Artículos (Medicina)

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104-week safety and effectiveness of dupilumab in the treatment of severe atopic dermatitis. The experience of 5 reference dermatology units in Spain
(Sociedade Brasileira de Dermatologia. Elsevier, 2021-11) Pereyra-Rodríguez, José-Juan; Domínguez Cruz, Javier; Armario Hita, José Carlos; Ruíz Villaverde, Ricardo; Universidad de Sevilla. Departamento de Medicina
Atopic Dermatitis (AD) is a multifactorial disease resulting from the interaction of genetic predisposition, environmental triggers, disruption of skin barrier function, and type 2 immune dysregulation. Management of mild forms of AD includes the use of emollients, topical corticosteroids or calcineurin inhibitors, and phototherapy, while systemic immunosuppressive agents such as oral corticosteroids and Cyclosporine A (CsA) are reserved for severe refractory cases.1 Nevertheless, severe cases are usually not adequately controlled with any of these therapies, requiring a further step to reach clinical control.2 Recently, FDA and EMA have authorized Dupilumab, a treatment targeting Th2 cytokines Il-4 and Il-13 which has shown to be effective to control the signs and symptoms of AD. Real-world experience with Dupilumab shows a similar effectivity as compared to randomized clinical trials, but it is yet to know how this drug will perform in the long term in routine medical practice
2018 consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology on the diagnosis and treatment of cancer of unknown primary
(Springer, 2018) Losa, F.; Iglesias, L.; Pane, M.; Sanz, J.; Nieto, B.; Fuste, V.; Cruz Merino, Luis de la; Concha, A.; Balana, C.; Matias-Guiu, X.; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. CTS151: Bioquímica médica.
Cancer of unknown primary (CUP) is defned as a heterogeneous group of tumours that present with metastasis, and in which attempts to identify the original site have failed. They difer from other primary tumours in their biological features and how they spread, which means that they can be considered a separate entity. There are several hypotheses regarding their origin, but the most plausible explanation for their aggressiveness and chemoresistance seems to involve chromosomal instability. Depending on the type of study done, CUP can account for 2–9% of all cancer patients, mostly 60–75 years old. This article reviews the main clinical, pathological, and molecular studies conducted to analyse and determine the origin of CUP.The main strategies for patient management and treatment, by both clinicians and pathologists, are also addressed.
5-year outcomes with cobimetinib plus vemurafenib in BRAFV600 mutation⇓positive advanced melanoma: extended follow-up of the coBRIM study
(American Association for Cancer Research, 2021) Ascierto, Paolo Antonio; Dreno, Brigitte; Larkin, James; Ribas, Antoni; Cruz Merino, Luis de la; McArthur, Grant A.; Universidad de Sevilla. Departamento de Medicina
Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation–positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. Patients and Methods: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1–21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3–28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0–19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5–14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6–7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation–positive advanced melanoma.
A case of pan-resistant Burkholderia cepacia complex bacteremic pneumonia, after lung transplantation treated with a targeted combination therapy
(Wiley, 2018-12-12) Cantón Bulnes, María Luisa; Hurtado Martínez, Ángela; López Cerero, Lorena; Arenzana Seisdedos, Ángel Paulino; Merino Bohórquez, Vicente; Garnacho Montero, José; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Farmacología; Universidad de Sevilla. Departamento de Medicina
We describe a case of one patient with cystic fibrosis who developed a pan-resistant Burkholderia cepacia complex rapidly progressive bacteraemic pneunonia, following bilateral lung transplantation. The patient was treated with a targeted combination antibiotic therapy (meropenem plus ceftazidime/avibactam plus high doses of nebulized colistimethate sodium). Evolution of the disease was complicated by multiple organ system dysfunction. Finally, clinical improvement and microbiological cure was achieved.
