Bipolar hybrid posterior instrumentation tecnique for the correction of Scheuermann's kyphosis.

Scheuermann´s kyphosis (SK) is the most common cause of painful and progressive structural hyperkyphosis in adolescents. Surgical treatment should be considered in cases of refractory pain or progressive deformities. We present the clinical and radiological results obtained using a bipolar, hybrid posterior instrumentation tecnique. We analysed 12 males and 6 females, with mean age of 15.8 years. Minimum follow-up was 2 years. We used transverse process hooks at the cranial level and polyaxial screws for the remaining levels. We did not instrument the periapical segment. We used the sagittal stable vertebra (SSV) as the lower instrumented vertebra (LIV) in most cases, the "barely touched SSV" if the above disc space is lordotic. The mean preoperative kyphosis was 73.6º, mean postoperative kyphosis 44.7º, and mean correction of 28.9º (p = 0.0002). The mean reduction in lumbar lordosis (LL) was 8.9º (p = 0.0018). There were no significant differences in the spinopelvic parameters or sagittal balance. The mean number of instrumented levels was 8.9. Type II osteotomies were necessary in only three patients. Three patients had a cranial sagittal angle greater than 10°, all of them asymptomatic. Postoperatively, all patients had VAS scores less than 2 and SRS-22 scores greater than 4. Hybrid bipolar posterior instrumentation offers adequate curve correction, less operative time, implant density, bleeding, material protrusion and risk of spinal cord injury, leaving a large periapical bed for graft supply. We propose to measure the flexibility of the curve in MRI. In flexible curves (those that correct at least 20% in the supine decubitus position), wide facetectomies offer adequate correction of the deformity.

Deformity correction from the convexity of the curve in neuromuscular scoliosis.

Background: "Convex Pedicle Screw Technique" reduces the theoretical risk of neurovascular injury. Our aim is to evaluate the efficacy of this technique in patients with neuromuscular scoliosis (NMS). Methods: Retrospective study of 12 patients who underwent a Convex Pedicle Screw Technique and were diagnosed with NMS. Patients who had undergone previous spinal surgery were excluded. The minimum follow-up required was 24 months. Demographic data, intraoperative data, neurovascular complications and neurophysiological events requiring implant repositioning, as well as pre- and postoperative radiological variables were collected. Results: Twelve patients diagnosed with NMS underwent surgery. The median operative time was 217 minutes. Mean blood loss was 3.8±1.1 g/dL hemoglobin (Hb). The median postoperative stay was 8.8±4 days. A reduction of the Cobb angle in primary curve of 49.1% (from 52.8°±18° to 26.5°±12.6°; P<0.001) and in secondary curve of 25.2% (from 27.8°±18.9° to 18.3°±13.3°; P=0.10) was achieved. Coronal balance improved by 69.4% (7.5±46.2 vs. 2.3±20.9 mm; P=0.72) and sagittal balance by 75% (from -14.1±71.8 vs. -3.5±48.6 mm; P=0.50). There were no neurovascular complications. There were no intraoperative neurophysiological events requiring implant repositioning, nor during reduction maneuvers. No infections were reported. Conclusions: The correction of the deformity from convexity in NMS achieves similar results to other techniques, and a very low complication rate.

Using a nonparametric item response theory model to identify patterns of cognitive decline: The Mokken scale analysis.

Cognitive decline, particularly in dementia, presents complex challenges in early detection and diagnosis. While Item Response Theory (IRT) has been instrumental in identifying patterns of cognitive impairment through psychometric tests, its parametric models often require large sample sizes and strict assumptions. This creates a need for more adaptable, less demanding analytical methods. This study aimed to evaluate the effectiveness of Mokken scale analysis (MSA), a nonparametric IRT model, in identifying hierarchical patterns of cognitive impairment from psychometric tests. Using data from 1164 adults over 60 years old, we applied MSA to the orientation subscale of ACE-III. Our analysis involved calculating scalability, monotone homogeneity, invariant item ordering (IIO) and response functions. The MSA effectively retrieved the hierarchical order of cognitive impairment patterns. Most items showed strong scalability and consistent patterns of cognitive performance. However, challenges with IIO were observed, particularly with items having adjacent difficulty parameters. The findings highlight MSA's potential as a practical alternative to parametric IRT models in cognitive impairment research. Its ability to provide valuable insights into patterns of cognitive deterioration, coupled with less stringent requirements, makes it a useful tool for clinicians and researchers.

