Instituto de Investigación Biomédica de Sevilla (IBIS)

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  • Publication
    A Probabilistic Model for Cushing’s Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study
    (Oxford University Press, 2016-08-14) Leon-Justel, Antonio; Madrazo-Atutxa, Ainara; Alvarez-Rios, Ana I.; Infantes-Fontan, Rocio; Garcia-Arnes, Juan A.; Lillo-Muñoz, Juan A.; Aulinas, Anna; Urgell-Rull, Eulalia; Boronat, Mauro; Sanchez-de-Abajo, Ana; Fajardo-Montañana, Carmen; Ortuño-Alonso, Mario; Salinas-Vert, Isabel; Granada, Maria L.; Cano, David A.; Leal-Cerro, Alfonso; CRISALIDA Study Group
    Context: Cushing’s syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. Objective: To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. Design: Observational, prospective, multicenter. Setting: Referral hospital. Patients: A cohort of 353 patients attending endocrinology units for outpatient visits. Interventions: All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. Main Outcome Measures: Diagnosis or exclusion of CS. Results: Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. Conclusions: We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.
  • Publication
    Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism
    (Elsevier, 2011-08-16) Leon-Justel, Antonio; Mangas, Miguel Angel; Infante-Fontán, Rocío; Castro-Luque, Jovanna; Venegas-Moreno, Eva; Madrazo-Atutxa, Ainara; Herrera del Rey, Teresa; Martin-Rodriguez, Juan Francisco; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso; [Leon-Justel,A; Infante Fontán,R; Castro Luque,J; Herrera del Rey,T] Department of Clinical Biochemistry, Virgen del Rocío University Hospital, Seville, Spain. [Mangas,MA; Venegas Moreno,E; Madrazo Atutxa,A; Martin-Rodriguez,JF; Soto-Moreno,A; Leal-Cerro,A] Division of Endocrinology, Virgen del Rocío University Hospital, Seville, Spain. [Castro Luque,J; Venegas Moreno,E; Madrazo Atutxa,A; Herrera del Rey,T; Martin-Rodriguez,JF; Soto-Moreno,A; Leal-Cerro,A] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
    Background: A single midnight serum cortisol (MSC) test has been reported to possess the best sensitivity and specificity for diagnosing Cushing's syndrome (CS). However, this test requires patient hospitalization, making it costly. This paper aims to compare the hospital budget impact and accuracy of using midnight salivary cortisol (MSVC), as opposed to MSC, in the diagnosis of hypercortisolism. Methods: 77 patients with at least two high urinary free cortisol (UFC) values (N360 nmol/24 h) were selected from 611 patients with clinical symptoms of CS. The costs of the method to confirm the diagnosis of hypercortisolism was calculated comparing Option A using MSC (UFCx2, low-dose dexamethasone suppression test [LDDST]) that requires patient hospitalization versus Option B using MSVC (UFCx2, LDDST) in which the evaluation is done outside the Hospital. A budget impact analysis for one year was developed, and a sensitivity analysis in different scenarios was performed. Reproducibility and diagnostic performance of MSVC and MSC were also measured. Results: Salivary cortisol is a sound analytical method for evaluating free serum cortisol due to its classification accuracy, good imprecision, linearity, and stability. AUCROC comparison between MSVC and MSC shows no significant differences. The substitution of the MSC for MSVC in our hospital could save between €16,762 and €132,804 in one year. Conclusions: The use of MSVC in the diagnosis of hypercortisolism can result in a substantial decrease in the budget impact, without losing diagnosis accuracy and reliability, a significant advantage considering the current emphasis on reducing the financial burden of health care.
  • Publication
    Point-of-care haemostasis monitoring during liver transplantation is cost effective
    (De Gruyter, 2019) Leon-Justel, Antonio; Alvarez-Rios Ana I; Noval-Padillo, Miguel A; Gómez-Bravo, Miguel Ángel; Porras, Manuel; Gomez-Sosa, Laura; Lopez-Romero, Juan L; Guerrero, Juan M; [Leon-Justel,A] Laboratory Medicine Department, Huelva University Hospital, Huelva, Spain. [Alvarez-Rios,A; Noval-Padillo,JA; Guerrero,JM] Department of Clinical Biochemistry, Virgen del Rocío University, Hospital, Seville, Spain; and Instituto de Biomedicina de Sevilla, IBIS (Universidad de Sevilla, HUVR, Junta de Andalucía, CSIC), Seville, Spain. [Gomez-Bravo,MA] Department of Hepatobiliary Surgery, Virgen del Rocío University Hospital, Seville, Spain. [Porras,M] Department of Intensive Care Medicine, Virgen del Rocío University Hospital, Seville, Spain. [Gomez-Sosa,L; Lopez-Romero,JL] Department of Anaesthesiology, Virgen del Rocío University Hospital, Seville, Spain.
