRT* + ALNS tied for the best average length, while RRT* + SA also achieved the co-lowest runtime at $v=60\mathrm{km}{\mathrm{h}}^{-1}$. The TWA-MILP reached proven optimality in 0.11 s, showing that a minimum of seven UAVs are required to satisfy all 20–30 min delivery windows in a single wave; a rolling demand of one request every 15 min can be sustained with three UAVs if each sortie (including service/recharge) completes within 45 min. To validate against a state-of-the-art operations-research baseline, we also implemented a Vehicle Routing Problem with Time Windows (VRPTW) in Google OR-Tools, confirming that our hybrid planners generate competitive or shorter NFZ-aware routes in complex corridors. Digital-twin validation in AirborneSIM confirmed CAP 722-compliant, flyable trajectories under wind and sensor noise. By hybridising a fast, probabilistically complete sampler (RRT*) with a sub-second refiner (SA/ALNS) and embedding energy-aware scheduling, the framework offers an actionable blueprint for emergency medical UAV networks. Full article

Although substantial research has been conducted on pecan cultivation, studies that account for variability in farm scale, from small to large commercial operations, are still needed. To address this gap, the primary objective of the present study was to quantify and compare groundwater recharge rates and crop yield in pecan orchards utilizing different irrigation systems. This investigation employed in-orchard water budget measurements combined with analytical water balance models to facilitate comparative analysis between orchard sizes. The study tested the hypothesis that groundwater recharge rates vary significantly with farm scale, with larger commercial orchards exhibiting higher recharge rates than their small-scale counterparts. Analysis of 2021–2023 irrigation data revealed significant variability in deep percolation (DP) as a percentage of total water applied (TWA) across orchard sites, ranging from 0% to 52%, with P1 exhibiting the highest recharge and yield, while P2 had the lowest due to limited irrigation. ANOVA revealed significant differences in DP and yield among sites, with P1 outperforming the others. CWP averaged 0.33 kg/m³ but varied considerably by site (0.12–0.42 kg/m³). The results showed significant variability in DP, highlighting its dependence on management practices. These findings emphasize the critical role of site-specific irrigation strategies in optimizing productivity. Full article

As the laying cycle is prolonged, the egg albumen quality exhibits a declining trend. A Haugh unit (HU) is a standard measure of the albumen quality, which reflects viscosity and freshness. During the late laying period, the HU not only decreased significantly, but also exhibited greater variability among individuals. The magnum, as the primary site of albumen synthesis, plays a central role in this process; however, the mechanisms by which it regulates the albumen quality remain unclear. To address this, we obtained genomic and transcriptomic data from 254 individuals, along with single-cell RNA sequencing (scRNA-seq) data of the magnum tissue. Genome-wide association studies (GWAS) across five laying stages (66, 72, 80, 90, and 100 weeks of age) identified 77 HU-associated single-nucleotide polymorphisms (SNPs). Expression quantitative trait locus (eQTL) mapping linked these variants to the expression of 12 genes in magnum tissue. In addition, transcriptomic analysis using linear regression and random forest models identified 259 genes that significantly correlated with the HU. Single-cell RNA sequencing further revealed two key cell types, plasma cells and a subset of epithelial cells, marked by ADAMTSL1 and OVAL, which are functionally relevant to the HU. Through integrated Transcriptome-Wide Association Study (TWAS) and Summary-data-based Mendelian Randomization (SMR) analyses, we identified four robust regulators of the albumen quality: CISD1, NQO2, SLC22A23, and CMTM6. These genes are functionally involved in mitochondrial function, antioxidant defense, and membrane transport. Overall, our findings uncovered the genetic and cellular mechanisms underlying age-related decline in the albumen quality and identified potential targets for improving the egg quality in aging flocks. Full article

