Publications by authors named "Ana Blanco"

90 Publications

Coinfections among hospitalized patients with covid-19 in the first pandemic wave.

Diagn Microbiol Infect Dis 2021 Nov 7;101(3):115416. Epub 2021 May 7.

Servicio de Microbiología y Parasitología, Hospital Central de la Defensa Gómez Ulla, Madrid, Spain.

Background: COVID19 is the novel respiratory illness caused by SARS-CoV-2. The presence of other potentially pathogenic microorganisms could worsen the prognosis of these patients.

Aim: The study aims to describe coinfections in COVID-19 patients and contrast it between standard ward and critical care patients at Hospital Central de la Defensa Gómez Ulla (HCDGU).

Methods: A retrospective study was carried out of patients with COVID-19 confirmed with RTPCR admitted to the HCDGU from March 5, 2020 to May 7 of 2020.

Findings: Of a total of 703 patients with COVID-19, 75(10.7%) had other microbiologically confirmed infections: 9% (58/648) in standard ward patients and 31.5%(17/54) in critical care patients. In total 86 samples of the 75 patients presented some microorganism; clinically relevant bacteraemias, 50%, respiratory cultures, 32.6% and pneumococcal positive antigens, 17.4%.

Conclusions: We found a low frequency of microorganism coinfection in COVID-19 patients, however in critical care these coinfections increased considerably.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102383PMC
November 2021

Predictive Model of Early Spontaneous Ductus Arteriosus Closure Based on Neonatologist Performed Echocardiography in Preterm Infants.

Front Pediatr 2021 26;9:644519. Epub 2021 Feb 26.

Department of Neonatology, La Paz University Hospital, Madrid, Spain.

Patent ductus arteriosus (PDA) treatment remains controversial. Modeling on the predictive capacity of early spontaneous PDA closure would help in decision-making. To design a predictive model of early spontaneous PDA closure. As part of a trial to assess efficacy and safety of two ibuprofen treatment schemes for PDA, infants below 29 weeks' gestation were scanned between 18 and 72 h of birth, and serially if indicated. PDA treatment was decided based on echocardiography signs of lung overflow or systemic hypoperfusion and clinical criteria. A PDA score that included the echocardiographic parameters significantly associated with treatment prescription was retrospectively applied. Perinatal variables and screening score were included in a backwards elimination model to predict early spontaneous closure. Among 87 eligible infants (27 weeks' gestation; age at screening 45 h), 21 received ibuprofen at 69 h of life [screening score = 7 (IQR = 5-8.5); score at treatment = 9 (IQR = 8-9)], while 42 infants had conservative management, [screening score = 1 (IQR = 0-4)]. Twenty four infants were excluded (ibuprofen contraindication, declined consent or incomplete echocardiography). Screening score showed an AUC = 0.93 to predict early spontaneous PDA closure, [cut-off value = 4.5 (sensitivity = 0.90, specificity = 0.86)]. The predictive model for early spontaneous PDA closure followed the equation: Log (p/1-p) = -28.41 + 1.23 gestational age -0.87 PDA screening score. A predictive model of early spontaneous PDA closure that includes gestational age and the screening PDA score is proposed to help clinicians in the decision- making for PDA treatment. In addition, this model could be used in future intervention trials aimed to prevent PDA related morbidities to improve the eligibility criteria.
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http://dx.doi.org/10.3389/fped.2021.644519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952525PMC
February 2021

Intravenous methylprednisolone induces rapid improvement in non-infectious uveitis: a multicentre study of 112 patients.

Clin Exp Rheumatol 2021 03 5. Epub 2021 Mar 5.

Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Universidad de Cantabria, Santander, Spain.

Objectives: Rapid control of intraocular inflammation in non-infectious uveitis (NIU) is mandatory to avoid irreversible structural and functional damage. In this study, we assessed the efficacy and safety of intravenous methylprednisolone (IVMP) pulses in the treatment of NIU.

Methods: A retrospective case series of 112 patients who received IVMP for the treatment of NIU, either isolated or associated with different underlying diseases, was studied. Intraocular inflammation (anterior chamber cells and vitritis) was the primary outcome measure. Secondary outcome measures were macular thickness and best corrected visual acuity (BCVA). Patients were assessed at baseline visit, and at days 2-5, 7, 15 and 30 after initiation of IVMP pulse therapy.

Results: A total of 112 patients (mean age 42±14.5 yrs) were assessed. An underlying immune-mediated disease was diagnosed in 73 patients. Inflammatory ocular patterns were panuveitis (n=68), posterior uveitis (n=30), anterior uveitis (AU) (n=12), and intermediate uveitis (n=2). Additionally, patients presented cystoid macular oedema (CME) (n=50), retinal vasculitis (n=37), and exudative retinal detachment (n=31). Therapies used before IVMP included intraocular glucocorticoids (n=4), high-dose oral systemic glucocorticoids (n=77), and conventional (n=107) or biologic (n=40) immunosuppressive drugs. IVMP dose ranged from 80 to 1,000 mg/day for 3-5 consecutive days. Improvement was observed in AU, vitritis, BCVA, CME, and retinal vasculitis. At first month evaluation, total remission was achieved in 19 patients. Side effects of IVMP were respiratory infections (n=3), uncontrolled hyperglycaemia (n=1), herpes zoster (n=1), and oral candidiasis (n=1).