    Background: Optimal haemostasis management in orthotropic liver transplant (OLT) could reduce blood loss and transfusion volume, improve patient outcomes and reduce cost. Methods: We performed a study including 336 OLTs to evaluate the clinical and cost effectiveness of a new pointof- care (POC)-based haemostatic management approach in OLT patients. Results: In terms of health benefit we found that the new approach showed a significant reduction in transfusion requirements (red blood cell transfusion units were reduced from 5.3 ± 4.6 to 2.8 ± 2.9 [p < 0.001], free frozen plasma from 3.1 ± 3.3 to 0.4 ± 1.0 [p < 0.001] and platelets from 2.9 ± 3.9 to 0.4 ± 0.9 [p < 0.001], transfusion avoidance, 9.7% vs. 29.1% [p < 0.001] and massive transfusion, 14.5% vs. 3.8% [p = 0.001]); we also found a significant improvement in patient outcomes, such, reoperation for bleeding or acute-kidney-failure (8.3% vs. 2.4%, p = 0.015; 33.6% vs. 5.4%, p < 0.001), with a significant reduction in the length of the hospital total stay (40.6 ± 13.8 days vs. 38.2 ± 14.4 days, p = 0.001). The lowest cost incurred was observed with the new approach (€73,038.80 vs. €158,912.90) with significant patient saving associated to transfusion avoidance (€1278.36), ICU-stay (€3037.26), total-stay (€3800.76) and reoperation for bleeding (€80,899.64). Conclusions: POC haemostatic monitoring during OLT is cost effective.
  • Publication
    S100B protein may detect brain death development after severe traumatic brain injury
    (Mary Ann Liebert, 2013-10-15) Egea-Guerrero, Juan J.; Murillo-Cabezas, Francisco; Gordillo-Escobar, Elena; Rodriguez-Rodriguez, Ana; Enamorado-Enamorado, Judy; Revuelto-Rey, Jaume; Pacheco-Sanchez, Maria; Leon-Justel, Antonio; Dominguez-Roldan, Jose M.; Vilches-Arenas, Angel; [Egea-Guerrero,JJ; Murillo-Cabezas,F; Gordillo-Escobar,E; Enamorado-Enamorado,J; Revuelto-Rey,J; Pacheco-Sanchez,M; Dominguez-Roldan,JM] NeuroCritical Care Unit, Virgen del Rocío University Hospital.; [Rodriguez-Rodriguez,A; Leon-Justel,A] Department of Clinical Biochemistry, Virgen del Rocı´o University Hospital.; [Vilches-Arenas,A] Department of Preventive Medicine and Public Health, IBIS/CSIC/University of Seville, Seville, Spain.
    Despite improvements in the process of organ donation and transplants, the number of organ donors is progressively declining in developed countries. Therefore, the early detection of patients at risk for brain death (BD) is a priority for transplant teams seeking more efficient identification of potential donors. In the extensive literature on S100B as a biomarker for traumatic brain injury (TBI), no evidence appears to exist on its prognostic capacity as a predictor of BD after severe TBI. The objective of this study is to assess the value of including acute S100B levels in standard clinical data as an early screening tool for BD after severe TBI. This prospective study included patients with severe TBI (Glasgow Coma Scale score [GCS] ≤8) admitted to our Neurocritical Care Unit over a 30 month period. We collected the following clinical variables: age, gender, GCS score, pupillary alterations at admission, hypotension and pre-hospital desaturation, CT scan results, isolated TBI or other related injuries, Injury Severity Score (ISS), serum S100B levels at admission and 24 h post-admission, and a final diagnosis regarding BD. Of the 140 patients studied, 11.4% developed BD and showed significantly higher S100B concentrations (p<0.001). Multivariate analysis showed that bilateral unresponsive mydriasis at admission and serum S100B at 24 h post-admission had odds ratios (ORs) of 21.35 (p=0.005) and 4.9 (p=0.010), respectively. The same analysis on patients with photomotor reflex in one pupil at admission left only the 24 h S100B sample in the model (OR=15.5; p=0.009). Receiver operating characteristics (ROC) curve analysis on this group showed the highest area under the curve (AUC) (0.86; p=0.001) for 24 h S100B determinations. The cut off was set at 0.372 μg/L (85.7% sensitivity, 79.3% specificity, positive predictive value [PPV]=18.7% and negative predictive value [NPV]=98.9%). This study shows that pupillary responsiveness at admission, as well as 24 h serum S100B levels, could serve as screening tools for the early detection of patients at risk for BD after severe TBI.