Background and Objectives: Electrocardiography (ECG), though non-specific, is widely applied as a valuable tool in the diagnostic work-up of acute myocarditis. Cardiac magnetic resonance (CMR) has become a key non-invasive tool. This study assessed the association of ECG findings (at baseline), echocardiographic parameters, circulating biomarkers, and CMR imaging features (myocardial edema and late gadolinium enhancement—LGE) in patients with acute myocarditis. Materials and Methods: This single-center, retrospective observational study included 86 patients admitted with acute myocarditis from January 2021 to December 2024. Data collected included demographics, clinical presentation, ECG, echocardiography, biomarkers (CRP, troponin I), and CMR imaging performed during hospitalization and at the six-month follow-up. Based on ECG findings, patients were stratified into three groups: no ST elevation or T-wave abnormalities (NSTG, n = 27), T-wave abnormalities (TWAG, n = 24), and ST elevation (STEG, n = 35). Results: We enrolled 86 patients (median age: 26 years; 87.2% male), and the most frequent CMR findings were either LGE (80.2%) and/or myocardial edema (75.6%). The prevalence of edema and LGE was higher in the STEG (both 91.2%) compared to TWAG (65.2%, 77.3%, respectively) and NSTG (57.7, 65.4%, respectively) (p < 0.05). Peak troponin levels were also higher in the STEG than other groups (p = 0.005). In logistic regression analysis, TWAs were independently associated with both edema (OR = 3.15, 95% CI: 1.078–9.189, p = 0.036) and LGE (OR = 3.93, 95% CI: 1.256–12.276, p = 0.019). Biomarkers were associated with lower LVEF in univariate analysis, but not in multivariate models. Conclusions: ECG abnormalities, particularly STE and TWA, are common in acute myocarditis and significantly associated with CMR findings. Although CMR remains essential for definitive diagnosis and risk stratification in acute myocarditis, ECG may serve as a valuable initial screening tool in the context of a multimodal diagnostic approach. Full article

Background/Objectives: The anti-Müllerian hormone (AMH) is a key biomarker of the ovarian reserve, correlating with ovarian follicle count, fertility outcomes, and menopause timing. Understanding its genetic determinants has broad implications for female reproductive health. However, prior genome-wide association studies (GWASs) have focused exclusively on women of European ancestry, limiting insights into diverse populations. Methods: We conducted a GWAS to identify genetic loci associated with circulating AMH levels in a sample of 1185 Samoan women from two independently recruited samples. Using a Cox mixed-effects model we accounted for AMH levels below detectable limits and meta-analysed the summary statistics using a fixed-effect model. To prioritize variants and genes, we used FUMA and performed colocalization and transcriptome-wide association analysis (TWAS). We also assessed whether any previously reported loci were replicated in our GWAS. Results: We identified eleven genome-wide suggestive loci, with the strongest signal at ARID3A (19-946163-G-C; p = 2.32 × 10⁻⁷) and replicated rs10093345 near EIF4EBP1. The gene-based testing revealed ARID3A and R3HDM4 as significant genes. Integrating GWAS results with expression quantitative trait loci via TWAS, we detected seven transcriptome-wide significant genes. The lead variant in ARID3A is in high linkage disequilibrium (r² = 0.79) with the known age-at-menopause variant 19-950694-G-A. Nearby KISS1R is a biologically plausible candidate gene that encodes the kisspeptin receptor, a regulator of ovarian follicle development linked to AMH levels. Conclusions: This study expands our understandings of AMH genetics by focusing on Samoan women. While these findings may be particularly relevant to Pacific Islanders, they hold broader implications for reproductive phenotypes such as the ovarian reserve, menopause timing, and polycystic ovary syndrome. Full article

Background: Obesity significantly impacts disease burden, with waist-to-hip ratio (WHR) as a key obesity indicator, but the genetic and biological pathways underlying WHR, particularly its sex-specific differences, remain poorly understood. Methods: This study explored WHR’s sexual dimorphism and its links to complex traits using cross-sectional surveys and genetic data from Giant and UK Biobank (UKB). We analyzed WHR heritability, performed tissue-specific transcriptome-wide association studies (TWAS) using FUSION, and conducted genetic correlation analyses with linkage disequilibrium score regression (LDSC) and Local Analysis of [co]Variant Association (LAVA). Polygenic scores (PGS) for WHR were constructed using the clumping and thresholding method (CT), and associations with complex traits were assessed via logistic or linear models. Results: The genetic analysis showed sex-specific heritability for WHR, with TWAS identifying female-specific (e.g., CCDC92) and male-specific (e.g., UQCC1) genes. Global genetic correlation analysis revealed sex-specific associations between WHR and 23 traits, while local analysis identified eight sex-specific loci across five diseases. Regression analysis highlighted sex-specific associations for 70 traits with WHR and 45 traits with WHR PGS, with stronger effects in females. Predictive models also performed better in females. Conclusions: This study underscores WHR’s sexual dimorphism and its distinct associations with complex traits, offering insights into sex-specific biological differences, health management, and clinical advancements. Full article