Conclusions: IVMP pulse therapy was effective and safe, and achieved rapid control of NIU.
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March 2021

European Society of Emergency Radiology: guideline on radiological polytrauma imaging and service (short version).

Insights Imaging 2020 Dec 10;11(1):135. Epub 2020 Dec 10.

European Society of Emergency Radiology, ESER Office, Am Gestade 1, 1010, Vienna, Austria.

Background: Although some national recommendations for the role of radiology in a polytrauma service exist, there are no European guidelines to date. Additionally, for many interdisciplinary guidelines, radiology tends to be under-represented. These factors motivated the European Society of Emergency Radiology (ESER) to develop radiologically-centred polytrauma guidelines.

Results: Evidence-based decisions were made on 68 individual aspects of polytrauma imaging at two ESER consensus conferences. For severely injured patients, whole-body CT (WBCT) has been shown to significantly reduce mortality when compared to targeted, selective CT. However, this advantage must be balanced against the radiation risk of performing more WBCTs, especially in less severely injured patients. For this reason, we recommend a second lower dose WBCT protocol as an alternative in certain clinical scenarios. The ESER Guideline on Radiological Polytrauma Imaging and Service is published in two versions: a full version (download from the ESER homepage, https://www.eser-society.org ) and a short version also covering all recommendations (this article).

Conclusions: Once a patient has been accurately classified as polytrauma, each institution should be able to choose from at least two WBCT protocols. One protocol should be optimised regarding time and precision, and is already used by most institutions (variant A). The second protocol should be dose reduced and used for clinically stable and oriented patients who nonetheless require a CT because the history suggests possible serious injury (variant B). Reading, interpretation and communication of the report should be structured clinically following the ABCDE format, i.e. diagnose first what kills first.
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http://dx.doi.org/10.1186/s13244-020-00947-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726597PMC
December 2020

A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.

Clin Chem 2021 03;67(3):518-533

Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

Background: Gene panel testing by massive parallel sequencing has increased the diagnostic yield but also the number of variants of uncertain significance. Clinical interpretation of genomic data requires expertise for each gene and disease. Heterozygous ATM pathogenic variants increase the risk of cancer, particularly breast cancer. For this reason, ATM is included in most hereditary cancer panels. It is a large gene, showing a high number of variants, most of them of uncertain significance. Hence, we initiated a collaborative effort to improve and standardize variant classification for the ATM gene.

Methods: Six independent laboratories collected information from 766 ATM variant carriers harboring 283 different variants. Data were submitted in a consensus template form, variant nomenclature and clinical information were curated, and monthly team conferences were established to review and adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria to ATM, which were used to classify 50 representative variants.

Results: Amid 283 different variants, 99 appeared more than once, 35 had differences in classification among laboratories. Refinement of ACMG/AMP criteria to ATM involved specification for twenty-one criteria and adjustment of strength for fourteen others. Afterwards, 50 variants carried by 254 index cases were classified with the established framework resulting in a consensus classification for all of them and a reduction in the number of variants of uncertain significance from 58% to 42%.

Conclusions: Our results highlight the relevance of data sharing and data curation by multidisciplinary experts to achieve improved variant classification that will eventually improve clinical management.
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http://dx.doi.org/10.1093/clinchem/hvaa250DOI Listing
March 2021

A Semi-quantitative method for the detection of fentanyl using surface-enhanced Raman scattering (SERS) with a handheld Raman instrument.

J Forensic Sci 2021 Mar 2;66(2):505-519. Epub 2020 Nov 2.

Field Detection, Molecular Spectroscopy, Agilent Technologies UK Ltd, Oxford, UK.

A handheld, spatially offset Raman spectroscopy (SORS) system was successfully used to obtain Surface-enhanced Raman Scattering (SERS) spectra of fentanyl under simulated field conditions. A series of aqueous fentanyl solutions were prepared with commercially available gold nanoparticle solution, at concentrations ranging from 0.003 to 1697 μM. These SERS spectra were then used to generate two concentration calibration models (via a plot of peak area (1026 cm ) versus concentration, and quantitative spectral decomposition using partial least squares (PLS1)). For both models, the relationship followed Langmuir adsorption and became non-linear at concentrations above ~0.2 μM, with a limit of detection (LOD) of approximately 3 nM. The same technique was successfully used to measure fentanyl in the presence of two common "cutting agents," heroin and glucose, at 1% and 2% fentanyl proportions (w/w). Fentanyl detection was successfully achieved, but mixture interference from the cutting agents prevented a calibration model being generated. Four fentanyl analogues were also investigated-butyrylfentanyl, furanylfentanyl, acetylfentanyl, and ocfentanyl. A concentration calibration model for each species was successfully generated, but differentiation from fentanyl proved more challenging, although several potential diagnostic peaks were identified. These results identified a pathway forward in using handheld equipment for the reliable detection of ultra-low concentrations of fentanyl and fentanyl analogues via SERS, even when mixed with diluents. However, quantitative detection is negatively impacted in the presence of heroin and glucose. This also provides a starting point for a SERS-based spectral library of fentanyl analogues, in combination with a range of different diluents.
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http://dx.doi.org/10.1111/1556-4029.14610DOI Listing
March 2021

Anti-IL-6 Receptor Tocilizumab in Refractory Graves' Orbitopathy: National Multicenter Observational Study of 48 Patients.