  • Publication
    Influence of reduction in the elution times on HPLC glycohaemoglobin results
    (Elsevier, 2009-07-16) Leon-Justel, Antonio; Santotoribio, Jose D.; Dominguez-Pascual, Inmaculada; Delgado, Ana L.; Macias, Carlos; Herrera, Maria T.; Leal, Alfonso; Mangas, Miguel A.; Acosta, Domingo; Guerrero, J.M.; [Leon-Justel,A; Santotoribio,JD; Dominguez-Pascual,I; Delgado,AL; Macias,C; Herrera,MT; Guerrero,JM] Department of Clinical Biochemistry, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain.; [Leal,A; Mangas,MA; Acosta,D] Clinical Management Unit for Endocrinology and Nutrition, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain.
    Objectives To compare HPLC methods with short and long elution times for HbA1c measurement in blood. Methods Comparison between G7-Tosoh (1.2 min); Bio-Rad-Variant-II-Turbo (1.3 min) and Arkray-HA-8160 (2.9 min). Results Passing–Bablok regression equations were: Y = 0.17 + 0.96X; Y = − 0.39 + 1.01X; Y = − 0.40 + 1.0X and the means of the differences using Bland–Altman Plot were 0.02; − 0.34; 0.32 for HA-8160/G7-Tosoh, HA-8160/Variant-II-Turbo and G7-Tosoh/Variant-II-Turbo, respectively. Conclusions Faster elution methods had no problems on reproducibility of results obtained by slower elution methods.
  • Publication
    A clinical profile of memory impairment in humans due to endogenous glucocorticoid excess
    (Wiley, 2009-01-19) León-Carrión, José; Atutxa, Ainara Madrazo; Mangas, Miguel Angel; Soto-Moreno, Alfonso; Pumar, Alfonso; Leon-Justel, Antonio; Martín-Rodriguez, Juan Francisco; Venegas, Eva; Domínguez-Morales, Mª Rosario; Leal-Cerro, Alfonso; [León-Carrión,J; Martín-Rodriguez,JF] Human Neuropsychology Laboratory, University of Seville.; [Atutxa, AM; Venegas, E] Division of Endocrinology, University Hospital Virgen del Rocío, Sevilla, Spain.; [Mangas, MA; Soto-Moreno,A; Pumar,A; Leal-Cerro,A] Institute of Biomedicine Seville (IBiS).; [Leon-Justel,A] Division of Chemical Analysis, University Hospital Virgen del Rocío, Sevilla, Spain.; [Domínguez-Morales, MR] Center for Brain Injury Rehabilitation (CRECER), Sevilla, Spain.
    Objective Glucocorticoid excess is commonly related to neuropsychiatric and neurological disorders, with memory impairment typically found among these disorders. The objective of this study is to offer a clinical profile of memory deficits resulting from exposure to chronic stress-level elevations of endogenous glucocorticoids in patients with Cushing's Syndrome (CS). Study subjects Thirty female participants of matching age and education level were studied: 15 had untreated CS (mean age 38 ± 14) and 15 were healthy. In all patients, CS was confirmed by histology of the lesion after surgery. Design Different learning and memory processes were assessed using an adapted version of Luria's Memory Words-Revised task (LMW-R). Participants’ performances were measured in an immediate condition and, 30 min later, in a delayed condition. Attentional and executive functions were also evaluated. Results Our data show that chronic exposure to elevated levels of cortisol is clinically associated with significant working memory deficits, which included less shot-term memory volume, slow learning rate, memory contamination and no accurate perception of own performance. Patients also show impairment in the delayed recall task. No relation was detected between learning and delayed conditions. CS group did not differ significantly from control group in basic attentional and executive functioning. Conclusions Our clinical profile of memory deficits related to CS relates chronic exposure to hypercortisolemia to impaired attentional-dependent working memory and delayed recall process, suggesting that cortisol levels play a critical role in the modulation of learning and memory. Possible damage to hippocampus and extrahippocampal areas is discussed.
