Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases?

Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.

Perinatal posttraumatic stress disorder as a predictor of mother-child bonding quality 8 months after childbirth: a longitudinal study.

BACKGROUND: Negative childbirth experiences can be related to the onset of perinatal post-traumatic stress symptomatology (P-PTSS), which significantly impacts the mother and the infant. As a response in the face of the discomfort caused by P-PTSS, maladaptive emotion regulation strategies such as brooding can emerge, contributing to the consolidation of post-partum depressive symptoms. Ultimately, both types of symptomatology, P-PTSS and post-partum depression, can act as risk factors for developing mother-child bonding difficulties. Still, this full set of temporal paths has to date remained untested. The present longitudinal study aimed to analyze the risk factors associated with the appearance of P-PTSS after post-partum and to test a path model considering the role of P-PTSS as an indirect predictor of bonding difficulties at eight months of postpartum. METHODS: An initial sample of pregnant women in the third trimester of gestation (N = 594) participated in a longitudinal study comprising two follow-ups at two and eight months of postpartum. The mothers completed online evaluations that included socio-demographic data and measures of psychological variables. A two-step linear regression model was performed to assess the predictive role of the variables proposed as risk factors for P-PTSS, and a path model was formulated to test the pathways of influence of P-PTSS on bonding difficulties. RESULTS: A history of psychopathology of the mother, the presence of depression during pregnancy, the presence of medical complications in the mother, and the occurrence of traumatic birth experiences all acted as significant predictors of P-PTSS, explaining 29.5% of its variance. Furthermore, the path model tested further confirmed an indirect effect of P-PTSS, triggered by a negative childbirth experience, on subsequent bonding difficulties eight months after labor through its association with higher levels of brooding and, ultimately, postpartum depression levels. A further path showed that bonding difficulties at two months postpartum can persist at eight months postpartum due to the onset of brooding and postpartum depression symptoms. CONCLUSION: We identified a set of robust predictors of P-PTSS: the mother's previous history of depression, perinatal depression during pregnancy, the presence of medical complications in the mother and the occurrence of traumatic birth experiences, which has important implications for prevention. This is particularly relevant, as P-PTSS, when triggered by a negative childbirth experience, further indirectly predicted the development of mother-child bonding difficulties through the mediation of higher use of brooding and symptoms of postpartum depression. These findings can serve as a basis for developing new longitudinal studies to further advance the understanding of perinatal mechanisms of mental health.

The RecD2 helicase balances RecA activities.

DNA helicases of the RecD2 family are ubiquitous. Bacillus subtilis RecD2 in association with the single-stranded binding protein SsbA may contribute to replication fork progression, but its detailed action remains unknown. In this work, we explore the role of RecD2 during DNA replication and its interaction with the RecA recombinase. RecD2 inhibits replication restart, but this effect is not observed in the absence of SsbA. RecD2 slightly affects replication elongation. RecA inhibits leading and lagging strand synthesis, and RecD2, which physically interacts with RecA, counteracts this negative effect. In vivo results show that recD2 inactivation promotes RecA-ssDNA accumulation at low mitomycin C levels, and that RecA threads persist for a longer time after induction of DNA damage. In vitro, RecD2 modulates RecA-mediated DNA strand-exchange and catalyzes branch migration. These findings contribute to our understanding of how RecD2 may contribute to overcome a replicative stress, removing RecA from the ssDNA and, thus, it may act as a negative modulator of RecA filament growth.

Temporal compartmentalization of viral infection in bacterial cells.

Virus infection causes major rearrangements in the subcellular architecture of eukaryotes, but its impact in prokaryotic cells was much less characterized. Here, we show that infection of the bacterium Bacillus subtilis by bacteriophage SPP1 leads to a hijacking of host replication proteins to assemble hybrid viral-bacterial replisomes for SPP1 genome replication. Their biosynthetic activity doubles the cell total DNA content within 15 min. Replisomes operate at several independent locations within a single viral DNA focus positioned asymmetrically in the cell. This large nucleoprotein complex is a self-contained compartment whose boundaries are delimited neither by a membrane nor by a protein cage. Later during infection, SPP1 procapsids localize at the periphery of the viral DNA compartment for genome packaging. The resulting DNA-filled capsids do not remain associated to the DNA transactions compartment. They bind to phage tails to build infectious particles that are stored in warehouse compartments spatially independent from the viral DNA. Free SPP1 structural proteins are recruited to the dynamic phage-induced compartments following an order that recapitulates the viral particle assembly pathway. These findings show that bacteriophages restructure the crowded host cytoplasm to confine at different cellular locations the sequential processes that are essential for their multiplication.