The Androgen Dehydroepiandrosterone Sulfate Shows a Greater Relationship with Impulsivity than Testosterone in a Healthy Male Sample.

This study was designed to examine the relationships among the impulsivity construct as a personality trait, the dehydroepiandrosterone sulfate (DHEA-S), and testosterone in a sample of 120 healthy middle-aged males (Mage = 44.39; SD = 12.88). The sum of the three BIS-11 scales, the SR, and the five UPPS-P scales correlated with DHEA-S 0.23 (p < 0.006) and testosterone 0.19 (p < 0.04), controlling for age. Partial correlations showed that DHEA-S was significantly related to motor impulsivity (0.24; p < 0.008), Sensitivity to Reward (0.29; p < 0.002), Lack of Premeditation (0.26; p < 0.05), and, to a lesser extent, Sensation Seeking (0.19; p < 0.04) and Positive Urgency (0.19; p < 0.04). Testosterone correlated with attention impulsivity (0.18; p < 0.04), Sensation Seeking (0.18; p < 0.04), and Positive Urgency (0.22; p < 0.01). Sensitivity to Reward, Negative Urgency, and Positive Urgency were significant predictors of DHEA-S (R2 = 0.28), and Positive Urgency for testosterone (R2 = 0.09). Non-parametric LOESS graphical analyses for local regression allowed us to visualize the non-linear relationships between the impulsivity scales with the two androgens, including non-significant trends. We discuss the implications of these results for impulsive biological personality traits, the limitations of our analyses, and the possible development of future research.

Cytomegalovirus surveillance after antiviral prophylaxis in CMV mismatched transplant patients: Does recurrent cytomegalovirus DNAemia impact patient survival?

BACKGROUND: Cytomegalovirus (CMV) mismatched, donor IgG-positive/recipient IgG-negative, solid organ transplant recipients (SOTRs) are at high risk of CMV invasive disease. Post-prophylaxis disease is an issue in this population. Some programs employ surveillance after prophylaxis (SAP) to limit the incidence of post-prophylaxis disease. METHODS: This was a single-center retrospective cohort study that included all CMV mismatched SOTRs from 2003 to 2017. Patients underwent SAP with weekly CMV plasma viral load for 12 weeks. The subjects were classified into three post-prophylaxis DNAemia patterns: no DNAemia, one episode of DNAemia, and multiple episodes of DNAemia. We calculated the cumulative incidence of each DNAemia pattern. We also determined 5-year mortality based on DNAemia pattern stratified by organ transplant type. RESULTS: Post-prophylaxis recurrent DNAemia occurred in 63% of lung recipients and 32% of non-lung recipients (p =  .003). Tissue invasive CMV disease was diagnosed in 3% of the population and CMV syndrome was diagnosed in 33%. Recurrent DNAemia was not associated with 5-year mortality. CONCLUSION: In this cohort, undergoing SAP tissue invasive disease was uncommon and CMV DNAemia recurrence did not have an impact on long-term mortality.

Levels of sCD163 in women rheumatoid arthritis: Relationship with cardiovascular risk markers.