J Clin Med 2020 Aug 31;9(9). Epub 2020 Aug 31.

Rheumatology, Ophthalmology and Internal Medicine, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, 39008 Santander, Spain.

Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Our aim was to assess the efficacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves' Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age ± standard deviation 51 ± 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone ( = 43), or selenium ( = 11). GO disease was moderate ( =29) or severe ( = 19) and dysthyroid optic neuropathy (DON) ( = 7). TCZ was used in monotherapy ( = 45) or combined ( = 3) at a dose of 8 mg/kg IV every four weeks ( = 43) or 162 mg/s.c. every week ( = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 ± 0.25 vs. 0.9 ± 0.16; = 0.0001), CAS (4.64 ± 1.5 vs. 1.05 ± 1.27; = 0.0001) and intraocular pressure (IOP) (19.05 ± 4.1 vs. 16.73 ± 3.4 mmHg; = 0.007). After a mean follow-up of 16.1 ± 2.1 months, low disease activity (CAS ≤ 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity ( = 25) or inefficacy ( = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.
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http://dx.doi.org/10.3390/jcm9092816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563792PMC
August 2020

Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune-Mediated Inflammatory Diseases. A Multicenter Study.

J Clin Med 2020 Aug 11;9(8). Epub 2020 Aug 11.

Rheumatology, Ophtalmology and Internal Medicine, Hospital Universitario Marqués de Valdecilla, Av. de Valdecilla, 25, 39008 Santander, Spain.

We aimed to assess the efficacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 ± 13.9 years). The underlying diseases were Bechet's disease ( = 5), neuromyelitis optica ( = 3), systemic lupus erythematosus ( = 2), sarcoidosis ( = 1), relapsing polychondritis ( = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis ( = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab ( = 6), rituximab ( = 6), infliximab ( = 5) and tocilizumab ( = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate ( = 11), azathioprine ( = 2), mycophenolate mofetil ( = 1) and hydroxychloroquine ( = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean ± SD BCVA (0.8 ± 0.3 LogMAR vs. 0.6 ± 0.3 LogMAR; = 0.03), mean ± SD RNFL (190.5 ± 175.4 μm vs. 183.4 ± 139.5 μm; = 0.02), mean ± SD MT (270.7 ± 23.2 μm vs. 369.6 ± 137.4 μm; = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10-61.5) mg/day at baseline to. 2.5 (0-5) mg/day after one year of follow-up; = 0.001. After a mean ± SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is effective in patients with refractory non-MS ON.
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http://dx.doi.org/10.3390/jcm9082608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464396PMC
August 2020

Biologic therapy in severe and refractory peripheral ulcerative keratitis (PUK). Multicenter study of 34 patients.

Semin Arthritis Rheum 2020 08 15;50(4):608-615. Epub 2020 May 15.

Rheumatology, Ophthalmology and Internal medicine, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain. Electronic address:

Purpose: We assessed the efficacy and safety of biologic therapy in severe and refractory Peripheral Ulcerative Keratitis (PUK).

Design: Open-label multicenter study of biologic-treated patients with severe PUK refractory to conventional immunosuppressive drugs.

Subjects: We studied 34 patients (44 affected eyes) (24 women/10 men; mean age, 55.26±17.4 years). PUK was associated with a well-defined condition in 29 of them (rheumatoid arthritis [n = 20], psoriatic arthritis [n = 2], inflammatory bowel disease [n = 2], Behçet disease [n = 1], granulomatosis with polyangiitis [n = 1], microscopic polyangiitis [n = 1], systemic lupus erythematosus [n = 1] and axial spondyloarthritis [n = 1]). Besides topical and oral systemic glucocorticoids, patients had received: methylprednisolone pulses [n = 9], and conventional immunosuppressive drugs, mainly methotrexate [n = 18], and leflunomide [n = 7]. Eleven patients had required ocular surgery prior to biologic therapy.

Methods: Following biologic therapy, baseline main outcomes were compared with those found at 1st week, 1st and 6th months and 1st year.

Main Outcome Measures: Efficacy and safety of biologic therapy. Efficacy was analyzed by the assessment of corneal inflammation (corneal thinning, central keratolysis and ocular perforation); other causes of ocular surface inflammation (scleritis, episcleritis); intraocular inflammation (uveitis); visual acuity and glucocorticoid sparing effect.

Results: The first biologic agents used were anti-TNFα drugs (n = 25); adalimumab (n = 16), infliximab (n = 8), etanercept (n = 1), and non-TNFα agents (n = 9); rituximab (n = 7), tocilizumab (n = 1) belimumab (n = 1) and abatacept (n = 1). During the follow-up, switching to a second biologic agent was required in 12 of the 25 (48%) patients treated with anti-TNFα drugs. However, no switching was required in those undergoing biologic therapy different from anti-TNFα agents. The main outcome variables showed a rapid and maintained improvement after a mean follow-up of 23.7 ± 20 months. Major adverse effects were tachyphylaxis, relapsing respiratory infections, supraventricular tachycardia, pulmonary tuberculosis and death, one each.

Conclusions: Biologic therapy is effective and relatively safe in patients with severe and refractory PUK. Non-anti-TNFα agents appear to be effective in these patients.
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http://dx.doi.org/10.1016/j.semarthrit.2020.03.023DOI Listing
August 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020

The Spectrum of Protein Truncating Variants in European Breast Cancer Cases.