Prostate Cancer and the Mevalonate Pathway.

Antineoplastic therapies for prostate cancer (PCa) have traditionally centered around the androgen receptor (AR) pathway, which has demonstrated a significant role in oncogenesis. Nevertheless, it is becoming progressively apparent that therapeutic strategies must diversify their focus due to the emergence of resistance mechanisms that the tumor employs when subjected to monomolecular treatments. This review illustrates how the dysregulation of the lipid metabolic pathway constitutes a survival strategy adopted by tumors to evade eradication efforts. Integrating this aspect into oncological management could prove valuable in combating PCa.

Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease.

Mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. GDAP1 is an atypical glutathione S-transferase (GST) of the outer mitochondrial membrane and the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs). Here, we investigate the role of this GST in the autophagic flux and the membrane contact sites (MCSs) between mitochondria and lysosomes in the cellular pathophysiology of GDAP1 deficiency. We demonstrate that GDAP1 participates in basal autophagy and that its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 also contributes to the maturation of lysosome by interacting with PYKfyve kinase, a pH-dependent master lysosomal regulator. GDAP1 deficiency causes giant lysosomes with hydrolytic activity, a delay in the autophagic lysosome reformation, and TFEB activation. Notably, we found that GDAP1 interacts with LAMP-1, which supports that GDAP1-LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria-lysosome MCSs in soma and axons of cultured mouse embryonic motor neurons and human neuroblastoma cells. GDAP1 deficiency reduces the MCSs between these organelles, causes mitochondrial network abnormalities, and decreases levels of cellular glutathione (GSH). The supply of GSH-MEE suffices to rescue the lysosome membranes and the defects of the mitochondrial network, but not the interorganelle MCSs nor early autophagic events. Overall, we show that GDAP1 enables the proper function of mitochondrial MCSs in both degradative and nondegradative pathways, which could explain primary insults in GDAP1-related CMT pathophysiology, and highlights new redox-sensitive targets in axonopathies where mitochondria and lysosomes are involved.

L-selectin regulates human neutrophil transendothelial migration.

The migration of circulating neutrophils towards damaged or infected tissue is absolutely critical to the inflammatory response. L-selectin is a cell adhesion molecule abundantly expressed on circulating neutrophils. For over two decades, neutrophil L-selectin has been assigned the exclusive role of supporting tethering and rolling - the initial stages of the multi-step adhesion cascade. Here, we provide direct evidence for L-selectin contributing to neutrophil transendothelial migration (TEM). We show that L-selectin co-clusters with PECAM-1 - a well-characterised cell adhesion molecule involved in regulating neutrophil TEM. This co-clustering behaviour occurs specifically during TEM, which serves to augment ectodomain shedding of L-selectin and expedite the time taken for TEM (TTT) to complete. Blocking PECAM-1 signalling (through mutation of its cytoplasmic tail), PECAM-1-dependent adhesion or L-selectin shedding, leads to a significant delay in the TTT. Finally, we show that co-clustering of L-selectin with PECAM-1 occurs specifically across TNF- but not IL-1ß-activated endothelial monolayers - implying unique adhesion interactomes forming in a cytokine-specific manner. To our knowledge, this is the first report to implicate a non-canonical role for L-selectin in regulating neutrophil TEM.

Anti-inflammatory effects and improved metabolic derangements in ob/ob mice by a newly synthesized prenylated benzopyran with pan-PPAR activity.