AIM: The soluble scavenger receptor differentiation antigen 163 (sCD163), a monocyte/macrophage activation marker, is related to cardiovascular mortality in the general population. This study aimed to evaluate their relationship between serum levels of sCD163 with cardiovascular risk indicators in rheumatoid arthritis (RA). METHODS: A cross-sectional study was performed on 80 women diagnosed with RA. The cardiovascular risks were determined using the lipid profile, metabolic syndrome, and QRISK3 calculator. For the assessment of RA activity, we evaluated the DAS28 with erythrocyte sedimentation rate (DAS28-ESR). The serum levels of sCD163 were determined by the ELISA method. Logistic regression models and receiver operating characteristics (ROC) curve were used to assess the association and predictive value of sCD163 with cardiovascular risk in RA patients. RESULTS: Levels of sCD163 were significantly higher in RA patients with high sensitivity protein C-reactive to HDL-c ratio (CHR)≥0.121 (p=0.003), total cholesterol/HDL-c ratio>7% (p=0.004), LDL-c/HDL-c ratio>3% (p=0.035), atherogenic index of plasma>0.21 (p=0.004), cardiometabolic index (CMI)≥1.70 (p=0.005), and high DAS28-ESR (p=0.004). In multivariate analysis, levels of sCD163≥1107.3ng/mL were associated with CHR≥0.121 (OR=3.43, p=0.020), CMI≥1.70 (OR=4.25, p=0.005), total cholesterol/HDL-c ratio>7% (OR=6.63, p=0.044), as well as with DAS28-ESR>3.2 (OR=8.10, p=0.008). Moreover, levels of sCD163 predicted CHR≥0.121 (AUC=0.701), cholesterol total/HDL ratio>7% (AUC=0.764), and DAS28-ESR>3.2 (AUC=0.720). CONCLUSION: Serum levels of sCD163 could be considered a surrogate of cardiovascular risk and clinical activity in RA.

Physicochemical changes in Amaranthus spp grains, flour, isolated starch, and nanocrystals during germination and malting.

Amaranth is a pseudocereal that contains between 50 and 60% starch, gluten-free protein, and essential amino acids. This study investigates the physicochemical changes in Amaranthus spp. grains, flour, isolated starch and nanocrystals during germination and malting. The moisture content increased from 8.9% to 41% over 2 h of soaking. The percentage of germination increased rapidly, reaching 96% after 60 h, a remarkable advantage over other cereals. The nutrient composition varied, including protein synthesis and lipid degradation. Lipid concentration decreased during malting, except for soaking, which increased by 62%. Scanning electron microscopy shows that germination does not cause morphological changes on the outer surface of the grains, while transmission electron microscopy indicates the presence of isolated nanocrystals with orthorhombic crystal structure confirmed by X-ray diffraction. The viscosity profile shows a decrease in peak viscosity. Therefore, amaranth is a potential pseudocereal that can be used as an additive in the production of fermented beverages.

Comparison of Printable Biomaterials for Use in Neural Tissue Engineering: An In Vitro Characterization and In Vivo Biocompatibility Assessment.

Nervous system traumatic injuries are prevalent in our society, with a significant socioeconomic impact. Due to the highly complex structure of the neural tissue, the treatment of these injuries is still a challenge. Recently, 3D printing has emerged as a promising alternative for producing biomimetic scaffolds, which can lead to the restoration of neural tissue function. The objective of this work was to compare different biomaterials for generating 3D-printed scaffolds for use in neural tissue engineering. For this purpose, four thermoplastic biomaterials, ((polylactic acid) (PLA), polycaprolactone (PCL), Filaflex (FF) (assessed here for the first time for biomedical purposes), and Flexdym (FD)) and gelatin methacrylate (GelMA) hydrogel were subjected to printability and mechanical tests, in vitro cell-biomaterial interaction analyses, and in vivo biocompatibility assessment. The thermoplastics showed superior printing results in terms of resolution and shape fidelity, whereas FD and GelMA revealed great viscoelastic properties. GelMA demonstrated a greater cell viability index after 7 days of in vitro cell culture. Moreover, all groups displayed connective tissue encapsulation, with some inflammatory cells around the scaffolds after 10 days of in vivo implantation. Future studies will determine the usefulness and in vivo therapeutic efficacy of novel neural substitutes based on the use of these 3D-printed scaffolds.

Early-life external exposome in children 2-5 years old in Colombia.