  • Publication
    Gene set enrichment analysis of pathophysiological pathways highlights oxidative stress in psychosis.
    (2022-09-21) Pistis, Giorgio; Vázquez-Bourgon, Javier; Fournier, Margot; Jenni, Raoul; Cleusix, Martine; Papiol, Sergi; Smart, Sophie E; Pardiñas, Antonio F; Walters, James T R; MacCabe, James H; Kutalik, Zoltán; Conus, Philippe; Crespo-Facorro, Benedicto; Q Do, Kim
    Polygenic risk prediction remains an important aim of genetic association studies. Currently, the predictive power of schizophrenia polygenic risk scores (PRSs) is not large enough to allow highly accurate discrimination between cases and controls and thus is not adequate for clinical integration. Since PRSs are rarely used to reveal biological functions or to validate candidate pathways, to fill this gap, we investigated whether their predictive ability could be improved by building genome-wide (GW-PRSs) and pathway-specific PRSs, using distance- or expression quantitative trait loci (eQTLs)- based mapping between genetic variants and genes. We focused on five pathways (glutamate, oxidative stress, GABA/interneurons, neuroimmune/neuroinflammation and myelin) which belong to a critical hub of schizophrenia pathophysiology, centred on redox dysregulation/oxidative stress. Analyses were first performed in the Lausanne Treatment and Early Intervention in Psychosis Program (TIPP) study (n = 340, cases/controls: 208/132), a sample of first-episode of psychosis patients and matched controls, and then validated in an independent study, the epidemiological and longitudinal intervention program of First-Episode Psychosis in Cantabria (PAFIP) (n = 352, 224/128). Our results highlighted two main findings. First, GW-PRSs for schizophrenia were significantly associated with early psychosis status. Second, oxidative stress was the only significantly associated pathway that showed an enrichment in both the TIPP (p = 0.03) and PAFIP samples (p = 0.002), and exclusively when gene-variant linking was done using eQTLs. The results suggest that the predictive accuracy of polygenic risk scores could be improved with the inclusion of information from functional annotations, and through a focus on specific pathways, emphasizing the need to build and study functionally informed risk scores.
  • Publication
    Structural brain alterations associated with suicidal thoughts and behaviors in young people: results from 21 international studies from the ENIGMA Suicidal Thoughts and Behaviours consortium.
    (2022-09-07) van Velzen, Laura S; Dauvermann, Maria R; Colic, Lejla; Villa, Luca M; Savage, Hannah S; Toenders, Yara J; Zhu, Alyssa H; Bright, Joanna K; Campos, Adrián I; Salminen, Lauren E; Ambrogi, Sonia; Ayesa-Arriola, Rosa; Banaj, Nerisa; Başgöze, Zeynep; Bauer, Jochen; Blair, Karina; Blair, Robert James; Brosch, Katharina; Cheng, Yuqi; Colle, Romain; Connolly, Colm G; Corruble, Emmanuelle; Couvy-Duchesne, Baptiste; Crespo-Facorro, Benedicto; Cullen, Kathryn R; Dannlowski, Udo; Davey, Christopher G; Dohm, Katharina; Fullerton, Janice M; Gonul, Ali Saffet; Gotlib, Ian H; Grotegerd, Dominik; Hahn, Tim; Harrison, Ben J; He, Mengxin; Hickie, Ian B; Ho, Tiffany C; Iorfino, Frank; Jansen, Andreas; Jollant, Fabrice; Kircher, Tilo; Klimes-Dougan, Bonnie; Klug, Melissa; Leehr, Elisabeth J; Lippard, Elizabeth T C; McLaughlin, Katie A; Meinert, Susanne; Miller, Adam Bryant; Mitchell, Philip B; Mwangi, Benson; Nenadić, Igor; Ojha, Amar; Overs, Bronwyn J; Pfarr, Julia-Katharina; Piras, Fabrizio; Ringwald, Kai G; Roberts, Gloria; Romer, Georg; Sanches, Marsal; Sheridan, Margaret A; Soares, Jair C; Spalletta, Gianfranco; Stein, Frederike; Teresi, Giana I; Tordesillas-Gutiérrez, Diana; Uyar-Demir, Aslihan; van der Wee, Nic J A; van der Werff, Steven J; Vermeiren, Robert R J M; Winter, Alexandra; Wu, Mon-Ju; Yang, Tony T; Thompson, Paul M; Rentería, Miguel E; Jahanshad, Neda; Blumberg, Hilary P; van Harmelen, Anne-Laura; ENIGMA Suicidal Thoughts and Behaviours Consortium; Schmaal, Lianne
    Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.