BACKGROUND AND PURPOSE: Selective peroxisome proliferator-activated receptors (PPARs) are widely used to treat metabolic complications; however, the limited effect of PPARα agonists on glucose metabolism and the adverse effects associated with selective PPARγ activators have stimulated the development of novel pan-PPAR agonists to treat metabolic disorders. Here, we synthesized a new prenylated benzopyran (BP-2) and evaluated its PPAR-activating properties, anti-inflammatory effects and impact on metabolic derangements. EXPERIMENTAL APPROACH: BP-2 was used in transactivation assays to evaluate its agonism to PPARα, PPARß/δ and PPARγ. A parallel-plate flow chamber was employed to investigate its effect on TNFα-induced leukocyte-endothelium interactions. Flow cytometry and immunofluorescence were used to determine its effects on the expression of endothelial cell adhesion molecules (CAMs) and chemokines and p38-MAPK/NF-κB activation. PPARs/RXRα interactions were determined using a gene silencing approach. Analysis of its impact on metabolic abnormalities and inflammation was performed in ob/ob mice. KEY RESULTS: BP-2 displayed strong PPARα activity, with moderate and weak activity against PPARß/δ and PPARγ, respectively. In vitro, BP-2 reduced TNFα-induced endothelial ICAM-1, VCAM-1 and fractalkine/CX3CL1 expression, suppressed mononuclear cell arrest via PPARß/δ-RXRα interactions and decreased p38-MAPK/NF-κB activation. In vivo, BP-2 improved the circulating levels of glucose and triglycerides in ob/ob mice, suppressed T-lymphocyte/macrophage infiltration and proinflammatory markers in the liver and white adipose tissue, but increased the expression of the M2-like macrophage marker CD206. CONCLUSION AND IMPLICATIONS: BP-2 emerges as a novel pan-PPAR lead candidate to normalize glycemia/triglyceridemia and minimize inflammation in metabolic disorders, likely preventing the development of further cardiovascular complications.

Associated Risk Factors and Impact in Clinical Outcomes of Multiorgan Failure in Patients with TBI.

BACKGROUND: Individual extracerebral organ dysfunction is common after severe traumatic brain injury (TBI) and impacts outcomes. However, multiorgan failure (MOF) has received less attention in patients with isolated TBI. Our objective was to analyze the risk factors associated with the development of MOF and its impact in clinical outcomes in patients with TBI. METHODS: This was an observational, prospective, multicenter study using data from a nationwide registry that currently includes 52 intensive care units (ICUs) in Spain (RETRAUCI). Isolated significant TBI was defined as Abbreviated Injury Scale (AIS) ≥ 3 in the head area with no AIS ≥ 3 in any other anatomical area. Multiorgan failure was defined using the Sequential-related Organ Failure Assessment as the alteration of two or more organs with a score of ≥ 3. We analyzed the contribution of MOF to crude and adjusted mortality (age and AIS head) by using logistic regression analysis. A multiple logistic regression analysis was performed to analyze the risk factors associated with the development of MOF in patients with isolated TBI. RESULTS: A total of 9790 patients with trauma were admitted to the participating ICUs. Of them, 2964 (30.2%) had AIS head ≥ 3 and no AIS ≥ 3 in any other anatomical area, and these patients constituted the study cohort. Mean age was 54.7 (19.5) years, 76% of patients were men, and ground-level falls were the main mechanism of injury (49.1%). In-hospital mortality was 22.2%. Up to 185 patients with TBI (6.2%) developed MOF during their ICU stay. Crude and adjusted (age and AIS head) mortality was higher in patients who developed MOF (odds ratio 6.28 [95% confidence interval 4.58-8.60] and odds ratio 5.20 [95% confidence interval 3.53-7.45]), respectively. The logistic regression analysis showed that age, hemodynamic instability, the need of packed red blood cells concentrates in the initial 24 h, the severity of brain injury, and the need for invasive neuromonitoring were significantly associated with MOF development. CONCLUSIONS: MOF occurred in 6.2% of patients with TBI admitted to the ICU and was associated with increased mortality. MOF was associated with age, hemodynamic instability, the need of packed red blood cells concentrates in the initial 24 h, the severity of brain injury, and the need for invasive neuromonitoring.

Difficulties in Pregnancy Adjustment as Predictors of Perinatal Depression: Indirect Effects through the Role of Brooding Rumination and Maternal-Fetal Bonding.

OBJECTIVE: The aim of this research was to study the ways in which problems of adaptation to pregnancy influence the development of symptoms of perinatal depression via the presence of brooding and low maternal-fetal bonding, in addition to other risk factors previously established in the literature. STUDY DESIGN: Representative sample of pregnant women in the third trimester of gestation (N = 594) completed an online survey that included sociodemographic data and measures of perinatal depression, adjustment to pregnancy, bonding, and brooding. Other risk factors were also assessed as covariates, such as previous history of depression, generalized anxiety, perceived social support, and experience of stressful life events. Descriptive and correlational analyses were performed on the scores obtained by the subjects with the different instruments. A path model was formulated to establish the pathways through which adjustment influences perinatal depression symptomatology. On the one hand, the presence of brooding (worst adjustment to pregnancy → high brooding → perinatal depression symptomatology), and on the other hand, the quality of maternal-fetal bonding (worst adjustment to pregnancy → poor quality fetal-maternal bonding → perinatal depression symptomatology) would act as a mediator. RESULTS: The factors proposed by the literature were predictive of perinatal depressive symptomatology and the quality of adjustment to pregnancy. Problems adjusting to changes during pregnancy and experiencing it unsatisfactorily may predict individual differences in perinatal depressive symptoms. Significantly, this relationship was mediated by two key factors, the presence of brooding and low quality of the maternal-fetal bond. CONCLUSION: Our results provide evidence in favor of the existence of multiple paths through which difficulties in adapting to pregnancy can favor the occurrence of higher levels of perinatal depressive symptoms and identify new avenues for developing research in this area and preventive interventions empirically informed.