Cancers (Basel) 2020 01 26;12(2). Epub 2020 Jan 26.

Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague 12853, Czech Republic.

Germline protein truncating variants (PTVs) in the gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with PTVs ascertained in 20 centers from 13 European countries. We identified 27 different PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique PTVs, 15 have not been previously reported. We provide here the initial spectrum of PTVs in European breast cancer cases.
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http://dx.doi.org/10.3390/cancers12020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073216PMC
January 2020

Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis due to Behçet's Disease: National Multicenter Study of 177 Cases.

Arthritis Rheumatol 2019 12 21;71(12):2081-2089. Epub 2019 Oct 21.

Hospital de Pontevedra, Pontevedra, Spain.

Objective: To compare the efficacy of infliximab (IFX) versus adalimumab (ADA) as a first-line biologic drug over 1 year of treatment in a large series of patients with refractory uveitis due to Behçet's disease (BD).

Methods: We conducted an open-label multicenter study of IFX versus ADA for BD-related uveitis refractory to conventional nonbiologic treatment. IFX or ADA was chosen as the first-line biologic agent based on physician and patient agreement. Patients received 3-5 mg/kg intravenous IFX at 0, 2, and 6 weeks and every 4-8 weeks thereafter, or 40 mg subcutaneous ADA every other week without a loading dose. Ocular parameters were compared between the 2 groups.

Results: The study included 177 patients (316 affected eyes), of whom 103 received IFX and 74 received ADA. There were no significant baseline differences between treatment groups in main demographic features, previous therapy, or ocular sign severity. After 1 year of therapy, we observed an improvement in all ocular parameters in both groups. However, patients receiving ADA had significantly better outcomes in some parameters, including improvement in anterior chamber inflammation (92.31% versus 78.18% for IFX; P = 0.06), improvement in vitritis (93.33% versus 78.95% for IFX; P = 0.04), and best-corrected visual acuity (mean ± SD 0.81 ± 0.26 versus 0.67 ± 0.34 for IFX; P = 0.001). A nonsignificant difference was seen for macular thickness (mean ± SD 250.62 ± 36.85 for ADA versus 264.89 ± 59.74 for IFX; P = 0.15), and improvement in retinal vasculitis was similar between the 2 groups (95% for ADA versus 97% for IFX; P = 0.28). The drug retention rate was higher in the ADA group (95.24% versus 84.95% for IFX; P = 0.042).

Conclusion: Although both IFX and ADA are efficacious in refractory BD-related uveitis, ADA appears to be associated with better outcomes than IFX after 1 year of follow-up.
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http://dx.doi.org/10.1002/art.41026DOI Listing
December 2019

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Hum Mutat 2019 09;40(9):1557-1578

Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
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http://dx.doi.org/10.1002/humu.23818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772163PMC
September 2019

Computational Tools for Splicing Defect Prediction in Breast/Ovarian Cancer Genes: How Efficient Are They at Predicting RNA Alterations?

Front Genet 2018 5;9:366. Epub 2018 Sep 5.

Oncogenetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

tools for splicing defect prediction have a key role to assess the impact of variants of uncertain significance. Our aim was to evaluate the performance of a set of commonly used splicing tools comparing the predictions against RNA results. This was done for natural splice sites of clinically relevant genes in hereditary breast/ovarian cancer (HBOC) and Lynch syndrome. A study divided into two stages was used to evaluate SSF-like, MaxEntScan, NNSplice, HSF, SPANR, and dbscSNV tools. A discovery dataset of 99 variants with unequivocal results of RNA studies, located in the 10 exonic and 20 intronic nucleotides adjacent to exon-intron boundaries of , and , was collected from four Spanish cancer genetic laboratories. The best stand-alone predictors or combinations were validated with a set of 346 variants in the same genes with clear splicing outcomes reported in the literature. Sensitivity, specificity, accuracy, negative predictive value (NPV) and Mathews Coefficient Correlation (MCC) scores were used to measure the performance. The discovery stage showed that HSF and SSF-like were the most accurate for variants at the donor and acceptor region, respectively. The further combination analysis revealed that HSF, HSF+SSF-like or HSF+SSF-like+MES achieved a high performance for predicting the disruption of donor sites, and SSF-like or a sequential combination of MES and SSF-like for predicting disruption of acceptor sites. The performance confirmation of these last results with the validation dataset, indicated that the highest sensitivity, accuracy, and NPV (99.44%, 99.44%, and 96.88, respectively) were attained with HSF+SSF-like or HSF+SSF-like+MES for donor sites and SSF-like (92.63%, 92.65%, and 84.44, respectively) for acceptor sites. We provide recommendations for combining algorithms to conduct splicing analysis that achieved a high performance. The high NPV obtained allows to select the variants in which the study by RNA analysis is mandatory against those with a negligible probability of being spliceogenic. Our study also shows that the performance of each specific predictor varies depending on whether the natural splicing sites are donors or acceptors.
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http://dx.doi.org/10.3389/fgene.2018.00366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134256PMC
September 2018

High-dose-rate interstitial brachytherapy as monotherapy in one fraction of 20.5 Gy for the treatment of localized prostate cancer: Toxicity and 6-year biochemical results.

Brachytherapy 2018 Nov - Dec;17(6):845-851. Epub 2018 Jul 18.

Department of Radiation Physics, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain.