A case-control analysis of the impact of venous thromboembolic disease on quality of life of patients with cancer: Quality of life in cancer (QCA) study
(Molecular Diversity Preservation International, 2020) Marin-Barrera, Lucia; Muñoz-Martin, Andres J.; Rios Herranz, Eduardo; Garcia-Escobar, Ignacio; Beato, Carmen; Otero, Remedios; Jara-Palomares, Luis; Universidad de Sevilla. Departamento de Medicina
Abstract: Although there is published research on the impact of venous thromboembolism (VTE) on quality of life (QoL), this issue has not been thoroughly investigated in patients with cancer—particularly using specific questionnaires. We aimed to examine the impact of acute symptomatic VTE on QoL of patients with malignancies. This was a multicenter, prospective, case-control study conducted in patients with cancer either with (cases) or without (controls) acute symptomatic VTE. Participants completed the EORTC QLQ-C30, EQ-5D-3L, PEmb-QoL, and VEINES-QOL/Sym questionnaires. Statistically significant and clinically relevant differences in terms of global health status were examined. Between 2015 and 2018, we enrolled 425 patients (128 cases and 297 controls; mean age: 60.2 ± 18.4 years). The most common malignancies were gastrointestinal (23.5%) and lung (19.8%) tumors. We found minimally important differences in global health status on the EQ-5D-3L (cases versus controls: 0.55 versus 0.77; mean difference: −0.22) and EORTC QLQ-C30 (47.7 versus 58.4; mean difference: −10.3) questionnaires. There were minimally important differences on the PEmb-QoL questionnaire (44.4 versus 23; mean difference: −21.4) and a significantly worse QoL on the VEINES-QOL/Sym questionnaire (42.7 versus 51.7; mean difference: −9). In conclusion, we showed that acute symptomatic VTE adversely affects the QoL of patients with malignancies.
A Comparative Study between Spanish and British SARS-CoV-2 Variants
(MDPI, 2021-11-16) Jiménez Ruiz, José Antonio; López Ramírez, Cecilia; López-Campos Bodineau, José Luis; Universidad de Sevilla. Departamento de Medicina
The study of the interaction between the SARS-CoV-2 spike protein and the angiotensin-converting enzyme 2 (ACE2) receptor is key to understanding binding affinity and stability. In the present report, we sought to investigate the differences between two already sequenced genome variants (Spanish and British) of SARS-CoV-2. Methods: In silico model evaluating the homology, identity and similarity in the genome sequence and the structure and alignment of the predictive spike by computational docking methods. Results: The identity results between the Spanish and British variants of the Spike protein were 28.67%. This close correspondence in the results between the Spanish and British SARS-CoV-2 variants shows that they are very similar (99.99%). The alignment obtained results in four deletions. There were 23 nucleotide substitutions also predicted which could affect the functionality of the proteins produced from this sequence. The interaction between the binding receptor domain from the spike protein and the ACE2 receptor produces some of the mutations found and, therefore, the energy of this ligand varies. However, the estimated antigenicity of the British variant is higher than its Spanish counterpart. Conclusions: Our results indicate that minimal mutations could interfere in the infectivity of the virus due to changes in the fitness between host cell recognition and interaction proteins. In particular, the N501Y substitution, situated in the RBD of the spike of the British variant, might be the reason for its extraordinary infective potential.