Assessment, diagnosis and treatment of peristomal skin lesions by remote imaging: An expert validation study.

BACKGROUND: Prevention and treatment of peristomal skin problems should be a priority for nurses caring for ostomates, even when the assessment of lesions must be done remotely. OBJECTIVE: To measure the level of agreement on assessment, diagnosis and care indications for peristomal skin lesions using remote imaging among nurses in Spain. DESIGN: Prospective observational multicentre study to assess the diagnostic validity and inter- and intraobserver agreement between nurses in peristomal skin lesions. Data were collected between March and October 2019. SETTINGS AND PARTICIPANTS: The research sample consisted of a group of 39 nurses with expertise in the care of ostomates. METHODS: A panel of experts established a list of 24 common signs/findings, 15 diagnostic options and 35 treatment approaches for peristomal skin lesions. Three expert stoma therapy nurses compiled the clinical cases, which they described thoroughly and documented with photographs. The 39 participating nurses evaluated the cases in two rounds to measure inter and intraobserver agreement. RESULTS: A high or very high level of agreement (κ > 0.61) was observed for the following signs: encrustation, nodules, mucocutaneous separation and varicose veins; for the following diagnoses: mucocutaneous dehiscence, allergic contact dermatitis, encrustation and varicose veins (caput medusae); for the following treatments: recommending a diet rich in vitamin C/blueberries, applying acetic acid dressings, applying cold and topical tacrolimus treatment. CONCLUSIONS: The most easily identifiable lesions were those most prevalent and with visible signs. There was a lower level of agreement in identifying lesions for which photographs required additional information (laboratory data, description of signs and symptoms, type of diet and level of self-care). It is important to train nurses caring for ostomates to correctly describe ostomy-related lesions, which is important for nursing records, continuity of care and telehealth care.

Overview of Cellular and Soluble Mediators in Systemic Inflammation Associated with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient's death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.

Association of chemokines IP-10/CXCL10 and I-TAC/CXCL11 with insulin resistance and enhance leukocyte endothelial arrest in obesity.

BACKGROUND AND AIMS: Obesity is a key contributing factor to incidental type 2 diabetes and cardiovascular disease. CXCR3 receptor and its ligands CXCL 10 and 11 are associated with atherosclerosis and cardiovascular disease. The aim of our study was to analyse the role of the CXCR3 ligands on insulin resistance (IR) and endothelial dysfunction in human obesity. METHODS AND RESULTS: We have studied 45 obese patients (mean age 44 ± 6 years, body mass index 45 ± 9 kg/m2) who were selected for Roux-Y-gastric bypass surgery and 21 non obese control subjects with similar age and gender distribution. We measured by ELISA the circulating levels of the CXCR3 ligands interferon-γ inducible protein 10 (IP-10/CXCL10) and interferon-γ-inducible T-cell alpha chemoattractant (I-TAC/CXCL11). Using an ex vivo procedure with the flow chamber assay, we have investigated the effect of such chemokines on endothelial leukocytes arrest under dynamic conditions. Peripheral blood levels of CXCL10 and CXCL11 were significantly higher in obese subjects than in controls (p < 0.001) and significantly correlated with BMI, waist circunference and HOMA-IR. Obese patients with HOMA-IR index above 75th percentile showed highest increase of circulating CXCL10 and CXCL11 values. Under dynamic flow conditions, the enhanced adhesion of patient leukocytes to TNFα-induced human arterial endothelial cells was partly dependent on CXCR3. CONCLUSIONS: The study demonstrates that CXCL10 and CXCL11 are associated with IR and enhance leukocyte endothelial arrest in obese subjects. Blockade of CXCR3 signaling might be a new therapeutic approach for the prevention of obesity-associated cardiovascular co-morbidities.