Background/Objectives: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. Methods: We performed a cross-tissue transcriptome-wide association study (TWAS) of DKD using expression quantitative trait loci (eQTL) data from 49 tissues in the Genotype—Tissue Expression (GTEx) version 8 (v8) resource. Five complementary analytical frameworks—sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)—were integrated to nominate candidate genes. Causal inference was refined using Mendelian randomization (MR), and biological significance was evaluated through pathway enrichment, protein interaction networks, and druggability profiling. Results: We identified 23 candidate genes associated with DKD risk, of which 13 were supported by MR analysis. Among these, 10 represent previously unreported susceptibility genes. Notably, four genes—HLA-DRB1, HLA-DRB5, NOTCH4, and CYP21A2—encode potentially druggable proteins, with HLA-DRB5 and CYP21A2 both qualifying as novel susceptibility genes and therapeutic targets. These genes converge on immune modulation, steroid biosynthesis, DNA repair, and transcriptional regulation—processes central to DKD pathogenesis. Conclusions: Our study represents the first systematic cross-tissue TWAS of DKD, revealing a prioritized set of genetically and functionally supported susceptibility genes. The identification of druggable targets among these genes provides critical insight into the mechanistic underpinnings of DKD and highlights their potential for future therapeutic development. These findings enhance our understanding of DKD pathophysiology and offer a foundation for precision medicine strategies in nephrology. Full article

Background/Objectives: Noninvasive arrhythmic risk stratification in patients with ischemic heart disease is poor nowadays, and further investigations are needed. The most correct approach is based on the use of electrocardiogram (ECG) with the extraction of indices such as ECG alternans (ECGA). The aim of this study is to monitor the ECG evidence of ischemic coronary artery occlusion by the ECGA and to verify its ability to monitor the time course of balloon inflation, with the final goal of contributing to the exploration of the prognostic role of ECGA in ischemic heart disease. Methods: The ECGA amplitude and magnitude were computed by the correlation method (CM) on the STAFF III database, where ischemic coronary artery occlusion was induced in a controlled manner through coronary artery blockage by balloon inflation. ECGA computed during balloon inflation was also compared with periods before and after the inflation. Results: ECGA values became statistically higher during inflation than in the pre-inflation period and increased as inflation time increased, although not always in a statistically significant manner. ECGA went from values in the range 4–7 µV and 169–396 µV·beat before inflation to values in the range 5–9 µV and 208–573 µV·beat during 5 min of inflation (resulting statistically higher than before inflation), returning towards values in the range 4–8 µV and 182–360 µV·beat after inflation for amplitude and magnitude, respectively. Conclusions: CM-based ECGA detection was able to track the balloon inflation period. Our ECGA investigation represents a contribution in the field of research exploring its prognostic role as a noninvasive electrical risk index in ischemic heart disease. Full article

Background: Multiple myeloma (MM) is a hematological malignancy originating from the plasma cells present in the bone marrow. Despite significant therapeutic advancements, relapse and drug resistance remain major clinical challenges, highlighting the urgent need for novel therapeutic targets. Methods: To identify potential druggable genes associated with MM, we performed Mendelian randomization (MR) analysis. Causal candidates were further validated using a single-tissue transcriptome-wide association study (TWAS), and colocalization analysis was conducted to assess shared genetic signals between gene expression and disease risk. Potential off-target effects were assessed through an MR phenome-wide association study (MR-PheWAS). Additionally, molecular docking and functional assays were used to evaluate candidate drug efficacy. Results: The MR analysis identified nine druggable genes (FDR < 0.05), among which Orosomucoid 1 (ORM1) and Oviductal Glycoprotein 1 (OVGP1) were supported by both TWAS and colocalization evidence (PPH4 > 0.75). Experimental validation demonstrated the significant downregulation of ORM1 and OVGP1 in MM cells (p < 0.05). Pregnenolone and irinotecan, identified as agonists of ORM1 and OVGP1, respectively, significantly inhibited MM cell viability, while upregulating their expression (p < 0.05). Conclusions: Our study highlights ORM1 and OVGP1 as novel therapeutic targets for MM. The efficacy of pregnenolone and irinotecan in suppressing MM cell growth suggests their potential for clinical application. These findings provide insights into MM pathogenesis and offer a promising strategy for overcoming drug resistance. Full article