A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21(WAF1/Cip1) Induction and Mitochondrial Dysfunction
(2014) Díaz Castro, Blanca; García Flores, Gloria Paula; Báez Palomo, Alicia; Millán Uclés, África; Pérez Simón, José Antonio; Piruat Palomo, José Ignacio; López Barneo, José; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Universidad de Sevilla. Departamento de Medicina
A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21(WAF1/Cip1) Induction and Mitochondrial Dysfunction
(Public Library Science, 2021-01-20) Millán-Uclés, África; Díaz-Castro, Blanca; García-Flores, Paula; Báez, Alicia; Pérez Simón, José Antonio; Piruat, José I.; Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica; Universidad de Sevilla. Departamento de Medicina; Instituto de Biomedicina de Sevilla (IBIS); Plan Nacional I+D+I del Ministerio de Ciencia y Tecnología Innovación; Junta de Andalucía
Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/ paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1a (Hif1a) at normal oxygen tension, a theory referred to as ‘‘pseudo-hypoxic drive’’. Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissuespecificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1a pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the ‘‘pseudohypoxic’’ response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21WAF1/Cip1, a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21WAF1/Cip1 will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1a in tumorigenesis
A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe
(Elsevier, 2020) Lazarus, Jeffrey V.; Ekstedt, Mattias; Marchesini, Giulio; Mullen, Jillian; Novak, Katja; Pericàs, Juan M.; Romero Gómez, Manuel; Anstee, Quentin M.; Universidad de Sevilla. Departamento de Medicina; Allergan Pharmaceutical International Ltd.; Bristol-Myers-Squibb Company; EASL International Liver Foundation from Gilead Sciences Europe Ltd.; Horizon 2020 Framework Program of the European Union; IMI2 Program of the European Union; Miguel Servet; Pfizer Inc.; Resoundant Inc.
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH). Methods: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively. Results: None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD. Conclusions: We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries. Lay summary: We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries. © 2019 European Association for the Study of the Liver
A Delphi Consensus Document on the Use of Single-Inhaler Fixed-Dose Triple Therapies in COPD Patients
(Dovepress, 2020) López Campos, José Luis; Alcázar Navarrete, Bernardino; Riesco Miranda, Juan Antonio; Cosío, Borja G.; de Torres, Juan P.; Celli, Bartolomé; Jiménez-Ruiz, Carlos A; Casanova Macario, Ciro; Universidad de Sevilla. Departamento de Medicina
Introduction: Despite the evidence provided by clinical trials, there are some uncertainties and controversies regarding the use of triple inhaled therapy. With the aim of evaluating clinical practice in specialized respiratory units, a Delphi consensus document was implemented on the use of single-inhaler fixed-dose triple therapies after 1 year of use in Spain. Methods: A scientific committee of COPD experts defined a thematic index, guided a systematic literature review and helped design the Delphi questionnaire. This was sent to the other 45 COPD experts between April and June 2019. Agreement/disagreement on 58 statements was tested in two rounds using a Likert scale. Replies were classified as a consensus when ≥80% of the panelists agreed; a majority when a degree of agreement of ≥66% was reached; and divergence if agreement was <66%. Results: After two rounds, 44.44% of the statements reached consensus, 14.81% reached majority and 40.74% were divergent. Panelists agreed that escalating from double bronchodilation should be phenotype-based and aim to prevent exacerbations but not for improving symptoms. The addition of an antimuscarinic to inhaled corticosteroids combinations achieves improvement in lung function, symptoms and exacerbation prevention. Main safety concerns included the increased risk of pneumonia as compared to bronchodilator therapies, with similar cardiovascular effects. There was no consensus agreement on patient type response based on blood eosinophil counts or obstruction severity. Conclusion: The low degree of consensus among panelists may reflect the complexity of severe COPD management. The information provided here may be useful to clinicians implementing personalized medicine for COPD patients.
A European Observational Study to Evaluate the Safety and the Effectiveness of Safinamide in Routine Clinical Practice: The SYNAPSES Trial
(IOS Press, 2021-02-02) Abbruzzese, Giovanni; Kulisevsky, Jaime; Bergmans, Bruno; Gómez Esteban, Juan C.; Kägi, Georg; Raw, Jason; Stefani, Alessandro; Warnecke, Tobias; Jost, Wolfgang H.; Mir Rivera, Pablo; Universidad de Sevilla. Departamento de Medicina
Background: Safinamide modulates both dopaminergic and glutamatergic systems with positive effects on motor and non-motor symptoms of Parkinson’s disease (PD). The drug utilization study SYNAPSES was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency. Objective: To describe the occurrence of adverse events in PD patients treated with safinamide in real-life conditions. Methods: The SYNAPSES trial is an observational, European, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months with analyses performed in the overall population and in patients aged >75 years, with relevant comorbidities and with psychiatric conditions. Results: Of the 1610 patients included, 82.4% were evaluable after 12 months with 25.1% of patients >75 years, 70.8% with relevant comorbidities and 42.4% with psychiatric conditions. During observation 45.8% patients experienced adverse events, 27.7% patients had adverse drug reactions and 9.2% patients had serious adverse events. The adverse events were those already described in the patients’ information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroup of patients. Clinically significant improvements were seen in the UPDRS motor score and in the UPDRS total score in ≥40% of patients, according to the criteria developed by Shulman et al. Conclusion: The SYNAPSES study confirms the good safety profile of safinamide even in special groups of patients. Motor complications and motor scores improved with clinically significant results in the UPDRS scale maintained in the long-term.
