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Atrial fibrillation and associated comorbidities pose a risk factor for mortality, morbidity and development of complications in patients admitted for COVID-19.To describe the clinical, epidemiological, radiological and analytical characteristics of patients with AF admitted for COVID-19 in Spain. Secondarily, we aim to identify those variables associated with mortality and poor prognosis of COVID-19 in patients with AF.Retrospective, observational, multicenter, nationwide, retrospective study of patients hospitalized for COVID-19 from March 1 to October 1, 2020. Data were obtained from the SEMI-COVID-19 Registry of the Spanish Society of Internal Medicine (SEMI) in which 150 Spanish hospitals participate.Between March 1 and October 1, 2020, data from a total of 16,461 patients were entered into the SEMI-COVID-19 registry. 1,816 (11%) had a history of AF and the number of deaths among AF patients amounted to 738 (41%). Regarding clinical characteristics, deceased patients were admitted with a higher heart rate (88.38 vs 84.95; p 0.01), with a higher percentage of respiratory failure (67.2% vs 20.1%; p 0.01) and high tachypnea (58% vs 30%; p 0.01). The comorbidities that presented statistically significant differences in the deceased group were: age, hypertension and diabetes with target organ involvement. There was also a higher prevalence of a history of cardiovascular disease in the deceased. On multivariate analysis, DOACs treatment had a protective role for mortality (OR:0,597) IC (0,402-0,888 ; p = 0.011).Previous treatment with DOACs and DOACs treatment during admission seem to have a protective role in patients with AF, although this fact should be verified in prospective studies.La fibrilación auricular y las comorbilidades asociadas a ella suponen un factor de riesgo de mortalidad, morbilidad y desarrollo de complicaciones en los pacientes ingresados por COVID-19.Describir las características clínicas, epidemiológicas, radiológicas y analíticas de los pacientes con FA ingresados por COVID-19 en España. De forma secundaria, se pretende identificar aquellas variables que se asocian con mortalidad y mal pronóstico de la COVID-19 en pacientes que presentan FA.Estudio retrospectivo, observacional y multicéntrico de ámbito nacional de pacientes hospitalizados por COVID-19 desde el 1 de marzo al 1 de octubre de 2020. Los datos fueron obtenidos del Registro SEMI-COVID-19 de la Sociedad Española de Medicina Interna (SEMI) en el que participan 150 hospitales españoles.De un total de 16.461 pacientes en el registro SEMI-COVID-19, 1.816 (11%) tenían antecedente de FA y el número de fallecidos entre los pacientes con FA ascendió a 738 (41%). En cuanto a la clínica, los pacientes fallecidos ingresaron con una frecuencia cardíaca mayor (88,38 vs 84,95; p 0,01), con mayor porcentaje de insuficiencia respiratoria (67,2% vs 20,1%; p 0,01) y mayor taquipnea (58% vs 30%; p 0,09). En el análisis multivariante, el tratamiento con ACOD tuvo un papel protector para la mortalidad por infección por COVID 19 (OR:0,597; IC (0,402-0,888; p = 0.011).El tratamiento previo con ACOD como el tratamiento con ACOD durante el ingreso parecen tener un papel protector en los pacientes con FA, aunque este hecho debería ser comprobado con estudios prospectivos.