Exposome studies are advancing in high-income countries to understand how multiple environmental exposures impact health. However, there is a significant research gap in low- and middle-income and tropical countries. We aimed to describe the spatiotemporal variation of the external exposome, its correlation structure between and within exposure groups, and its dimensionality. A one-year follow-up cohort study of 506 children under 5 in two cities in Colombia was conducted to evaluate asthma, acute respiratory infections, and DNA damage. We examined 48 environmental exposures during pregnancy and 168 during childhood in eight exposure groups, including atmospheric pollutants, natural spaces, meteorology, built environment, traffic, indoor exposure, and socioeconomic capital. The exposome was estimated using geographic information systems, remote sensing, spatiotemporal modeling, and questionnaires. The median age of children at study entry was 3.7 years (interquartile range: 2.9-4.3). Air pollution and natural spaces exposure decreased from pregnancy to childhood, while socioeconomic capital increased. The highest median correlations within exposure groups were observed in meteorology (r = 0.85), traffic (r = 0.83), and atmospheric pollutants (r = 0.64). Important correlations between variables from different exposure groups were found, such as atmospheric pollutants and meteorology (r = 0.76), natural spaces (r = -0.34), and the built environment (r = 0.53). Twenty principal components explained 70%, and 57 explained 95% of the total variance in the childhood exposome. Our findings show that there is an important spatiotemporal variation in the exposome of children under 5. This is the first characterization of the external exposome in urban areas of Latin America and highlights its complexity, but also the need to better characterize and understand the exposome in order to optimize its analysis and applications in local interventions aimed at improving the health conditions and well-being of the child population and contributing to environmental health decision-making.

A Novel In Vitro Pathological Model for Studying Neural Invasion in Non-Melanoma Skin Cancer.

Neural Invasion (NI) is a key pathological feature of cancer in the colonization of distant tissues, and its underlying biological mechanisms are still scarcely known. The complex interactions between nerve and tumor cells, along with the stroma, make it difficult to reproduce this pathology in effective study models, which in turn has limited the understanding of NI pathogenesis. In this study, we have designed a three-dimensional model of NI squamous cell carcinoma combining human epidermoid carcinoma cells (hECCs) with a complete peripheral nerve segment encapsulated in a fibrine-agarose hydrogel. We recreated two vital processes of NI: a pre-invasive NI model in which hECCs were seeded on the top of the nerve-enriched stroma, and an invasive NI model in which cancer cells were immersed with the nerve in the hydrogel. Histological, histochemical and immunohistochemical analyses were performed to validate the model. Results showed that the integration of fibrin-agarose advanced hydrogel with a complete nerve structure and hECCs successfully generated an environment in which tumor cells and nerve components coexisted. Moreover, this model correctly preserved components of the neural extracellular matrix as well as allowing the proliferation and migration of cells embedded in hydrogel. All these results suggest the suitability of the model for the study of the mechanisms underlaying NI.

The impact of colonization by multidrug resistant bacteria on graft survival, risk of infection, and mortality in recipients of solid organ transplant: systematic review and meta-analysis.