A framework to develop semiautomated surveillance of surgical site infections: An international multicenter study
(Cambridge University Press, 2020) Van Rooden, Stephanie M.; Tacconelli, Evelina; Pujol, Miquel; Gomila, Aina; Kluytmans, Jan A.J.W.; Romme, Jannie; Rodríguez-Baño, Jesús; Van Mourik, Maaike S.M.; Universidad de Sevilla. Departamento de Medicina; EPI-NetCOMBACTE-MAGNET project - Innovative Medicines Initiative Joint Undertaking; European Federation of Pharmaceutical Industries and Associations; European Union Seventh Framework Programme
Objective: Automated surveillance of healthcare-associated infections reduces workload and improves standardization, but it has not yet been adopted widely. In this study, we assessed the performance and feasibility of an easy implementable framework to develop algorithms for semiautomated surveillance of deep incisional and organ-space surgical site infections (SSIs) after orthopedic, cardiac, and colon surgeries. Design: Retrospective cohort study in multiple countries. Methods: European hospitals were recruited and selected based on the availability of manual SSI surveillance data from 2012 onward (reference standard) and on the ability to extract relevant data from electronic health records. A questionnaire on local manual surveillance and clinical practices was administered to participating hospitals, and the information collected was used to pre-emptively design semiautomated surveillance algorithms standardized for multiple hospitals and for center-specific application. Algorithm sensitivity, positive predictive value, and reduction of manual charts requiring review were calculated. Reasons for misclassification were explored using discrepancy analyses. Results: The study included 3 hospitals, in the Netherlands, France, and Spain. Classification algorithms were developed to indicate procedures with a high probability of SSI. Components concerned microbiology, prolonged length of stay or readmission, and reinterventions. Antibiotics and radiology ordering were optional. In total, 4,770 orthopedic procedures, 5,047 cardiac procedures, and 3,906 colon procedures were analyzed. Across hospitals, standardized algorithm sensitivity ranged between 82% and 100% for orthopedic surgery, between 67% and 100% for cardiac surgery, and between 84% and 100% for colon surgery, with 72%–98% workload reduction. Center-specific algorithms had lower sensitivity. Conclusions: Using this framework, algorithms for semiautomated surveillance of SSI can be successfully developed. The high performance of standardized algorithms holds promise for large-scale standardization.
A genetic analysis of a Spanish population with early onset Parkinson’s disease
(Public Library Science, 2020) Tejera-Parrado, Cristina; Mir Rivera, Pablo; Teresa Periñán, María; Vela Desojo, Lydia; Abreu Rodríguez, Irene; Alonso Cánovas, Araceli; Gómez-Garre, Pilar; Universidad de Sevilla. Departamento de Medicina
Introduction Both recessive and dominant genetic forms of Parkinson’s disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson’s disease in a cohort from central Spain. Methods/patients We analyzed a cohort of 117 unrelated patients with early onset Parkinson’s disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson’s disease and other Parkinsonisms and CNV screening. Results Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes. Conclusions Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson’s disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson’s disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson’s disease.