  • Publication
    Correction: Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.
    (2022) McWhinney, Sean R; Brosch, Katharina; Calhoun, Vince D; Crespo-Facorro, Benedicto; Crossley, Nicolas A; Dannlowski, Udo; Dickie, Erin; Dietze, Lorielle M F; Donohoe, Gary; Du Plessis, Stefan; Ehrlich, Stefan; Emsley, Robin; Furstova, Petra; Glahn, David C; Gonzalez-Valderrama, Alfonso; Grotegerd, Dominik; Holleran, Laurena; Kircher, Tilo T J; Knytl, Pavel; Kolenic, Marian; Lencer, Rebekka; Nenadić, Igor; Opel, Nils; Pfarr, Julia-Katharina; Rodrigue, Amanda L; Rootes-Murdy, Kelly; Ross, Alex J; Sim, Kang; Škoch, Antonín; Spaniel, Filip; Stein, Frederike; Švancer, Patrik; Tordesillas-Gutiérrez, Diana; Undurraga, Juan; Vázquez-Bourgon, Javier; Voineskos, Aristotle; Walton, Esther; Weickert, Thomas W; Weickert, Cynthia Shannon; Thompson, Paul M; van Erp, Theo G M; Turner, Jessica A; Hajek, Tomas
  • Publication
    Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.
    (2022-06-14) McWhinney, Sean R; Brosch, Katharina; Calhoun, Vince D; Crespo-Facorro, Benedicto; Crossley, Nicolas A; Dannlowski, Udo; Dickie, Erin; Dietze, Lorielle M F; Donohoe, Gary; Du Plessis, Stefan; Ehrlich, Stefan; Emsley, Robin; Furstova, Petra; Glahn, David C; Gonzalez-Valderrama, Alfonso; Grotegerd, Dominik; Holleran, Laurena; Kircher, Tilo T J; Knytl, Pavel; Kolenic, Marian; Lencer, Rebekka; Nenadić, Igor; Opel, Nils; Pfarr, Julia-Katharina; Rodrigue, Amanda L; Rootes-Murdy, Kelly; Ross, Alex J; Sim, Kang; Škoch, Antonín; Spaniel, Filip; Stein, Frederike; Švancer, Patrik; Tordesillas-Gutiérrez, Diana; Undurraga, Juan; Vázquez-Bourgon, Javier; Voineskos, Aristotle; Walton, Esther; Weickert, Thomas W; Weickert, Cynthia Shannon; Thompson, Paul M; van Erp, Theo G M; Turner, Jessica A; Hajek, Tomas
    Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.
  • Publication
    An Updated View of the Trypanosoma cruzi Life Cycle: Intervention Points for an Effective Treatment.
    (2022-06-02) Martín-Escolano, Javier; Marín, Clotilde; Rosales, María J; Tsaousis, Anastasios D; Medina-Carmona, Encarnación; Martín-Escolano, Rubén
    Chagas disease (CD) is a parasitic, systemic, chronic, and often fatal illness caused by infection with the protozoan Trypanosoma cruzi. The World Health Organization classifies CD as the most prevalent of poverty-promoting neglected tropical diseases, the most important parasitic one, and the third most infectious disease in Latin America. Currently, CD is a global public health issue that affects 6-8 million people. However, the current approved treatments are limited to two nitroheterocyclic drugs developed more than 50 years ago. Many efforts have been made in recent decades to find new therapies, but our limited understanding of the infection process, pathology development, and long-term nature of this disease has made it impossible to develop new drugs, effective treatment, or vaccines. This Review aims to provide a comprehensive update on our understanding of the current life cycle, new morphological forms, and genetic diversity of T. cruzi, as well as identify intervention points in the life cycle where new drugs and treatments could achieve a parasitic cure.