In recent decades, adopting alternative resources in infrastructure applications has garnered global attention to address environmental concerns. Olive waste ash (OWA), a locally available byproduct obtained from the olive oil production process, is a promising green material that plays a vital role as a partial cement substitute. This paper evaluates the mechanical and durability properties of cement paste—a key component of paving blocks—incorporating OWA at replacement levels of 0, 5, 10, 15, and 20%, with a constant water-to-cementitious ratio of 0.45. Density, compressive strength, and flexural strength are assessed at 1, 7, 28, and 90 days, while total water absorption (TWA) and capillary water absorption (CWA) are measured at 28 days. The results reveal that OWA slightly reduces density, compressive strength, and flexural strength, with the optimal results observed at a substitution level of 10%. At 90 days, the compressive strength of the control cement paste is 50 MPa, whereas the 10% OWA mixture exhibits a value of 46 MPa, corresponding to only an 8% reduction. Additionally, two predictive models are proposed: the hyperbolic model for compressive strength variation with curing time and the capillary-diffusive model for capillary water absorption as a function of time. Both models demonstrate a strong fit with experimental data. Correlations between different properties indicate a strong correlation between compressive strength, density, and flexural strength, while a negative linear relationship exists between compressive strength and water absorption. This study underscores OWA’s potential to improve sustainable paving blocks by providing suitable mechanical and durability characteristics, offering both environmental and economic benefits. Full article

Background/Objectives: Inadvertent intraoperative hypothermia is a common occurrence during major surgery, and some preclinical studies have reported its association with postoperative anastomotic leakage (AL). In the present study, we demonstrated the correlation between intraoperative hypothermia and postoperative outcomes after Ivor Lewis (IL) esophagectomy for cancer. Methods: Retrospectively, patients were divided into three groups on the basis of their time-weighted average temperatures (TWA): normothermia (N-TWA 36–37.5 °C), mild hypothermia (M-TWA 35–36 °C), and severe hypothermia (S-TWA < 35 °C). Results: Starting from 254 consecutive patients, 95 were included in the final analysis, classified according to intraoperative temperature: S-TWA = 19 (20%), M-TWA = 62 (65.3%), and N-TWA = 14 (14.7%). S-TWA was related to lower BMI (p = 0.001), diagnosis of squamous cell carcinoma (p = 0.029), and shorter operation times (p = 0.006). In the same way, AL was more related to S-TWA when compared with M-TWA and N-TWA (31.6% vs. 6.5% vs. 14.3%, p = 0.015). After multivariate analysis, S-TWA remained as the only predictive factor of AL (OR 5.385, 95%CI 1.502; 19.310; p = 0.010). Instead, higher BMI was found to be a protective factor for S-TWA (OR 0.818, 95%CI 0.723; 0.926: p = 0.001). Conclusions: S-TWA seems to be a major independent risk factor for AL after IL esophagectomy. Implementation of perioperative measures, aimed to prevent severe intraoperative hypothermia, could potentially be crucial to improve surgical outcomes. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder with potential progression to stricturing (B2) or penetrating (B3) phenotypes, leading to significant complications. Early identification of patients at risk for these complications is critical for personalized management. This study aimed to develop a predictive model using clinical data and a Korean-specific transcriptome-wide association study (TWAS) to forecast early progression in CD patients. A retrospective analysis of 430 Korean CD patients from 15 hospitals was conducted. Genotyping was performed using the Korea Biobank Array, and gene expression predictions were derived from a TWAS model based on terminal ileum data. Logistic regression models incorporating clinical and gene expression data predicted progression to B2 or B3 within 24 months of diagnosis. Among the cohort, 13.9% (60 patients) progressed to B2 and 16.9% (73 patients) to B3. The combined model achieved mean area under the curve (AUC) values of 0.788 for B2 and 0.785 for B3 progression. Key predictive genes for B2 included CCDC154, FAM189A2, and TAS2R19, while PUS7, CCDC146, and MLXIP were linked to B3 progression. This integrative model provides a robust approach for identifying high-risk CD patients, potentially enabling early, targeted interventions to reduce disease progression and associated complications. Full article

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) and African ancestry (AA) samples to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha = p < 2.9 × 10⁻⁶), some of which had been previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, the downregulation of ICA1L was associated with a higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS on cognitive function and neurocognitive disorders that used expression mapping studies for multiple ancestries. This work may expand the benefits of TWASs beyond a single ancestry group and help to identify gene targets for pharmaceuticals or preventative treatments for dementia. Full article