A genetic profling guideline to support diagnosis and clinical management of lymphomas
(Springer Nature, 2023) Sánchez Beato, Margarita; Méndez, Miriam; Criado Guirado, María José; Pedrosa, Lucía; Sequero, Silvia; Yanguas-Casás, Natalia; Cruz Merino, Luis de la; Gálvez, Laura; Llanos, Marta; García, Juan Fernando; Provencio, Mariano; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. CTS151: Bioquímica médica.
The new lymphoma classifcations (International Consensus Classifcation of Mature Lymphoid Neoplasms, and 5th World Health Organization Classifcation of Lymphoid Neoplasms) include genetics as an integral part of lymphoma diagnosis, allowing better lymphoma subclassifcation, patient risk stratifcation, and prediction of treatment response. Lymphomas are characterized by very few recurrent and disease-specifc mutations, and most entities have a heterogenous genetic landscape with a long tail of recurrently mutated genes. Most of these occur at low frequencies, refecting the clinical heterogeneity of lymphomas. Multiple studies have identifed genetic markers that improve diagnostics and prognostication, and next generation sequencing is becoming an essential tool in the clinical laboratory. This review provides a “next-generation sequencing” guide for lymphomas. It discusses the genetic alterations of the most frequent mature lymphoma entities with diagnostic, prognostic, and predictive potential and proposes targeted sequencing panels to detect mutations and copy-number alterations for B- and NK/T-cell lymphomas.
A genome-wide association study on liver stiffness changes during hepatitis c virus infection cure
(MDPI, 2021-08-20) Corma-Gómez, A; Macías Sánchez, Juan; Rivero, A.; Rivero-Juárez, A.; Santos, I. de los; Reus-Bañuls, S.; González-Serna Martín, Manuel Alejandro; Pineda Vergara, Juan Antonio; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. Departamento de Fisiología; Consejería de Salud Junta de Andalucía; Instituto de Salud Carlos III
Liver stiffness (LS) at sustained virological response (SVR) after direct-acting antivirals (DAA)-based therapy is a predictor of liver events in hepatitis C virus (HCV)-infected patients. The study aim was to identify genetic factors associated with LS changes from the moment of starting anti-HCV therapy to SVR. This prospective study included HCV-infected patients from the GEHEP 011 cohort who achieved SVR with DAA-based therapy, with LS pre-treatment ≥9.5 kPa and LS measurement available at SVR. Plink and Magma software were used to carry out genome-wide single-nucleotide polymorphism (SNP)-based and gene-based association analyses, respectively. The ShinyGO application was used for exploring enrichment in Gene Ontology (GO) categories for biological processes. Overall, 242 patients were included. Median (quartile 1, quartile 3) LS values at pre-treatment and at SVR were 16.8 (12, 28) kPa and 12.0 (8.5, 19.3) kPa, respectively. Thirty-five SNPs and three genes reached suggestive association with LS changes from the moment of starting anti HCV therapy to SVR. GO categories related to DNA packaging complex, DNA conformation change, chromosome organization and chromatin organization were significantly enriched. Our study reports possible genetic factors associated with LS changes during HCV-infection cure. In addition, our results suggest that processes related to DNA conformation are also involved in these changes.