BACKGROUND: The Global increase in colonization by multidrug-resistant (MDR) bacteria poses a significant concern. The precise impact of MDR colonization in solid organ transplant recipients (SOTR) remains not well established. OBJECTIVES: To assess the impact of MDR colonization on SOTR's mortality, infection, or graft loss. METHODS AND DATA SOURCES: Data from PROSPERO, OVID Medline, OVID EMBASE, Wiley Cochrane Library, ProQuest Dissertations, Theses Global, and SCOPUS were systematically reviewed, spanning from inception until 20 March 2023. The study protocol was registered with PROSPERO (CRD42022290011) and followed the PRISMA guidelines. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, INTERVENTIONS, AND ASSESSMENT OF RISK OF BIAS: Cohorts and case-control studies that reported on adult SOTR colonized by Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum ß-lactamase (ESBL) or carbapenem-resistant Enterobacteriaceae. (CRE), or MDR-pseudomonas, and compared to noncolonized, were included. Two reviewers assessed eligibility, conducted a risk of bias evaluation using the Newcastle-Ottawa Scale, and rated certainty of evidence using the GRADE approach. METHODS OF DATA SYNTHESIS: We employed RevMan for a meta-analysis, using random-effects models to compute pooled odds ratios (OR) and 95% confidence intervals (CI). Statistical heterogeneity was determined using the I2 statistic. RESULTS: 15,202 SOTR (33 cohort, six case-control studies) were included, where liver transplant and VRE colonization (25 and 14 studies) were predominant. MDR colonization significantly increased posttransplant 1-year mortality (OR, 2.35; 95% CI, 1.63-3.38) and mixed infections (OR, 10.74; 95% CI, 7.56-12.26) across transplant types (p < 0.001 and I2 = 58%), but no detected impact on graft loss (p 0.41, I2 = 0). Subgroup analysis indicated a higher association between CRE or ESBL colonization with outcomes (CRE: death OR, 3.94; mixed infections OR, 24.8; ESBL: mixed infections OR, 10.3; no mortality data) compared to MRSA (Death: OR, 2.25; mixed infection: OR, 7.75) or VRE colonization (Death: p 0.20, mixed infections: OR, 5.71). CONCLUSIONS: MDR colonization in SOTR, particularly CRE, is associated with increased mortality. Despite the low certainty of the evidence, actions to prevent MDR colonization in transplant candidates are warranted.

Not just emotion regulation, but cognition: An experience sampling study testing the relations of ecological interpretation biases and use of emotion regulation strategies with momentary affective states during daily life functioning.

BACKGROUND: Current research is moving from studying cognitive biases and maladaptive emotion regulation (ER) as relatively stable phenomena contributing to affective disturbances, adopting ecological methodologies, such as Experience Sampling Methods (ESM). However, there is still limited ESM evidence on the interactions between stress and ER strategies' use, and negative interpretation biases, regarding their relations with momentary affective states. In this study, we used a new ESM design to disentangle the contextual, regulatory and cognitive processes implicated in daily affective experiences. METHOD: A sample of 103 participants completed an ESM study (3 times a day for 10 days) that included self-reports of momentary affect, stress intensity, ER strategies' use and a cognitive task measuring momentary negative interpretation biases. RESULTS: Multilevel analyses supported significant interactions of both rumination and worry with stress intensity, to account for momentary higher negative and lower positive affect levels. Furthermore, higher state negative interpretation bias levels uniquely predicted both higher negative and lower positive momentary affect levels. CONCLUSION: This study implemented a novel online cognitive task within an ESM procedure, which helped to disentangle how contextual ER strategies' use and momentary cognitive biases uniquely relate to affective experiences in daily life.

Prefrontal activity during IOWA Gambling Task in young adult women.

This study aims to investigate the relationships between personality traits of impulsivity, using the UPPS-P Impulsive Behaviour Scales shortened version, and prefrontal cortex (PFC) activity during the IOWA Gambling Task (IGT) in young adult women. The study included a sample of 83 young, healthy females (19.8 ± 1.4 years), who voluntarily took part in the study. Repeated measures analysis during the IGT revealed a significant increase in HbO (all p <.001; ηp2 >.31) and a decrease in Hbr (all p <.003; ηp2 >.08) in all prefrontal quadrants. This increase in oxygenation occurs primarily during the choice period under ambiguity (r =.23; p =.039). Additionally, there was a significant linear decrease in selecting the decks associated with a high frequency of losses (p <.001), while the favorable deck with low losses showed a linear increase (F = 12.96; p <.001). Notably, discrepancies were found between UPPS-P and IGT impulsivity ratings. The Lack of Perseverance and Lack of Premeditation scales from the UPPS-P were identified as significant predictors of HbO levels, mainly in the two quadrants of the left hemisphere's, lateral (adjusted R2 =.23; p <.001; f2 =.34) and rostral (adjusted R2 =.13; p <.002; f2 =.17). These findings suggest that young adult women predominantly adopt a punishment-avoidance strategy during IGT, exhibiting increased activation in the left hemisphere, especially during the task's initial phase characterized by ambiguity.