Using hyperrealistic simulations to improve digital informed consent for endourological procedures.

OBJECTIVES: To show that digital informed consent (DIC) improves the subjective understanding of information and, therefore, informed consent. PATIENTS AND METHODS: A nonblinded randomized controlled trial was performed in 84 patients who had undergone transurethral resection of bladder, transurethral resection of prostate, or ureterorenoscopy between July 2017 and March 2018. The DIC group watched a hyperrealistic simulation on a tablet device before surgery. After surgery and again 30 days later, both groups completed a validated questionnaire that measured subjective understanding, anxiety, and utility of and need for information. RESULTS: The mean ± SD age of the participants was 68.7 ± 11.1 years. Nine of 84 patients (10.7%) did not complete the questionnaire. A total of 42 patients were allocated to the DIC group and 42 to the control group. The mean ± SD score for immediate subjective understanding in the DIC group was 14.5% higher than in the control group (72% ± 17.5% vs 57.5% ± 23.5%, respectively; P = 0.006). There was no statistical difference in anxiety, utility of and need for information relative to delayed subjective understanding. In subgroup analysis, subjective understanding scores were higher, but not significantly so, among patients with low and higher education levels in the DIC group than in the control group (68% ± 18.1% vs 54% ± 22.5% [P = 0.06] and 76% ± 18.3% vs and 66% ± 21.9%, respectively [P = 0.89]). CONCLUSION: Hyperrealistic simulations improved subjective understanding of information and, therefore, informed consent for endourological procedures.

Synthesis and biological studies of "Polycerasoidol" and "trans-δ-Tocotrienolic acid" derivatives as PPARα and/or PPARγ agonists.

2-Prenylated benzopyrans represent a class of natural and synthetic compounds showing a wide range of significant activities. Polycerasoidol is a natural prenylated benzopyran isolated from the stem bark of Polyalthia cerasoides (Annonaceae) that exhibits dual PPARα/γ agonism and an anti-inflammatory effect by inhibiting mononuclear leukocyte adhesion to the dysfunctional endothelium. Herein, we report the synthesis of three new series of prenylated benzopyrans containing one (series 1), two (series 2, "polycerasoidol" analogs) and three (series 3, "trans-δ-tocotrienolic acid" analogs) isoprenoid units in the hydrocarbon side chain at the 2-position of the chroman-6-ol (6-hydroxy-dihydrobenzopyran) scaffold. Isoprenoid moieties were introduced through a Grignard reaction sequence, followed by Johnson-Claisen rearrangement and subsequent Wittig olefination. hPPAR transactivation activity and the structure activity relationships (SAR) of eleven novel synthesized 2-prenylated benzopyrans were explored. PPAR transactivation activity demonstrated that the seven-carbon side chain analogs (series 1) displayed selectivity for hPPARα, while the nine-carbon side chain analogs (polycerasoidol analogs, series 2) did so for hPPARγ. The side chain elongation to 11 or 13 carbons (series 3) resulted in weak dual PPARα/γ activation. Therefore, 2-prenylated benzopyrans of seven- and nine-carbon side chain (polycerasoidol analogs) are good lead compounds for developing useful candidates to prevent cardiovascular diseases associated with metabolic disorders.

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition.

Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 µM.

Design and Validation of an Expanded Disability Status Scale Model in Multiple Sclerosis.

INTRODUCTION: We aimed to develop and validate an Expanded Disability Status Scale (EDSS) model through clinical, optical coherence tomography (OCT), and magnetic resonance imaging (MRI) measures. METHODS: Sixty-four multiple sclerosis (MS) patients underwent peripapillary retinal nerve fiber layer and segmented macular layers evaluation through OCT (Spectralis, Heidelberg Engineering). Brain parenchymal fraction was quantified through Freesurfer, while cervical spinal cord (SC) volume was assessed manually guided by Spinal Cord Toolbox software analysis. EDSS, neuroradiological, and OCT assessment were carried out within 3 months. OCT parameters were calculated as the average of both nonoptic neuritis (ON) eyes, and in case the patient had previous ON, the value of the fellow non-ON eye was taken. Brain lesion volume, sex, age, disease duration, and history of disease-modifying treatment (1st or 2nd line disease-modifying treatments) were tested as covariables of the EDSS score. RESULTS: EDSS values correlated with patient's age (r = 0.543, p = 0.001), SC volume (r = -0.301, p = 0.034), and ganglion cell layer (GCL, r = -0.354, p = 0.012). Using these correlations, an ordinal regression model to express probability of diverse EDSS scores were designed, the highest of which was the most probable (Nagelkerke R2 = 43.3%). Using EDSS cutoff point of 4.0 in a dichotomous model, compared to a cutoff of 2.0, permits the inclusion of GCL as a disability predictor, in addition to age and SC. CONCLUSIONS: MS disability measured through EDSS is an age-dependent magnitude that is partly conditioned by SC and GCL. Further studies assessing paraclinical disability predictors are needed.