  • Publication
    Bioactive Peptides from Lupin (Lupinus angustifolius) Prevent the Early Stages of Atherosclerosis in Western Diet-Fed ApoE-/- Mice.
    (2022-06-29) Santos-Sánchez, Guillermo; Cruz-Chamorro, Ivan; Álvarez-Ríos, Ana Isabel; Álvarez-Sánchez, Nuria; Rodríguez-Ortiz, Beatriz; Álvarez-López, Ana Isabel; Fernández-Pachón, María-Soledad; Pedroche, Justo; Millán, Francisco; Millán-Linares, María Del Carmen; Lardone, Patricia Judith; Bejarano, Ignacio; Carrillo-Vico, Antonio
    We have previously reported the in vitro hypocholesterolemic, anti-inflammatory, and antioxidant effects of Alcalase-generated lupin protein hydrolysate (LPH). Given that lipoprotein deposition, oxidative stress, and inflammation are the main components of atherogenesis, we characterized the LPH composition, in silico identified LPH-peptides with activities related to atherosclerosis, and evaluated the in vivo LPH effects on atherosclerosis risk factors in a mouse model of atherosclerosis. After 15 min of Alcalase hydrolysis, peptides smaller than 8 kDa were obtained, and 259 peptides out of 278 peptides found showed biological activities related to atherosclerosis risk factors. Furthermore, LPH administration for 12 weeks reduced the plasma lipids, as well as the cardiovascular and atherogenic risk indexes. LPH also increased the total antioxidant capacity, decreased endothelial permeability, inflammatory response, and atherogenic markers. Therefore, this study describes for the first time that LPH prevents the early stages of atherosclerosis.
  • Publication
    Molecular epidemiology of paediatric invasive pneumococcal disease in Andalusia, Spain.
    (2022-08-22) de Felipe, Beatriz; Obando Pacheco, Pablo; Carazo Gallego, Begoña; López Martín, David; Santos Pérez, Juan Luis; González Jiménez, Yolanda; Muñoz Vilches, María José; Cardelo Autero, Nerea; González Galán, Verónica; Morón, Francisco José; Cordero Varela, Juan Antonio; Torres Sánchez, María José; Medina Claros, Antonio; Moreno Pérez, David; Obando, Ignacio
    This study aimed to assess the impact of the introduction of pneumococcal conjugate vaccine 13 (PCV13) on the molecular epidemiology of invasive pneumococcal disease (IPD) in children from Andalusia. A population-based prospective surveillance study was conducted on IPD in children aged
  • Publication
    Can epigenetics shine a light on the biological pathways underlying major mental disorders?
    (2022-02-23) Alameda, Luis; Trotta, Giulia; Quigley, Harriet; Rodriguez, Victoria; Gadelrab, Romayne; Dwir, Daniella; Dempster, Emma; Wong, Chloe C Y; Forti, Marta Di
    A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.
  • Publication
    Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study.
    (2022-01-25) Rodriguez, Victoria; Alameda, Luis; Quattrone, Diego; Tripoli, Giada; Gayer-Anderson, Charlotte; Spinazzola, Edoardo; Trotta, Giulia; Jongsma, Hannah E; Stilo, Simona; La Cascia, Caterina; Ferraro, Laura; La Barbera, Daniele; Lasalvia, Antonio; Tosato, Sarah; Tarricone, Ilaria; Bonora, Elena; Jamain, Stéphane; Selten, Jean-Paul; Velthorst, Eva; de Haan, Lieuwe; Llorca, Pierre-Michel; Arrojo, Manuel; Bobes, Julio; Bernardo, Miguel; Arango, Celso; Kirkbride, James; Jones, Peter B; Rutten, Bart P; Richards, Alexander; Sham, Pak C; O'Donovan, Michael; Van Os, Jim; Morgan, Craig; Di Forti, Marta; Murray, Robin M; Vassos, Evangelos
    Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case-control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. In case-control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case-case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54-0.92] and PRS-D (OR = 1.31, 95% CI 1.06-1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23-3.74). Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.
  • Publication
    Daily consumption of wild olive (acebuche) oil reduces blood pressure and ameliorates endothelial dysfunction and vascular remodelling in rats with NG-nitro-L-arginine methyl ester-induced hypertension.