A Global Survey of Physicians Knowledge About Nonalcoholic Fatty Liver Disease
(Elsevier, 2022) Younossi, Zobair M.; Ong, Janus P.; Takahashi, Hirokazu; Yilmaz, Yusuf; Eguc‘hi, Yuichiro; El Kassas, Mohamed; Romero Gómez, Manuel; Stepanova, Maria; Universidad de Sevilla. Departamento de Medicina
Background & Aims Despite rapidly increasing nonalcoholic fatty liver disease (NAFLD) prevalence, providers’ knowledge may be limited. We assessed NAFLD knowledge and associated factors among physicians of different specialties globally. Methods NAFLD knowledge surveys containing 54 and 59 questions covering 3 domains (epidemiology/pathogenesis, diagnostics, and treatment) were completed electronically by hepatologists, gastroenterologists (GEs), endocrinologists (ENDOs), and primary care physicians (PCPs) from 40 countries comprising 5 Global Burden of Disease super-regions. Over 24 months, 2202 surveys were completed (488 hepatologists, 758 GEs, 148 ENDOs, and 808 PCPs; 50% high-income Global Burden of Disease super-region, 27% from North Africa and Middle East, 12% Southeast Asia, and 5% South Asian and Latin America). Results Hepatologists saw the greatest number of NAFLD patients annually: median 150 (interquartile range, 60–300) vs 100 (interquartile range, 35–200) for GEs, 100 (interquartile range, 30–200) for ENDOs, and 10 (interquartile range, 4–50) for PCPs (all P < .0001). The primary sources of NAFLD knowledge acquisition for hepatologists were international conferences (33% vs 8%–26%) and practice guidelines for others (39%–44%). The Internet was the second most common source of NAFLD knowledge for PCPs (28%). NAFLD knowledge scores were higher for hepatologists than GEs: epidemiology, 62% vs 53%; diagnostics, 80% vs 73%; and treatment, 61% vs 58% (P < .0001), and ENDOs scores were higher than PCPs: epidemiology, 70% vs 60%; diagnostics, 71% vs 64%; and treatment, 79% vs 68% (P < .0001). Being a hepatologist or ENDO was associated with higher knowledge scores than a GE or PCP, respectively (P < .05). Higher NAFLD knowledge scores were associated independently with a greater number of NAFLD patients seen (P < .05). Conclusions Despite the growing burden of NAFLD, a significant knowledge gap remains for the identification, diagnosis, and management of NAFLD.
A lipopolysaccharide-free outer membrane vesicle vaccine protects against Acinetobacter baumannii infection
(Elsevier, 2020-01) Pulido, Marina R.; García Quintanilla, Meritxell de Jesús; Pachón Díaz, Jerónimo; McConnell, Michael J.; Universidad de Sevilla. Departamento de Microbiología; Universidad de Sevilla. Departamento de Medicina; Universidad de Sevilla. CTS210: Resistencia a Antimicrobianos; Universidad de Sevilla. CTS203: Estudio de las Enfermedades Infecciosas
Outer membrane vesicles (OMVs) were isolated from an Acinetobacter strain deficient in lipopolysaccharide (LPS) due to a mutation in lpxD (IB010). Two immunizations with 10 µg of IB010 OMVs elicited total IgG, IgM, IgG1 and IgG2c titers similar to those observed after immunization with OMVs derived from the parental strain (ATCC 19606), and IB010 OMVs plus purified LPS. Immunization with IB010 OMVs resulted in significantly reduced post-infection spleen bacterial loads and serum IL-1β and IL-6 levels compared to control mice in a disseminated sepsis model. Mice immunized with 10 µg IB010 OMVs demonstrated significant, but partial, protection (75%) against infection, whereas mice immunized with ATCC 19606 OMVs or IB010 OMVs plus purified LPS were completely protected. Immunization of mice with 100 µg of IB010 OMVs completely protected mice from infection. This study demonstrates that LPS deficient A. baumannii produces OMVs, and that immunization with these OMVs elicits protective immunity against infection.
A machine learning approach enables quantitative measurement of liver histology and disease monitoring in NASH
(Wiley, 2021) Taylor-Weiner, Amaro; Pokkalla, Harsha; Han, Ling; Jia, Catherine; Huss, Ryan; Chung, Chuhan; Romero Gómez, Manuel; Younossi, Zobair M.; Universidad de Sevilla. Departamento de Medicina
BACKGROUND AND AIMS: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APP ROA CH AND RESULT S: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression. CONCLUSIONS: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies. (Hepatology 2021;74:133-147).