Impact of anxiety and depression on the prognosis of copd exacerbations.

BACKGROUND: Frequent and highly prevalent as comorbidities in Chronic Obstructive Pulmonary Disease (COPD) patients, both depression and anxiety seem to have an impact on COPD prognosis. However, they are underdiagnosed and rarely treated properly. AIM: To establish the prevalence of depression and anxiety in patients admitted for Acute Exacerbation of COPD (AECOPD) and determine their influence on COPD prognosis. METHODS: Prospective observational study conducted from October 1, 2016 to October 1, 2018 at the following centers in Galicia, Spain: Salnés County Hospital, Arquitecto Marcide, and Clinic Hospital Complex of Santiago de Compostela. Patients admitted for AECOPD who agreed to participate and completed the anxiety and depression scale (HADS) were included in the study. RESULTS: 288 patients (46.8%) were included, mean age was 73.7 years (SD 10.9), 84.7% were male. 67.7% patients were diagnosed with probable depression, and depression was established in 41.7%; anxiety was probable in 68.2% and established in 35.4%. 60.4% of all patients showed symptoms of both anxiety and depression. Multivariate analysis relates established depression with a higher risk of late readmission (OR 2.06, 95% CI 1.28; 3.31) and a lower risk of mortality at 18 months (OR 0.57, 95% CI 0.37; 0.90). CONCLUSION: The prevalence of anxiety and depression in COPD patients is high. Depression seems to be an independent factor for AECOPD, so early detection and a multidisciplinary approach could improve the prognosis of both entities. The study was approved by the Ethical Committee of Galicia (code 2016/460).

Modeling trade-offs across carbon sequestration, biodiversity conservation, and equity in the distribution of global REDD+ funds.

The program on Reducing Emissions from Deforestation and Forest Degradation (REDD+) is one of the major attempts to tackle climate change mitigation in developing countries. REDD+ seeks to provide result-based incentives to promote emission reductions and increase carbon sinks in forest land while promoting other cobenefits, such as the conservation of biodiversity. We model different scenarios of international REDD+ funds distribution toward potential recipient countries using 2 carbon emission reduction targets (20% and 50% compared to the baseline scenario, i.e., deforestation and forest degradation without REDD+) by 2030. The model combines the prioritization of environmental outcomes in terms of carbon sequestration and biodiversity conservation and social equity, accounting for the equitable distribution of international REDD+ funds. Results highlight the synergy between carbon sequestration and biodiversity conservation under alternative fund allocation criteria, especially for scenarios of low carbon emission reduction. Trade-offs increase when distributional equity is considered as an additional criterion, especially under higher equity requirements. The analysis helps to better understand the inherent trade-offs between enhancing distributional equity and meeting environmental targets under alternative REDD+ fund allocation options.

Development of oculomotor control throughout childhood: A multicenter and multiethnic study.

Although steady fixation is a key aspect of a proper visual function, it is only subjectively assessed in young and uncooperative children. In the present study, we characterize the development of fixational behavior throughout childhood in a large group of healthy children 5 months of age and up, recruited in five geographically diverse sites. In order to do it, we examined 802 healthy children from April 2019 to February 2020. Their oculomotor behavior was analyzed by means of an automated digital system, based on eye-tracking technology. Oculomotor outcomes were gaze stability, fixation stability and duration of fixations (for both long and short fixational tasks), and saccadic reaction time. Ninety-nine percent of all recruited children were successfully examined. Fixational and saccadic performance improved with age throughout childhood, with more pronounced changes during the first 2 years of life. Gaze and fixation tended to be more stable with age (p < 0.001 for most the outcomes), and saccades tended to be faster. In a multivariate analysis, including age and ethnicity as independent variables and adjusting by data quality, age was related with most fixational outcomes. Our automated digital system and eye-tracking data allow us to quantitatively describe the development of oculomotor control during childhood, assess visual fixation and saccadic performance in children 5 months of age and up, and provide a normative reference of fixational outcomes for clinical practice.