    (2022-01-10) Reyes-Goya, Claudia; Santana-Garrido, Álvaro; Aguilar-Espejo, Gema; Pérez-Camino, M Carmen; Mate, Alfonso; Vázquez, Carmen M
    Despite numerous reports on the beneficial effects of olive oil in the cardiovascular context, very little is known about the olive tree's wild counterpart (Olea europaea, L. var. sylvestris), commonly known as acebuche (ACE) in Spain. The aim of this study was to analyse the possible beneficial effects of an extra virgin ACE oil on vascular function in a rodent model of arterial hypertension (AH) induced by NG-nitro-l-arginine methyl ester (L-NAME). Four experimental groups of male Wistar rats were studied: (1) normotensive rats (Control group); (2) normotensive rats fed a commercial diet supplemented with 15 % (w/w) ACE oil (Acebuche group); (3) rats made hypertensive following administration of L-NAME (L-NAME group); and (4) rats treated with L-NAME and simultaneously supplemented with 15 % ACE oil (LN + ACE group). All treatments were maintained for 12 weeks. Besides a significant blood pressure (BP)-lowering effect, the ACE oil-enriched diet counteracted the alterations found in aortas from hypertensive rats in terms of morphology and responsiveness to vasoactive mediators. In addition, a decrease in hypertension-related fibrotic and oxidative stress processes was observed in L-NAME-treated rats subjected to ACE oil supplement. Therefore, using a model of AH via nitric oxide depletion, here we demonstrate the beneficial effects of a wild olive oil based upon its vasodilator, antihypertensive, antioxidant, antihypertrophic and antifibrotic properties. We postulate that regular inclusion of ACE oil in the diet can alleviate the vascular remodelling and endothelial dysfunction processes typically found in AH, thus resulting in a significant reduction of BP.
  • Publication
    Global multi-stakeholder endorsement of the MAFLD definition.
    (2022-03-03) Méndez-Sánchez, Nahum; Bugianesi, Elisabetta; Gish, Robert G; Lammert, Frank; Tilg, Herbert; Nguyen, Mindie H; Sarin, Shiv K; Fabrellas, Núria; Zelber-Sagi, Shira; Fan, Jian-Gao; Shiha, Gamal; Targher, Giovanni; Zheng, Ming-Hua; Chan, Wah-Kheong; Vinker, Shlomo; Kawaguchi, Takumi; Castera, Laurent; Yilmaz, Yusuf; Korenjak, Marko; Spearman, C Wendy; Ungan, Mehmet; Palmer, Melissa; El-Shabrawi, Mortada; Gruss, Hans-Juergen; Dufour, Jean-François; Dhawan, Anil; Wedemeyer, Heiner; George, Jacob; Valenti, Luca; Fouad, Yasser; Romero-Gomez, Manuel; Eslam, Mohammed; Global multi-stakeholder consensus on the redefinition of fatty liver disease
  • Publication
    Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study.
    (2022-09-06) Ghorashian, Sara; Jacoby, Elad; De Moerloose, Barbara; Rives, Susana; Bonney, Denise; Shenton, Geoff; Bader, Peter; Bodmer, Nicole; Quintana, Agueda Molinos; Herrero, Blanca; Algeri, Mattia; Locatelli, Franco; Vettenranta, Kim; Gonzalez, Berta; Attarbaschi, Andishe; Harris, Stephen; Bourquin, Jean Pierre; Baruchel, André
    Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia. We did an international, multicentre, retrospective cohort study at 15 hospitals across ten countries in Europe. Eligible patients were children aged younger than 3 years at screening between Sept 1, 2018, and Sept 1, 2021, who were screened for tisagenlecleucel therapy for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia according to licensed indications. Patients received a single intravenous infusion of tisagenlecleucel. We tracked chimeric antigen receptor T-cell therapy outcomes using a standardised data reporting form. Overall survival, event-free survival, stringent event-free survival, B-cell aplasia, and toxicity were assessed in all patients who received a tisagenlecleucel infusion. 38 eligible patients were screened, of whom 35 (92%) received a tisagenlecleucel infusion. 29 (76%) of 38 patients had KMT2A-rearranged acute lymphoblastic leukaemia, and 25 (66%) had relapsed after previous allogeneic haematopoietic stem-cell transplantation (HSCT). Patients had previously received a median of 2 lines (IQR 2-3) of (non-HSCT) therapy. Seven (18%) of 38 patients had received inotuzumab and 14 (37%) had received blinatumomab. After a median of 14 months (IQR 9-21) of follow-up, overall survival at 12 months after tisagenlecleucel infusion was 84% (64-93; five patients had died), event-free survival was 69% (47-83; nine events), and stringent event-free survival was 41% (23-58; 18 events). The probability of ongoing B-cell aplasia was 70% (95% CI 46-84; seven events) at 12 months. Adverse events included cytokine release syndrome, which occurred at any grade in 21 (60%) of 35 patients and at grade 3 or worse in five (14%), and neurotoxicity at any grade in nine (26%), none of which were severe. Measurable residual disease-negative complete response with or without haematological recovery occurred in 24 (86%) of 28 patients who had measurable disease. These data suggest that tisagenlecleucel has antitumour activity and has an acceptable safety profile for young children and infants with B-cell precursor acute lymphoblastic leukaemia. None.