A meta-analysis of medications directed against PCSK9 in familial hypercholesterolemia
(Elsevier Ireland, 2021) Brandts, Julia; Dharmayat, Kanika I.; Vallejo Vaz, Antonio Javier; Azar Sharabiani, Mansour Taghavi; Jones, Rebecca; Kastelein, John J.P.; Raal, Frederick J.; Ray, Kausik K.; Universidad de Sevilla. Departamento de Medicina
Background and aims Several medications targeting PCSK9 reduce LDL-cholesterol (LDL-C) in heterozygous familial hypercholesterolemia (HeFH). We aimed to assess in patients diagnosed clinically as HeFH, whether LDL-C reduction varied by different therapeutic approaches to PCSK9-targeting or by the underlying genetic variant. Methods We conducted a random-effects meta-analysis of randomised clinical trials assessing PCSK9-targeting therapies, namely alirocumab, evolocumab and inclisiran, in patients with clinically diagnosed HeFH and restricted analyses to those patients in whom genotypic data were available. A search of MEDLINE and Embase identified eligible trials published between inception and June 29, 2020. We included trials of sufficient duration to allow for a stable treatment effect: ~12 weeks for monoclonal antibodies (mAbs) (alirocumab, evolocumab) and ~1 year for small interfering RNA (siRNA) (inclisiran). Single-moderator meta-regression comparing mean percentage LDL-C reduction between mAbs and siRNA as well as PCSK9-targeting therapies between different genotypes was used to assess heterogeneity. Results Eight trials of HeFH met our inclusion criteria, including 1887 genotyped patients. Among monogenic HeFH cases (N = 1347) the LDL-C reduction from baseline was 46.12% (95%CI 48.4-43.9) for siRNA and 50.4% (59.3-41.4) for mAbs compared to control, without evidence of significant heterogeneity between treatment (QM = 0.32, df = 1, p = 0.57). Irrespective of therapeutic approach to PCSK9-targeting, reductions in LDL-C were generally consistent across genetic variants (LDL-Receptor variants, LDL-Receptor variants of unknown significance, Apolipoprotein B variants, two variants and no variant) (QM = 8.3, df = 4, p = 0.08). Conclusions Among patients with HeFH, the LDL-C-lowering effect of PCSK9-targeting medications did not show statistical heterogeneity across different drug-classes and across genetic variants.
A multicenter randomized clinical trial to evaluate the efficacy of telemonitoring in patients with advanced heart and lung chronic failure. Study protocol for the ATLAN_TIC project
(Elsevier B.V., 2020) Hernandez-Quiles, Carlos; Bernabeu Wittel, Máximo; Garcia-Serrano, Maria del Rocio; Vergara López, Salvador; Pérez de León, José Antonio; Barón-Franco, Bosco; Ollero Baturone, Manuel; Univerdsidad de Sevilla
Abstract Background Using technologies of information and communication (TICs) is emerging in medical assistance. TICs application for medical assistance is promising. Its applicability in advanced heart and/or respiratory failure is still controversial because studies have shown methodological weakness which could put in danger their conclusions. Our objective is to evaluate efficacy of the application of home monitoring biological parameters in a multi-level model of coordinated clinical care for patients with chronic diseases with advanced heart (HF) and/or respiratory failure (RF) in comparison with conventional clinical care. Method /Design: Multicentric, phase III, randomized, parallel groups, controlled clinical trial. Patients with advanced HF and/or RF were eligible to participate. Patients received medical assistance by a multi-level model of coordinated clinical care with or without home monitoring. Follow up was performed until 180 days after inclusion. Primary efficacy outcome was defined as the percentage of patients with hospitalization/emergency room visits. Secondary efficacy outcomes were hospital admissions, admissions to hospital emergencies and Primary Care Emergencies, number of days of hospital stay, total cost per patient in euros, mortality, change in functional status, quality of life, assistance and technology devices. Intention to treat, as well as per protocol, and incremental cost-effectiveness analysis will be performed. The number of recruits patients per arm is set at 255, a total of 510 patients. Discussion This trial could provide some knowledge about the real impact of home monitoring for patients with advanced HF and/or RF within a multi-level model of integrated care.

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