Purpose: To evaluate acute and late genitourinary toxicity, the gastrointestinal toxicity, and the long-term biochemical control after high-dose-rate (HDR) monotherapy in one fraction (20.5 Gy).

Materials And Methods: Between May 2011 and October 2014, 60 consecutive patients with low- and intermediate-risk prostate cancer were treated; the median followup was 51 months (range 30-79). All patients received one implant and one fraction of 20.5 Gy HDR real-time U/S planned with transperineal hyaluronic acid injection into the perirectal. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 (CTAE v4.03) by the National Cancer Institute. Biochemical failure was defined according to the "Phoenix definition".

Results: Our experience in a single fraction of 20.5 Gy HDR brachytherapy is well-tolerated. No intraoperative or perioperative complications occurred. Grade 1 acute genitourinary toxicity occurred in 36% of patients, Grade 2 or more was not observed, only 1 patient requiring the use of a catheter for 7 days in the immediate postoperative period. No gastrointestinal toxicity was observed. No chronic toxicity has been observed after treatment. Morbidity is practically the same as that obtained with 19 Gy in our previously published article but the actuarial biochemical control was better, 82% (±3%) at 6 years.

Conclusions: A single dose of 20.5 Gy resulted in a low genitourinary morbidity and no gastrointestinal toxicity and achieves good levels of biochemical disease control.
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http://dx.doi.org/10.1016/j.brachy.2018.06.002DOI Listing
April 2019

Accelerated partial breast irradiation in a single 18 Gy fraction with high-dose-rate brachytherapy: preliminary results.

J Contemp Brachytherapy 2018 Feb 28;10(1):58-63. Epub 2018 Feb 28.

Department of Radiation Oncology.

Purpose: To evaluate the feasibility of acute and chronic toxicity in patients suitable for accelerated partial breast irradiation (APBI) in a single 18 Gy fraction with multicatheter high-dose-rate (HDR) brachytherapy, as well as cosmetic and oncological outcomes.

Material And Methods: Between September 2014 and March 2016, twenty consecutive patients with low-risk invasive and ductal carcinoma in situ were treated with interstitial multicatheter HDR brachytherapy in a single 18 Gy fraction.

Results: Median age was 63.5 years (range, 51-79). Acute toxicity was observed in seven patients, while the pain during following days and hematoma were seen in four patients. With a median follow-up of 24 months, late toxicity was found in one patient with fat necrosis g2 and fibrosis g2 in another patient. The overall survival (OS) and locoregional control (LC) was 100%. Disease-free survival (DFS) and distant control was 95%. Good to excellent cosmetic outcomes were noted in 80% of patients and fair in 4 patients (20%).

Conclusions: This is the first report in the medical literature that focuses on feasibility and acute and chronic toxicity, with a median follow-up of 24 months (range, 20-40). The protocol is viable and convenient. However, a longer follow-up is needed to know chronic toxicity and oncologic outcomes.
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http://dx.doi.org/10.5114/jcb.2018.73994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881592PMC
February 2018

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

Ophthalmology 2018 09 27;125(9):1444-1451. Epub 2018 Mar 27.

Rheumatology, Hospital de Mérida, Mérida, Spain.

Purpose: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent.

Design: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants.

Subjects: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients.

Methods: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed.

Main Outcome Measures: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed.

Results: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01).

Conclusion: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.
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http://dx.doi.org/10.1016/j.ophtha.2018.02.020DOI Listing
September 2018

Susceptibility of Enterococcus faecalis and Propionibacterium acnes to antimicrobial photodynamic therapy.

J Photochem Photobiol B 2018 Jan 5;178:545-550. Epub 2017 Dec 5.

Universidade Estadual Paulista (Unesp), Faculdade de Ciências Farmacêuticas, Araraquara. Rodovia Araraquara-Jaú, Km1, Campus Ville, Araraquara, SP, CEP 14800-903, Brazil. Electronic address:

Bacterial resistance to available antibiotics nowadays is a global threat leading researchers around the world to study new treatment modalities for infections. Antimicrobial photodynamic therapy (aPDT) has been considered an effective and promising therapeutic alternative in this scenario. Briefly, this therapy is based on the activation of a non-toxic photosensitizing agent, known as photosensitizer (PS), by light at a specific wavelength generating cytotoxic singlet oxygen and free radicals. Virtually all studies related to aPDT involve a huge screening to identify ideal PS concentration and light dose combinations, a laborious and time-consuming process that is hardly disclosed in the literature. Herein, we describe an antimicrobial Photodynamic Therapy (aPDT) study against Enterococcus faecalis and Propionibacterium acnes employing methylene blue, chlorin-e6 or curcumin as PS. Similarities and discrepancies between the two bacterial species were pointed out in an attempt to speed up and facilitate futures studies against those clinical relevant strains. Susceptibility tests were performed by the broth microdilution method. Our results demonstrate that aPDT mediated by the three above-mentioned PS was effective in eliminating both gram-positive bacteria, although P. acnes showed remarkably higher susceptibility to aPDT when compared to E. faecalis. PS uptake assays revealed that P. acnes is 80 times more efficient than E. faecalis in internalizing all three PS molecules. Our results evidence that the cell wall structure is not a limiting feature when predicting bacterial susceptibility to aPDT treatment.
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http://dx.doi.org/10.1016/j.jphotobiol.2017.11.035DOI Listing
January 2018

Characterization of Enterococcus faecalis isolates by chicken embryo lethality assay and ERIC-PCR.