Background Sarcoidosis is a heterogeneous disease with high variability in natural history and clinical spectrum. The study aimed to reveal different clinical phenotypes of patients with similar characteristics and prognosis. Methods Cluster analysis including 26 phenotypic variables was performed in a large cohort of 694 sarcoidosis patients, collected and followed-up from 1976 to 2018 at Bellvitge University Hospital, Barcelona, Spain. Results Six homogeneous groups were identified after cluster analysis: C1 (n=47; 6.8%), C2 (n=85; 12.2%), C3 (n=153; 22%), C4 (n=29; 4.2%), C5 (n=168; 24.2%), and C6 (n=212; 30.5%). Presence of bilateral hilar lymphadenopathy (BHL) ranged from 65.5% (C4) to 97.9% (C1). Patients with Lofgren syndrome (LS) were distributed across 3 phenotypes (C1, C2, and C3). In contrast, phenotypes with pulmonary (PS) and/or extrapulmonary sarcoidosis (EPS) were represented by groups C4 (PS 100% with no EPS), C5 (PS 88.7% plus EPS), and C6 (EPS). EPS was concentrated in groups C5 (skin lesions, peripheral and abdominal lymph nodes, and hepatosplenic involvement) and C6 (skin lesions, peripheral lymph nodes, and neurological and ocular involvement). Unlike patients from LS groups, most patients with PS and/or EPS were treated with immunosuppressive therapy, and evolved to chronicity in higher proportion. Finally, the cluster model worked moderately well as a predictive model of chronicity (AUC=0.705). Conclusion Cluster analysis identified 6 different clinical patterns with similar phenotypic variables and predicted chronicity in our large cohort of patients with sarcoidosis. Classification of sarcoidosis into phenotypes with prognostic value may help physicians to improve the efficacy of clinical decisions.

Population-scale biobanks that combine genetic data and high-dimensional phenotyping for a large number of participants provide an exciting opportunity to perform genome-wide association studies (GWAS) to identify genetic variants associated with diverse quantitative traits and diseases. A major challenge for GWAS in population biobanks is ascertaining disease cases from heterogeneous data sources such as hospital records, digital questionnaire responses, or interviews. In this study, we use genetic parameters including genetic correlation to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of diseases implicate similar disease genetics across a range of effect sizes. We find that hospital record and questionnaire GWAS largely identify similar genetic effects for many complex phenotypes and that combining together both phenotyping methods improves power to detect genetic associations. We also show that family GWAS using cases ascertained on family history of disease agrees with combined hospital record/questionnaire GWAS and that family history GWAS has better power to detect genetic associations for some phenotypes. Overall, this work demonstrates that digital phenotyping and unstructured phenotype data can be combined with structured data such as hospital records to identify cases for GWAS in biobanks and improve the ability of such studies to identify genetic associations.

Just a few series of Löfgren's syndrome have been reported. Our aim was to describe the epidemiology and clinical profile of sarcoidosis patients presenting with Löfgren's syndrome vs. non-Löfgren's syndrome.Retrospective cohort study of 691consecutive patients with sarcoidosis diagnosed at the Bellvitge University Hospital in Barcelona, Spain, between 1976 and 2018.Three hundred and nine patients (44.7%) were diagnosed with Löfgren's syndrome and 382with non-Löfgren's syndrome (55.3%). The mean age at diagnosis was 39.8years-old (SD 11.7) vs. 46.6 (SD 14.5) (P0.001). 249 patients (80.6%) vs. 218 (57.1%) were female (P0.001), and mostly Caucasians (304, 98.4% vs. 351, 91.9%, P=0.002). Out of the total 309, Löfgren's syndrome patients developed more frequently fever and articular involvement, and 45 (14.6%) presented with isolated periarticular ankle inflammation. When compared, radiological stages at diagnosis were more advanced in non-Löfgren's syndrome patients: stage 0 (2.9% vs. 14.7%), stage I (82.5% vs. 41.4%), stage II (14.6% vs. 29.3%), and stage III/IV (0 vs. 14.7%) (P0.001). Chronic trend2years was more prevalent in non-Löfgren's syndrome (66, 22.6% vs. 233, 67.4%; P0.001), as well as the proportion of patients in whom treatment was needed (58, 18.8% vs. 224, 58.6%; P0.001). Risk factors related to chronic trend2 years were older age, stage II at diagnosis and the need of treatment.Löfgren's syndrome is a well-differentiated form of sarcoidosis with persuasive different epidemiological, clinical, radiological and prognostic features.

Summary Background Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Funding An unrestricted grant from Boehringer Ingelheim International.