Association of PADI2 and PADI4 polymorphisms in COVID-19 host severity and non-survival.

Background: Enzymes of the peptidylarginine deiminase family (PADs) play a relevant role in the pathogenesis of COVID-19. However, the association of single nucleotide polymorphisms (SNPs) in their genes with COVID-19 severity and death is unknown. Methodology: We included 1045 patients who were diagnosed with COVID-19 between October 2020 and December 2021. All subjects were genotyped for PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) SNPs by TaqMan assays and their associations with disease severity, death, and inflammatory biomarkers were evaluated. Results: 291 patients presented had severe COVID-19 according to PaO2/FiO2, and 393 had a non-survival outcome. Carriers of the rs1005753 G/G genotype in the PADI2 gene presented susceptibility for severe COVID-19, while the heterozygous carriers in rs11203366, rs11203367, and rs874881 of the PADI4 gene showed risk of death. The GTACC haplotype in PADI2-PADI4 was associated with susceptibility to severe COVID-19, while the GCACC haplotype was a protective factor. The GCGTG haplotype was associated with severe COVID-19 but as a protective haplotype for death. Finally, the GTACC haplotype was associated with platelet-to-lymphocyte ratio (PLR), the GCACC haplotype with neutrophil-to-hemoglobin and lymphocyte and the GCGTG haplotype as a protective factor for the elevation of procalcitonin, D-dimer, CRP, LCRP, NHL, SII, NLR, and PLR. Conclusions: Our results suggest that the haplotypic combination of GTACC and some individual genotypes of PADI2 and PADI4 contribute to the subjects' susceptibility for severity and death by COVID-19.

Digital Twin Platform for Water Treatment Plants Using Microservices Architecture.

The effects of climate change and the rapid growth of societies often lead to water scarcity and inadequate water quality, resulting in a significant number of diseases. The digitalization of infrastructure and the use of Digital Twins are presented as alternatives for optimizing resources and the necessary infrastructure in the water cycle. This paper presents a framework for the development of a Digital Twin platform for a wastewater treatment plant, based on a microservices architecture which optimized its design for edge computing implementation. The platform aims to optimize the operation and maintenance processes of the plant's systems, by employing machine learning techniques, process modeling and simulation, as well as leveraging the information contained in BIM models to support decision-making.

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues.

Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.

Genipin crosslinking promotes biomechanical reinforcement and pro-regenerative macrophage polarization in bioartificial tubular substitutes.

Traumatic nerve injuries are nowadays a significant clinical challenge and new substitutes with adequate biological and mechanical properties are in need. In this context, fibrin-agarose hydrogels (FA) have shown the possibility to generate tubular scaffolds with promising results for nerve repair. However, to be clinically viable, these scaffolds need to possess enhanced mechanical properties. In this line, genipin (GP) crosslinking has demonstrated to improve biomechanical properties with good biological properties compared to other crosslinkers. In this study, we evaluated the impact of different GP concentrations (0.05, 0.1 and 0.2% (m/v)) and reaction times (6, 12, 24, 72 h) on bioartificial nerve substitutes (BNS) consisting of nanostructured FA scaffolds. First, crosslinked BNS were studied histologically, ultrastructurally and biomechanically and then, its biocompatibility and immunomodulatory effects were ex vivo assessed with a macrophage cell line. Results showed that GP was able to improve the biomechanical resistance of BNS, which were dependent on both the GP treatment time and concentration without altering the structure. Moreover, biocompatibility analyses on macrophages confirmed high cell viability and a minimal reduction of their metabolic activity by WST-1. In addition, GP-crosslinked BNS effectively directed macrophage polarization from a pro-inflammatory (M1) towards a pro-regenerative (M2) phenotype, which was in line with the cytokines release profile. In conclusion, this study considers time and dose-dependent effects of GP in FA substitutes which exhibited increased biomechanical properties while reducing immunogenicity and promoting pro-regenerative macrophage shift. These tubular substitutes could be useful for nerve application or even other tissue engineering applications such as urethra.