Avian Pathol 2018 Feb 31;47(1):23-32. Epub 2017 Aug 31.

a Lohmann Tierzucht GmbH , Cuxhaven , Germany.

Enterococcus faecalis is the major causative agent of amyloid arthropathy in chickens. Given the difficulty of estimating the risk from field strains, the embryo lethality assay (ELA) is proposed in this study as a model to predict the virulence of 68 avian E. faecalis strains. Additionally, Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) was used to characterize the genetic diversity of the E. faecalis strains. The ELA was performed 10 times with subsets of 7-8 E. faecalis strains each on a sample of 9987 eggs, including control groups. An estimated 3-24 colony-forming units were inoculated into the allantoic cavity of 10-day-old embryos. The embryonic mortality rate (EMR) was determined by means of candling the eggs over a period of seven days. The ELA was able to distinguish the virulence of the E. faecalis strains. Twenty-six strains were considered as avirulent strains with an EMR of below 40%. Five strains were highly virulent with an EMR above 80%. The remaining 37 strains were classified as strains of moderate virulence, causing an EMR between 40% and 80%. The highest EMR occurred three and four days post-inoculation (p.i.). From the fourth day p.i., almost no embryonic mortality was observed. Therefore, the ELA could be optimized by reducing experiment duration to four days p.i. ERIC-PCR did not cluster the strains according to its virulence, although ERIC banding patterns revealed a considerable genetic diversity. In conclusion, the ELA can be considered a reliable and useful tool to predict the virulence of avian E. faecalis strains.
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http://dx.doi.org/10.1080/03079457.2017.1359404DOI Listing
February 2018

Antibiotic resistance in Helicobacter pylori.

Curr Opin Infect Dis 2017 Oct;30(5):489-497

aDepartment of Microbiology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa bDepartment of Preventive Medicine, Public Health and Microbiology, Medical School, Autonomous University of Madrid, Madrid, Spain.

Purpose Of Review: Treatment of Helicobacter pylori is difficult nowadays because of its high resistance. The prevalence and mechanism of resistance, the different methods to detect it and the clinical implication of resistance were addressed in several research papers last year.

Recent Findings: Clarithromycin-resistant H. pylori has been recognized by the WHO as 'high priority', for which new antibiotics are needed. Moreover, the Maastricht consensus recommended, in areas with high resistance, that susceptibility tests should be performed, at least after a treatment failure.

Summary: Metronidazole and clarithromycin resistance rates are alarming although they vary among populations. Tetracycline and amoxicillin-resistance are very low in most countries. H. pylori resistance can be detected by phenotypic or by molecular methods. Different break points may be used when performing an antimicrobial susceptibility test, so comparing resistance among different populations is challenging. Genomic techniques open new possibilities in the diagnosis of H. pylori, and the detection of H. pylori and its antimicrobial resistance in faeces is an interesting approach. Eradication rates are dependent on the susceptibility of the strain to metronidazole and clarithromycin, being lower in patients infected with a resistant strain.
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http://dx.doi.org/10.1097/QCO.0000000000000396DOI Listing
October 2017

Chicken embryo lethality assay for determining the lethal dose and virulence of Enterococcus faecalis.

Avian Pathol 2017 Oct 13;46(5):548-555. Epub 2017 Jun 13.

b Departamento de Produccion Animal, Escuela Técnica Superior de Ingeniería Agronómica, Alimentaria y de Biosistemas , Universidad Politécnica de Madrid , Madrid , Spain.

Enterococcus faecalis is the major pathogen found in field cases of amyloid arthropathy in chickens. Given the need for a better understanding of the virulence mechanisms of the causative strains, the embryo lethality assay (ELA) is proposed in the present study as a model to evaluate the virulence of E. faecalis strains, specifically the pathogenic avian strain K923/96, which was previously related with amyloid arthropathy. Hence, 0.2 ml of five doses of the cited strain (from 2.5 to 2500 colony-forming units (CFU) per ml) were inoculated into the allantoic cavity of 10-day-old embryos. The embryo mortality rate (EMR) was determined by daily candling of the eggs over a period of seven days and based on this information the median lethal dose (LD) was calculated. The ELA was repeated four times on a sample of 3443 eggs. The infectious dose showed a significant effect on the EMR. The EMR with the doses of 2.5, 5, 25, 250 and 2500 CFU/ml was 43%, 45%, 63%, 90% and 93%, respectively. The estimated dose at LD was 6.6 CFU/ml. As expected, the higher the infectious dose, the greater the EMR and the lower the embryo survival time. The highest EMR was recorded after three and four days post-inoculation in all doses. In conclusion, these results can be used as a basis for further researches on the E. faecalis virulence. In order to corroborate its model capacity to predict the virulence of this bacterium, more ELAs with different E. faecalis strains are required.
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http://dx.doi.org/10.1080/03079457.2017.1324942DOI Listing
October 2017

Adding access blood flow surveillance reduces thrombosis and improves arteriovenous fistula patency: a randomized controlled trial.

J Vasc Access 2017 Jul 20;18(4):352-358. Epub 2017 Apr 20.

Nephrology Unit, Hospital Gregorio Marañón, Madrid - Spain.

Purpose: Stenosis is the main cause of arteriovenous fistula (AVF) failure. It is still unclear whether surveillance based on vascular access blood flow (QA) enhances AVF function and longevity.