OBJECTIVES: Left ventricular diastolic dysfunction (LVDD) remains poorly studied in Systemic Sclerosis (SSc). To determine the prevalence and to define factors associated with LVDD and survival in a large cohort of patients with SSc. METHODS: An observational study was conducted with data from the multicentre Spanish Scleroderma Registry (RESCLE) to identify factors associated with LVDD and estimate survival. RESULTS: Out of 1517 patients, 319 (21.0%) had LVDD. The subset of sine scleroderma SSc was associated to LVDD (14.7% vs. 10.6%, p =0.048), whilst diffuse cutaneous SSc was more prevalent in non-LVDD (16.0 % vs. 21.2%, p =0.041). Multivariable analysis identified that LVDD was associated with older age at diagnosis of SSc (OR 1.05; 95% CI 1.04 to 1.06), longer time from diagnosis (OR 1.04; 95% CI 1.03 to 1.06), presence of telangiectasia (OR 1.42; 95% CI 1.08 to 1.88), treatment with calcium channel blockers (CCB) (OR 1.51; 95% CI 1.16 to 1.96), and inversely related to angiotensin-converting-enzyme inhibitors (ACEi) use (OR 0.59; 95% CI 0.44 to 0.80). SSc patients with LVDD had increased mortality (23.8 vs. 17.4%, p =0.010) and shortened survival from the first SSc symptom (p =0.040), even though it was not found to be an independent risk factor for death. CONCLUSIONS: LVDD is relatively common in SSc patients, and it is associated with worst prognosis, older age, longer time from diagnosis of SSc, presence of telangiectasia and vasodilator treatment.

Copy-number variations (CNVs) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy-number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high mortality, we describe genetic burden from potentially pathogenic and previously uncharacterized CNV loci across more than 3,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, previously uncharacterized variation at 9p23, and several genic associations in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy-number variation, as well as a series of dosage-mediated genic associations across the medical phenome.

61 Páginas.-- 5 Tablas.-- 1 Figura, 1H NMR fingerprinting of edible oils and a set of multivariate classification and regression models organised in a decision tree is proposed as a stepwise strategy to assure the authenticity and traceability of olive oils and their declared blends with other vegetable oils (VOs). Oils of the 'virgin olive oil' and 'olive oil' categories and their mixtures with the most common VOs, i.e. sunflower, high oleic sunflower, hazelnut, avocado, soybean, corn, refined palm olein and desterolized high oleic sunflower oils, were studied. Partial least squares (PLS) discriminant analysis provided stable and robust binary classification models to identify the olive oil type and the VO in the blend. PLS regression afforded models with excellent precisions and acceptable accuracies to determine the percentage of VO in the mixture. The satisfactory performance of this approach, tested with blind samples, confirm its potential to support regulations and control bodies., This work was developed in the framework of the project OLEUM “Advanced solutions for assuring authenticity and quality of olive oil at global scale” funded by the European Commission within the Horizon 2020 Programme (2014–2020), grant agreement No. 635690; and the project AUTENFOOD funded by ACCIÓ-Generalitat de Catalunya and the European Union through the Programa Operatiu FEDER Catalunya 2014-2020 (Ref COMRDI-15-1-0035). The information contained in this article reflects the authors’ views; the European Commission is not liable for any use of the information contained herein. The authors would like to thank all producers that supplied the olive oils, virgin olive oils and vegetable oils for this study, and the technical and staff support provided by SGIker (UPV/EHU, MICINN, GV/EJ, ESF).