  • Publication
    Gambling disorder in the UK: key research priorities and the urgent need for independent research funding.
    (2022-02-15) Bowden-Jones, Henrietta; Hook, Roxanne W; Grant, Jon E; Ioannidis, Konstantinos; Corazza, Ornella; Fineberg, Naomi A; Singer, Bryan F; Roberts, Amanda; Bethlehem, Richard; Dymond, Simon; Romero-Garcia, Rafa; Robbins, Trevor W; Cortese, Samuele; Thomas, Shane A; Sahakian, Barbara J; Dowling, Nicki A; Chamberlain, Samuel R
    Gambling in the modern era is pervasive owing to the variety of gambling opportunities available, including those that use technology (eg, online applications on smartphones). Although many people gamble recreationally without undue negative effects, a sizeable subset of individuals develop disordered gambling, which is associated with marked functional impairment including other mental health problems, relationship problems, bankruptcy, suicidality, and criminality. The National UK Research Network for Behavioural Addictions (NUK-BA) was established to promote understanding of, research into, and treatments for behavioural addictions including gambling disorder, which is the only formally recognised behavioural addiction. In this Health Policy paper, we outline the status of research and treatment for disordered gambling in the UK (including funding issues) and key research that should be conducted to establish the magnitude of the problem, vulnerability and resilience factors, the underlying neurobiology, long-term consequences, and treatment opportunities. In particular, we emphasise the need to: (1) conduct independent longitudinal research into the prevalence of disordered gambling (including gambling disorder and at-risk gambling), and gambling harms, including in vulnerable and minoritised groups; (2) select and refine the most suitable pragmatic measurement tools; (3) identify predictors (eg, vulnerability and resilience markers) of disordered gambling in people who gamble recreationally, including in vulnerable and minoritised groups; (4) conduct randomised controlled trials on psychological interventions and pharmacotherapy for gambling disorder; (5) improve understanding of the neurobiological basis of gambling disorder, including impulsivity and compulsivity, genetics, and biomarkers; and (6) develop clinical guidelines based on the best contemporary research evidence to guide effective clinical interventions. We also highlight the need to consider what can be learnt from approaches towards mitigating gambling-related harm in other countries.
  • Publication
    Diagnosis, prognosis, and treatment of brief psychotic episodes: a review and research agenda.
    (2021-11-29) Fusar-Poli, Paolo; Salazar de Pablo, Gonzalo; Rajkumar, Ravi Philip; López-Díaz, Álvaro; Malhotra, Savita; Heckers, Stephan; Lawrie, Stephen M; Pillmann, Frank
    Brief psychotic episodes represent an intriguing paradox in clinical psychiatry because they elude the standard knowledge that applies to the persisting psychotic disorders such as schizophrenia. This Review describes key diagnostic considerations such as conceptual foundations, current psychiatric classification versus research-based operationalisations, epidemiology, and sociocultural variations; prognostic aspects including the risk of psychosis recurrence, types of psychotic recurrences, other clinical outcomes, prognostic factors; and therapeutic issues such as treatment guidelines and unmet need of care. The advances and challenges associated with the scientific evidence are used to set a research agenda in this area. We conclude that brief psychotic episodes can be reconceptualised within a clinical staging model to promote innovative translational research and improve our understanding and treatment of psychotic disorders.