Methods: We conducted a three-year follow-up randomized, controlled, multicenter, open-label trial to compare QA-based surveillance and pre-emptive repair of subclinical stenosis with standard monitoring/surveillance techniques in prevalent mature AVFs. AVFs were randomized to either the control group (surveillance based on classic alarm criteria; n = 104) or to the QA group (QA measured quarterly using Doppler ultrasound [M-Turbo®] and ultrasound dilution [Transonic®] added to classic surveillance; n = 103).The criteria for intervention in the QA group were: 25% reduction in QA, QA<500 mL/min or significant stenosis with hemodynamic repercussion (peak systolic velocity [PSV] more than 400 cm/sc or PSV pre-stenosis/stenosis higher than 3).

Results: At the end of follow-up we observed a significant reduction in the thrombosis rate in the QA group (0.025 thrombosis/patient/year in the QA group vs. 0.086 thrombosis/patient/year in the control group [p = 0.007]). There was a significant improvement in the thrombosis-free patency rate (HR, 0.30; 95% CI, 0.11-0.82; p = 0.011) and in the secondary patency rate in the QA group (HR, 0.49; 95% CI, 0.26-0.93; p = 0.030), with no differences in the primary patency rate between the groups (HR, 0.98; 95% CI, 0.57-1.61; p = 0.935).There was greater need for a central venous catheter and more hospitalizations associated with vascular access in the control group (p = 0.034/p = 0.029).Total vascular access-related costs were higher in the control group (€227.194 vs. €133.807; p = 0.029).

Conclusions: QA-based surveillance combining Doppler ultrasound and ultrasound dilution reduces the frequency of thrombosis, is cost effective, and improves thrombosis free and secondary patency in autologous AVF.
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http://dx.doi.org/10.5301/jva.5000700DOI Listing
July 2017

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.

Hum Mol Genet 2016 06 23;25(11):2256-2268. Epub 2016 Mar 23.

Ambry Genetics, Aliso Viejo, CA 92656, USA.

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
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http://dx.doi.org/10.1093/hmg/ddw094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081057PMC
June 2016

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy.

J Med Genet 2017 01 8;54(1):38-46. Epub 2016 Sep 8.

Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, PTS Granada, Granada, Spain.

Background: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci.

Methods: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method.

Results: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci.

Conclusions: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition.
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http://dx.doi.org/10.1136/jmedgenet-2016-104144DOI Listing
January 2017

Low-dose-rate brachytherapy for patients with transurethral resection before implantation in prostate cancer. Longterm results.

Int Braz J Urol 2016 Jan-Feb;42(1):47-52

Department of Radiation Physics, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain.

Objectives: We analyzed the long-term oncologic outcome for patients with prostate cancer and transurethral resection who were treated using low-dose-rate (LDR) prostate brachytherapy.

Methods And Materials: From January 2001 to December 2005, 57 consecutive patients were treated with clinically localized prostate cancer. No patients received external beam radiation. All of them underwent LDR prostate brachytherapy. Biochemical failure was defined according to the "Phoenix consensus". Patients were stratified as low and intermediate risk based on The Memorial Sloan Kettering group definition.

Results: The median follow-up time for these 57 patients was 104 months. The overall survival according to Kaplan-Meier estimates was 88% (±6%) at 5 years and 77% (±6%) at 12 years. The 5 and 10 years for failure in tumour-free survival (TFS) was 96% and respectively (±2%), whereas for biochemical control was 94% and respectively (±3%) at 5 and 10 years, 98% (±1%) of patients being free of local recurrence. A patient reported incontinence after treatment (1.7%). The chronic genitourinary complains grade I were 7% and grade II, 10%. At six months 94% of patients reported no change in bowel function.

Conclusions: The excellent long-term results and low morbidity presented, as well as the many advantages of prostate brachytherapy over other treatments, demonstrates that brachytherapy is an effective treatment for patients with transurethral resection and clinical organ-confined prostate cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811225PMC
http://dx.doi.org/10.1590/S1677-5538.IBJU.2014.0531DOI Listing
March 2017

High-dose-rate interstitial brachytherapy as monotherapy in one fraction for the treatment of favorable stage prostate cancer: Toxicity and long-term biochemical results.

Radiother Oncol 2016 06 22;119(3):411-6. Epub 2016 Apr 22.

Department of Radiation Physics, Hospital Universitario Central de Asturias, Oviedo, Spain.

Background: To evaluate acute and late genitourinary, the gastrointestinal toxicity and the long-term biochemical control after HDR monotherapy in one fraction (19Gy).

Patients And Methods: Between April 2008 and October 2010, 60 consecutive patients were treated with favorable clinically localized prostate cancer; the median follow-up was 72months (range 32-91). All patients received one implant and one fraction of HDR. Fraction dose was 19Gy. Toxicity was reported according to the Common Toxicity Criteria for Adverse Event, Version 4.0 (CTAE v4.02) by the National Cancer Institute.

Results: No intraoperative or perioperative complications occurred. Acute toxicity grade 2 or more was not observed in any patients. No chronic toxicity, such as incontinence, late urinary retention, urethral narrowing, rectal bleeding, anal ulcer and/or rectourethral fistula has been observed after treatment. The overall survival and failure in tumor-free survival (TFS) according to Kaplan-Meier estimates was 90% (±5%) and 88% (±5%) respectively at 6years. The actuarial biochemical control was 66% (±6%) at 6years.