Background: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19 This work examines the impact of each at-home glucose-lowering drugs individually or in combination with metformin on mortality and other adverse outcomes in patients with type 2 diabetes hospitalized for COVID-19 Methods: We selected all patients with type 2 diabetes in the Spanish Society of Internal Medicine’s SEMI-COVID-19 Registry, an observational, multicenter, nationwide registry of patients admitted for COVID-19 in Spain from March 1, 2020 Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs by propensity scores To evaluate treatment effect on study outcomes, both conditional logit and mixed effect logistic regression were used when simple size ≥100 Findings: A total of 2,666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected No at-home glucose-lowering drugs showed a significant association with in-hospital death;the composite outcome of need of intensive care unit admission, mechanical ventilation, or in-hospital death;in-hospital complications;or long-time hospital stays Interpretation: In patients with type 2 diabetes admitted for COVID-19, at-home glucose-lowering drugs had a neutral effects on mortality and adverse outcomes Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed

Protein truncating variants (PTVs) are likely to modify gene function and have been linked to hundreds of Mendelian disorders. However, the impact of PTVs on complex traits has been limited by the available sample size of whole-exome sequencing studies (WES). Here we assemble WES data from 100,304 individuals to quantify the impact of rare PTVs on 13 quantitative traits and 10 diseases. We focus on those PTVs that occur in PTV-intolerant (PI) genes, as these are more likely to be pathogenic. Carriers of at least one PI-PTV were found to have an increased risk of autism, schizophrenia, bipolar disorder, intellectual disability and ADHD (P-value (p) range: 5x10-3-9x10-12). In controls, without these disorders, we found that this burden associated with increased risk of mental, behavioral and neurodevelopmental disorders as captured by electronic health record information. Furthermore, carriers of PI-PTVs tended to be shorter (p=2x10-5), have fewer years of education (p=2x10-4) and be younger (p=2x10-7); the latter observation possibly reflecting reduced survival or study participation. While other gene-sets derived from in vivo experiments did not show any associations with PTV-burden, gene sets implicated in GWAS of cardiovascular-related traits and inflammatory bowel disease showed a significant PTV-burden with corresponding traits, mainly driven by established genes involved in familial forms of these disorders. We leveraged population health registries from 14,117 individuals to study the phenome-wide impact of PI-PTVs and identified an increase in the number of hospital visits among PI-PTV carriers. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Background Genome-wide association studies (GWASs) have identified >200 genomic regions associated with IBD. These signals are mainly driven by common variants in noncoding regions, making it a challenge to extract biological insight. Targeted sequencing of genes in these regions has successfully identified putative causal variants, often rarer and independent of the initial GWAS hit. These coding variants have led to more direct functional experiments demonstrating causal mechanisms for at least ten genes. Methods To further rare variant-based discovery, we pursued large-scale exome sequencing of more than 30,000 Crohn's disease (CD) cases and population controls from more than 20 centers in the International IBD Genetics Consortium. Sequencing was performed at the Broad Institute using both Nextera (11,125 CD cases) and TWIST (7,442 CD cases) exome captures - and at the Sanger Institute (whole genomes 6,404 CD cases and Agilent exome 3,848 CD cases). Further replication was performed with a sample of 4,359 cases from Kiel sequenced at Regeneron. In each technical experiment, a comparable or larger number of sequenced controls were available for genetic association analysis. Results We conducted meta-analysis of two exome captures at the Broad Institute. To expand on GWAS, we focused on rare and low-frequency coding variants between 0.01% and 10% and estimated roughly 85% of all protein coding variants in this frequency range are reliably analyzed in both exome captures. 119 variants (figure below) were identified with p Conclusion These findings provide novel launch points for mechanistic studies that will further our understanding of disease pathogenesis. For example, SDF2L1 (R161H) flags a gene not previously implicated in IBD but which is reported to regulate feeding-induced ER stress, with a series of CRISPR screens identifying it as an essential regulator of ER homeostasis. Download : Download high-res image (141KB) Download : Download full-size image Effect size versus frequency for significant low frequency coding variants (credit: Hailiang Huang)

Objectives According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. Methods The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. Results 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria ( p = 0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1–47.2). Conclusions The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment.