Shared and Compartment-Specific Processes in Nucleus Pulposus and Annulus Fibrosus During Intervertebral Disc Degeneration.

Elucidating how cell populations promote onset and progression of intervertebral disc degeneration (IDD) has the potential to enable more precise therapeutic targeting of cells and mechanisms. Single-cell RNA-sequencing (scRNA-seq) is performed on surgically separated annulus fibrosus (AF) (19,978; 26,983 cells) and nucleus pulposus (NP) (20,884; 24,489 cells) from healthy and diseased human intervertebral discs (IVD). In both tissue types, depletion of cell subsets involved in maintenance of healthy IVD is observed, specifically the immature cell subsets - fibroblast progenitors and stem cells - indicative of an impairment of normal tissue self-renewal. Tissue-specific changes are also identified. In NP, several fibrotic populations are increased in degenerated IVD, indicating tissue-remodeling. In degenerated AF, a novel disease-associated subset is identified, which expresses disease-promoting genes. It is associated with pathogenic biological processes and the main gene regulatory networks include thrombospondin signaling and FOXO1 transcription factor. In NP and AF cells thrombospondin protein promoted expression of genes associated with TGFß/fibrosis signaling, angiogenesis, and nervous system development. The data reveal new insights of both shared and tissue-specific changes in specific cell populations in AF and NP during IVD degeneration. These identified mechanisms and molecules are novel and more precise targets for IDD prevention and treatment.

Convergence of coronary artery disease genes onto endothelial cell programs.

Linking variants from genome-wide association studies (GWAS) to underlying mechanisms of disease remains a challenge1-3. For some diseases, a successful strategy has been to look for cases in which multiple GWAS loci contain genes that act in the same biological pathway1-6. However, our knowledge of which genes act in which pathways is incomplete, particularly for cell-type-specific pathways or understudied genes. Here we introduce a method to connect GWAS variants to functions. This method links variants to genes using epigenomics data, links genes to pathways de novo using Perturb-seq and integrates these data to identify convergence of GWAS loci onto pathways. We apply this approach to study the role of endothelial cells in genetic risk for coronary artery disease (CAD), and discover 43 CAD GWAS signals that converge on the cerebral cavernous malformation (CCM) signalling pathway. Two regulators of this pathway, CCM2 and TLNRD1, are each linked to a CAD risk variant, regulate other CAD risk genes and affect atheroprotective processes in endothelial cells. These results suggest a model whereby CAD risk is driven in part by the convergence of causal genes onto a particular transcriptional pathway in endothelial cells. They highlight shared genes between common and rare vascular diseases (CAD and CCM), and identify TLNRD1 as a new, previously uncharacterized member of the CCM signalling pathway. This approach will be widely useful for linking variants to functions for other common polygenic diseases.

An integrative analysis of potential mechanisms of reduced positive affect in daily life in depression: an ESM study.

Decreased levels of positive affect (PA) are a hallmark of depression. Current models propose as potential main mechanisms a dysfunctional use of emotion regulation (ER) strategies (i.e. dampening, positive rumination), and a maladaptive activation of pro-hedonic goals. However, the role of these mechanisms in PA in daily life remains understudied. We used a 10-day ESM design to assess how these mechanisms influence each other and contribute to depressive symptomatology-related low momentary PA in 139 individuals. Higher depressive symptoms were associated with lower PA, pro-hedonic goals, more frequent use of positive rumination, and higher use of dampening. Further, experiencing higher levels of PA predicted lower following time point use of dampening in individuals with higher symptoms. Finally, using positive rumination was more beneficial (i.e. predicted higher PA increases one moment later) for individuals with higher symptomatology. Our findings suggest that moment-to-moment changes in PA daily life are affected by, and have an effect on, both pro-hedonic goals and the use of dampening and positive rumination, highlighting specific cognitive-affective mechanisms that should be considered when designing interventions aimed at improving low PA characterising depression symptomatology.