Conclusions: This protocol is feasible and very well tolerated with low genitourinary morbidity, no gastrointestinal toxicity but no the same level of LDR biochemical control at 6years.
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http://dx.doi.org/10.1016/j.radonc.2016.04.006DOI Listing
June 2016

Using NS5B Sequencing for Hepatitis C Virus Genotyping Reveals Discordances with Commercial Platforms.

PLoS One 2016 20;11(4):e0153754. Epub 2016 Apr 20.

Servicio de Microbiología, Complejo Hospitalario Universitario Granada-Hospital San Cecilio, Instituto de Investigación Biosanitaria IBS, Granada, Spain.

We aimed to evaluate the correct assignment of HCV genotypes by three commercial methods-Trugene HCV genotyping kit (Siemens), VERSANT HCV Genotype 2.0 assay (Siemens), and Real-Time HCV genotype II (Abbott)-compared to NS5B sequencing. We studied 327 clinical samples that carried representative HCV genotypes of the most frequent geno/subtypes in Spain. After commercial genotyping, the sequencing of a 367 bp fragment in the NS5B gene was used to assign genotypes. Major discrepancies were defined, e.g. differences in the assigned genotype by one of the three methods and NS5B sequencing, including misclassification of subtypes 1a and 1b. Minor discrepancies were considered when differences at subtype levels, other than 1a and 1b, were observed. The overall discordance with the reference method was 34% for Trugene and 15% for VERSANT HCV2.0. The Abbott assay correctly identified all 1a and 1b subtypes, but did not subtype all the 2, 3, 4 and 5 (34%) genotypes. Major discordances were found in 16% of cases for Trugene HCV, and the majority were 1b- to 1a-related discordances; major discordances were found for VERSANT HCV 2.0 in 6% of cases, which were all but one 1b to 1a cases. These results indicated that the Trugene assay especially, and to a lesser extent, Versant HCV 2.0, can fail to differentiate HCV subtypes 1a and 1b, and lead to critical errors in clinical practice for correctly using directly acting antiviral agents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153754PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838212PMC
August 2016

Tempol improves xanthine oxidoreductase-mediated vascular responses to nitrite in experimental renovascular hypertension.

Redox Biol 2016 08 5;8:398-406. Epub 2016 Apr 5.

Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil. Electronic address:

Upregulation of xanthine oxidoreductase (XOR) increases vascular reactive oxygen species (ROS) levels and contributes to nitroso-redox imbalance. However, XOR can generate nitric oxide (NO) from nitrite, and increased superoxide could inactivate NO formed from nitrite. This study tested the hypothesis that XOR contributes to the cardiovascular effects of nitrite in renovascular hypertension, and that treatment with the antioxidant tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) improves XOR-mediated effects of nitrite. Blood pressure was assessed weekly in two-kidney one-clip (2K1C) and control rats. After six weeks of hypertension, the relaxing responses to nitrite were assessed in aortic rings in the presence of the XOR inhibitor oxypurinol (or vehicle), either in the absence or in the presence of tempol. Moreover, in vivo hypotensive responses to nitrite were also examined in the presence of oxypurinol (or vehicle) and tempol (or vehicle). Aortic XOR activity and expression were evaluated by fluorescence and Western blot, respectively. Vascular ROS production was assessed by the dihydroethidium assay. 2K1C hypertensive rats showed increased aortic XOR activity and vascular ROS production compared with control rats. Oxypurinol shifted the nitrite concentration-response curve to the right in aortic rings from 2K1C rats (but not in controls). Oxypurinol also attenuated the hypotensive responses to nitrite in 2K1C rats (but not in controls). These functional findings agree with increased aortic and plasma XOR activity found in 2K1C rats. Tempol treatment enhanced oxypurinol-induced shift of the nitrite concentration-response curve to the right. However, antioxidant treatment did not affect XOR-mediated hypotensive effects of nitrite. Our results show that XOR is important to the cardiovascular responses to nitrite in 2K1C hypertension, and XOR inhibitors commonly used by patients may cancel this effect. This finding suggests that nitrite treatment may not be effective in patients being treated with XOR inhibitors. Moreover, while tempol may improve the vascular responses to nitrite, antihypertensive responses are not affected.
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http://dx.doi.org/10.1016/j.redox.2016.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022046PMC
August 2016

Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples.

J Med Genet 2016 08 8;53(8):548-58. Epub 2016 Apr 8.

Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

Background: BRCA1 and BRCA2 are the two principal tumour suppressor genes associated with inherited high risk of breast and ovarian cancer. Genetic testing of BRCA1/2 will often reveal one or more sequence variants of uncertain clinical significance, some of which may affect normal splicing patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation or defects in gene function. To understand which novel splicing events are associated with splicing mutations and which are part of the normal BRCA2 splicing repertoire, a study was undertaken by members of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events.

Methods: mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary or agarose gel electrophoresis, followed by sequencing.

Results: We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines.

Conclusions: These naturally occurring alternate-splicing events contribute to the array of cDNA fragments that may be seen in assays for mutation-associated splicing defects. Caution must be observed in assigning alternate-splicing events to potential splicing mutations.
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http://dx.doi.org/10.1136/jmedgenet-2015-103570DOI Listing
August 2016
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