The present study aimed to assess the prevalence and incidence rate of pulmonary arterial hypertension (PAH) in Systemic Sclerosis (SSc). The review was undertaken using MEDLINE and SCOPUS from June 1962 to May 2019 and the terms: ("Scleroderma, Systemic"[MesH]) AND "Hypertension, Pulmonary"[MesH]. The Newcastle-Ottawa Scale (NOS) was used for the qualifying assessment. The inverse variance-weighted method was performed. Twenty-four studies were included in the global PAH prevalence study. They comprised data from 9804 SSc patients. The overall PAH prevalence found was 6.4% (95%CI 5%-8.3%). Fourteen studies were included in the PAH prevalence study for lcSSc. They comprised data from 4987 lcSSc patients. The PAH prevalence found in lcSSc was 7.7% (95%CI 5.3%-11.1%). Twelve studies were included in the PAH prevalence study for dcSSc. They comprised data from 1790 dcSSc patients. The PAH prevalence found in dcSSc was 6.3% (95%CI 4.5%-8.9%). Fifteen studies showed PAH incidence of an entire SSc cohort. They comprised data from 5926 SSc patients. The overall PAH incidence found was 18.2 cases per 1000 person-years (95%CI 12-27.4). Eight studies showed PAH incidence for lcSSc. They comprised data from 2721 patients. The overall PAH incidence found in lcSSc was 20.4 cases per 1000 person-years (95%CI 10.1-41.1). Seven studies showed PAH incidence for dcSSc. They comprised data from 942 dcSSc patients. The overall PAH incidence found in dcSSc was 16.6 cases per 1000 person-years (95%CI 8.5-32.1). CONCLUSION: The overall PAH prevalence found was 6.4% (95%CI 5%-8.3%) and the overall PAH incidence 18.2 cases per 1000 person-years (95%CI 12-27.4).

14 Páginas; 9 Figuras, Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its derivatives diphosphoinositol phosphates (DPIPs) play key signaling and regulatory roles. However, a direct function of these molecules in lipid and membrane homeostasis remains obscure. Here, we have studied the cold tolerance phenotype of yeast cells lacking the Inp51-mediated phosphoinositide-5-phosphatase. Genetic and biochemical approaches showed that increased metabolism of PI(4,5)P2 reduces the activity of the Pho85 kinase by increasing the levels of the DPIP isomer 1-IP7. This effect was key in the cold tolerance phenotype. Indeed, pho85 mutant cells grew better than the wild-type at 15 °C, and lack of this kinase abolished the inp51-mediated cold phenotype. Remarkably, reduced Pho85 function by loss of Inp51 affected the activity of the Pho85-regulated target Pah1, the yeast phosphatidate phosphatase. Cells lacking Inp51 showed reduced Pah1 abundance, derepression of an INO1-lacZ reporter, decreased content of triacylglycerides and elevated levels of phosphatidate, hallmarks of the pah1 mutant. However, the inp51 phenotype was not associated to low Pah1 activity since deletion of PAH1 caused cold sensitivity. In addition, the inp51 mutant exhibited features not shared by pah1, including a 40%-reduction in total lipid content and decreased membrane fluidity. These changes may influence the activity of membrane-anchored and/or associated proteins since deletion of INP51 slows down the transit to the vacuole of the fluorescent dye FM4-64. In conclusion, our work supports a model in which changes in the PI(4,5)P2 pool affect the 1-IP7 levels modulating the activity of Pho85, Pah1 and likely additional Pho85-controlled targets, and regulate lipid composition and membrane properties., This research has been supported by the Comisión Interministerial de Ciencia y Tecnología Project (AGL2010-17516) from the Spanish Ministry of Economy and Competitiveness (MINECO). IC-S was supported by a pre-doctoral fellowship within the “FPI” Program (MINECO).

To evaluate the clinical characteristics and outcomes of patients with asymptomatic pulmonary sarcoidosis (APS) detected incidentally and compare them with symptomatic non-Löfgren sarcoidosis (SnLS) patients.Patients diagnosed as having APS at a University hospital in Barcelona, Spain, followed prospectively from 1976 to 2018. APS was defined as the presence of bilateral hilar lymphadenopathy (BHL) with or without lung parenchymal involvement discovered incidentally on chest radiograph or CT scan. APS was compared with SnLS.APS was diagnosed in 50 (13.6%) and SnLS in 317 (86.4%) patients. At diagnosis, stage I chest radiograph was significantly more frequent in APS than in SnLS (p 0.001) and there were no asymptomatic patients with stages III and IV. SnLS showed more severe impairment in FVC (p = 0.009) and forced expiratory volume in 1st second (FEV1) (p = 0.003) than APS, while DLco was similar in both groups. Extrathoracic involvement at diagnosis and during the follow up was less frequent in APS than in SnLS patients (p 0.005). Endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS) was the most used diagnostic tool. Treatment was more frequently required in the SnLS than in APS (p 0.001). At five years, APS patients showed less presence of active disease than SnLS (p = 0.054).APS showed earlier radiological stages, lesser impairment in lung function, extrapulmonary organ involvement and need for treatment than SnLS. EBUS was the most useful diagnostic tool. In spite of its benign presentation, around one third of patients evolved to persistent disease but usually with mild clinical and functional impairment.

Therapy for advanced melanoma has deeply changed in the last decade with the introduction of checkpoint and BRAF/MEK inhibitors. Granulomatous reactions have been reported related to these drugs. We performed a systematic review of all the cases described in the medical literature by the search ((“Melanoma”[Mesh]) AND (“Sarcoidosis”[Mesh] OR “Granuloma”[Mesh])). Ninety-one patients under immunotherapy were included in the analyses. The time from the initiation of the immunotherapy until the onset of sarcoidosis or sarcoid-like reaction (SLR) was 7.1 months (SD 9). Peripheral lymph nodes as the mode of onset were seen more frequently in patients under CTLA-4 inhibitors (p = .016) whereas in patients under BRAF/MEK inhibitors used to be in the form of specific skin lesions (p = .006). Chest X-ray stage I-II was the rule in the CTLA-4 and PD-1 groups. On the contrary, stage 0 accounted for 80% of the patients in the BRAF/MEK group examined for pulmonary involvement. Specific skin involvement was the most common manifestation apart from pulmonary involvement. It was more frequent in patients under BRAF/MEK inhibitors and especially in the form of papules. Splenic involvement was found also more frequently in patients under CTLA-4 inhibitors. Specific treatment for sarcoidosis/SLR was prescribed in 50 patients (58.8%), without differences among groups. Almost all patients presented a good prognosis independently of the decision made regarding their previous immunotherapy. Conclusion Physicians should bear in mind the possibility of sarcoidosis/SLR after the initiation of checkpoint or BRAF/MEK inhibitors in patients diagnosed with advanced melanoma, especially in the form of skin involvement and mediastinal and peripheral lymph nodes. It is important to achieve an accurate diagnosis to rule out the possibility of cancer involvement. What to do with these drugs is yet to be clarified. It seems reasonable to prioritize cancer treatment so it is not mandatory to stop these drugs.

Background: In public health research, there is currently a need to close the gap between care delivery and cohort identification. We need dedicated tagging staff to allocate a considerable amount of effort to assigning clinical codes after reading patient summaries. Machine learning automation can facilitate the classification of these clinical narratives, but sufficient availability of electronic medical records is still a bottleneck. Veterinary medical records represent a largely untapped data source that could be used to benefit both human and non-human patients. Very few approaches utilizing veterinary data sources currently exist. Methods: In this retrospective cross-sectional and chart review study, we trained separate long short-term memory (LSTM) Recurrent Neural Networks (RNNs) on 52,722 human records and 89,591 veterinary records, tested the models' efficacy in a standard train-test split setup, and probed the portability of these models across species domains. We trained versions of our models using first the free-text clinical narratives, and then only using extracted clinically relevant terms from MetaMap Lite, a natural language processing tool intended for this purpose. Findings: We show that our LSTM approach correctly classifies across toplevel codes in the veterinary records (F1 score =0·83), and identifies top-level neoplasia records in veterinary records (F1 score = 0·93). The model trained with veterinary data can be ported over to identify neoplasia records in the human records (F1 score = 0·70). Interpretation: Our findings suggest that free-text clinical narratives can be used to learn classification models that allow the rapid identification of patient cohorts. Ultimately, this effort can lead to new insights that can address emerging public health concerns. Digitization of health information will continue to be a reality in both human and veterinary data; our approach serves as first proof-of-concept regarding how these two domains can learn from, and inform, one another. Funding Statement: Stanford University & The Chan Zuckerberg Biohub Investigator Award Declaration of Interests: CDB is Principal and Chairman of CDB Consulting LTD. He has advised Imprimed, Embark Vet and Etalon DX as a member of their respective Scientific Advisory Boards, and is a Director of Etalon DX. The remaining authors declare no conflicts of interest. Ethics Approval Statement: This research was reviewed and approved by Stanford’s Institutional Review Board (IRB), which provided a nonhuman subject determination under eProtocol 46979. Consent was not required.

Resumen Fundamento y objetivo Describir nuestra cohorte de pacientes con nefritis lupica mesangial proliferativa y su seguimiento a largo plazo, con especial atencion a los factores de mal pronostico. Pacientes y metodo Se evaluaron 27 pacientes de forma retrospectiva y controlados en el Servicio de Medicina Interna del Hospital Universitario de Bellvitge entre 1974 y 2010. Se realizo un control al ano, a los 3 y a los 5 anos de la biopsia. Resultados Habia 22 mujeres (81,5%), con una edad media (DE) en el momento del diagnostico de la nefritis de 34,83 (13,45) anos. Al ano de la biopsia 21 pacientes habian alcanzado la remision parcial o completa (80,77%) y a los 5 anos de control 21 pacientes (77,77%) estaban en remision. Cuatro pacientes sufrieron transformacion a otra clase histologica. Recidivaron 7 pacientes (29,63%). En estos 36 anos de seguimiento fallecieron 7 pacientes, 3 de ellos por causas relacionadas con el lupus eritematoso sistemico. Conclusiones El factor pronostico mas claramente relacionado con una mala respuesta es el inicio de la nefritis por encima de los 45 anos, por lo que se deberia valorar el uso de inmunodepresores de entrada asociados a glucocorticoides en estos pacientes.

The regulation of microsomal and plastidial oleate desaturases by low and high temperature, darkness, and wounding was investigated. To this end, their gene expression levels and the fatty acid composition was determined in the mesocarp tissue of olive fruit from the Picual and Arbequina varieties subjected to the corresponding stress treatments. Firstly, a plastidial oleate desaturase from olive was cloned and its functional identity was confirmed by overexpression in Escherichia coli. The results showed that temperature and light regulate olive oleate desaturase genes at transcriptional level. However, no correlation between their expression levels and the linoleic acid content in microsomal and plastidial lipids was found. In addition, the involvement of microsomal but not plastidial oleate desaturases in the wounding response of olive fruit mesocarp is demonstrated. The fatty acid analysis revealed the appearance of palmitolinoleic acid only in microsomal lipids, reaching a maximum 3 h after wounding. © 2010 Elsevier Ltd. All rights reserved., This work was supported by Research Projects AGL2004-02060 from MEC (Spain) and P06-AGR-02151 from Junta de Andalucía (Spain).

Fundamento y objetivo El tratamiento combinado de la hepatitis cronica por el virus de la hepatitis C con interferon α-2b mas ribavirina es el mas adecuado hoy dia tanto en pacientes coinfectados con el virus de la inmunodeficiencia humana (VIH) como en los que no lo estan. En un intento de evitar efectos secundarios a los pacientes y costes sanitarios al Estado, se esta buscando indicadores de respuesta virologica precoz (RVP). En este estudio se pretende valorar la eficacia de la RVP a las 4 y 12 semanas del inicio del tratamiento combinado. Pacientes y metodo Se ha estudiado a 127 pacientes consecutivos con hepatitis cronica por el virus C que recibieron tratamiento combinado durante 12 meses en los genotipos 1 y 4, y durante 6 meses en los genotipos 2 y 3. De ellos, 62 estaban coinfectados por el VIH y 65 no presentaban coinfeccion. Se valoraron la respuesta virologica sostenida al final del seguimiento y la RVP a las 4 y 12 semanas del inicio del tratamiento. Resultados La respuesta virologica sostenida fue mayor en ambos grupos para los genotipos 2 y 3. En los genotipos 1 y 4 fue mayor en el grupo de los no coinfectados que en el de los coinfectados. La RVP tuvo un valor predictivo negativo del 100% en ambos grupos a las 12 semanas de tratamiento para los genotipos 1 y 4, y disminuyo a un 79% cuando se valoro a las 4 semanas. En los genotipos 2 y 3 no se observaron diferencias. Conclusiones La RVP a las 12 semanas del inicio del tratamiento tiene un valor predictivo negativo del 100% tanto en coinfectados como en no coinfectados por el VIH. El cumplimiento del tratamiento es un valor predictivo de respuesta a este.

Two different cDNA sequences, designated OepFAD2-1 and OepFAD2-2, encoding two microsomal oleate desaturases (FAD2) have been isolated from olive (Olea europaea cv. Picual) using a PCR approach. Both deduced amino acid sequences showed the three histidine boxes characteristic of all membrane-bound desaturases, and possess a C-terminal endoplasmic reticulum retention signal. Phylogenetic analysis shows that OepFAD2-1 and OepFAD2-2 are grouped with other plant FAD2 sequences. Functional expression of the corresponding FAD2 cDNAs in yeast confirmed that they encode microsomal oleate desaturases. Genomic Southern blot analysis is consistent with the presence of at least two copies of each OepFAD2 gene in the olive genome. OepFAD2-1 transcript was strongly detected in very young seeds and in leaves, showing low levels in mesocarps, while the transcript of the OepFAD2-2 gene was moderately expressed in developing seeds, ripening mesocarp and leaves. These expression data suggest differential functions for the two olive microsomal oleate desaturase genes, with FAD2-1 possibly responsible for the desaturation of reserve lipids in the young seed, while FAD2-2 may be mainly involved in storage lipid desaturation in the mature seeds and the mesocarp.

Fundamento y objetivo Presentamos el estudio descriptivo de una unidad de diagnostico rapido (UDR) en regimen ambulatorio como alternativa al ingreso hospitalario tradicional. Material y metodos La UDR ha estado constituida durante el tiempo que abarca este estudio por un medico internista, un radiologo y una enfermera. Para llevar a cabo el estudio estadistico descriptivo, revisamos la historia clinica de 1.132 pacientes visitados en el primer ano y medio. Resultados Hemos atendido a 1.132 pacientes, el 71% procedentes de Urgencias y el 26%, de Atencion Primaria. El estudio se llevo a cabo en unos 9 dias de mediana. Los principales motivos de consulta fueron anemia, sindrome constitucional y adenopatias perifericas. El 38% de los pacientes fue dado de alta, el resto requirio seguir el estudio o bien en consultas externas (52%) o bien bajo ingreso hospitalario (10%). Hasta 199 pacientes (18%) fueron diagnosticados de cancer, los mas frecuentes colon, linfoma y pulmon. Estimamos que se han podido evitar 4,5 camas/dia en el Servicio de Medicina Interna. Conclusiones La UDR ha demostrado ser en nuestro centro una alternativa eficiente de la hospitalizacion en pacientes en estudio de patologia potencialmente grave, pero en los cuales el estado general permite una atencion ambulatoria.