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Objective : Intravenous immunoglobulins (IVIG) are an established treatment in several immune-mediated diseases such as dermatomyositis or Kawasaki disease and they have been used in distinct clinical scenarios in systemic lupus erythematosus (SLE). However, in this latter disease no clear evidence besides hematological or renal involvement supports its use. The aim of the present study is to establish evidence for the treatment of non-renal non-hematological lupus with IVIG. Methods : We have carried out a systematic literature review following PRYSMA principles on the use of this treatment in SLE patients with no renal no hematologic manifestations. Results : We found 35 articles which were split into two subtypes, those with individualized data (29) and those with grouped data. Overall, 198 lupus patients treated with IVIGs [178 (90%) women and 20 (10%) men] were included. In 167 (84.3%) a clinical response was obtained [62 (31.3%) complete and 105 (53%) a partial one]. Adverse events were reported in 40 patients (20.2%), most of them mild with only 2 (1%) severe. According to individualized data, all cases with respiratory problems (5), 82.4% of those with cardiac involvement (18) and 53.8% of those with neuropsychiatric manifestations (18) achieved a complete response as more outstanding results. Conclusions : After reviewing the experience of the use of IVIGs in extra-renal and extra-hematologic SLE patients, this treatment is demonstrated to be useful in refractory cases, especially in pulmonary, cardiac or neuropsychiatric complications with a good safety profile., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Patch test results may be influenced by age-related factors. However, there is still discordant evidence between age and patch test results., Objectives: We aim to evaluate the patch test results reflecting skin sensitisation, their relevance and association with clinical features by age group., Methods: Prospective multicentric study of all patients patch tested with the Spanish baseline series in participating centres. Age groups were pre-defined as children (0- to 11-years), adolescents (12- to 18-years), young adults (19- to 30-years), middle-aged adults (31- to 65-years) and older adults (≥66-years). Occurrence of sensitisation, relevance and clinical features were compared by age group. Factors associated with skin sensitisation were investigated with multivariate logistic regression., Results: A total of 13 368 patients were patch-tested. Differences in positive patch test results and relevance by age were detected with the highest proportion in middle-aged adults. Age-related trend differences were found for nickel, potassium dichromate, caines, colophony, Myroxylon pereirae resin, 2-hydroxyethyl methacrylate and limonene hydroperoxide. The multivariate logistic analysis (adjusted for sex, atopic dermatitis, body location and occupational dermatitis) showed an association between the age group of 31-65 (OR: 1.41, 95% CI: 1.26-1.58) and above 66-years (OR: 1.15, 95% CI: 1.01-1.32) with a higher proportion of positive results, compared with young adults., Conclusions: Positive patch test results vary according to age, with the highest occurrence in middle-aged adults. Most haptens did not present age-related differences, reinforcing the use of baseline series regardless of age., (© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: There is still limited clinical-practice data on specific clinical and patch test features, as well as on allergen clusters in polysensitization (PS)., Objectives: To determine the frequency, relevance, symptoms duration and risk factors in polysensitized patients and to assess possible allergen aggregation., Methods: Prospective multicentric study (January 2019-December 2022) conducted in setting of the Spanish Contact Dermatitis Register (REIDAC). Clinical and patch test data of polysensitized and oligosensitized patients were compared, and risk factors of PS were investigated with logistic multivariate regression. Unsupervised hierarchical clustering and network analysis were used to study allergen aggregation in PS., Results: A total of 10,176 patients were analysed. PS was found in 844 (8.3%). Current relevance was significantly higher in polysensitized patients (p < 0.01). Risk factors for PS were atopic dermatitis (OR: 1.58, 95% CI: 1.24-2.02), age (≥60 years vs. ≤24 years, OR: 1.75, 95% CI: 1.25-2.44) and some special locations (legs vs. face OR: 1.54, 95% CI: 1.05-2.25, hands vs. face OR: 1.46, 95% CI:1.15-1.85, arms vs. face OR: 1.49, 95% CI:1.01-2.20, trunk vs. face OR: 1.40, 95% CI:1.06-1.85). Cluster and network analyses revealed specific-allergen clusters and significant associations, including allergens belonging to metals group, fragrances and botanicals group, topical drugs group, rubber allergens and biocides., Conclusions: This study confirms that PS is structured by discernible patterns of specific-allergen clusters and reinforces significant allergen associations in PS. Cross-reactivity and/or concomitant sensitization could explain the formation of allergen clusters in PS., (© 2024 European Academy of Dermatology and Venereology.)

Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

After the meeting held by the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) back in October 2021, changes were suggested to the Spanish Standard Series patch testing. Hydroxyethyl methacrylate (2% pet.), textile dye mixt (6.6% pet.), linalool hydroperoxide (1% pet.), and limonene hydroperoxide (0.3% pet.) were, then, added to the series that agreed upon in 2016. Ethyldiamine and phenoxyethanol were excluded. Methyldibromoglutaronitrile, the mixture of sesquiterpene lactones, and hydroxyisohexyl 3-cyclohexene (Lyral) were also added to the extended Spanish series of 2022., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: Systemic lupus erythematosus (SLE) is an autoimmune condition that can highly impact patients' quality of life (QoL). However, there is a lack of knowledge about SLE, affecting the general population and health care professionals (HCPs) alike. This lack of knowledge has negative implications for patients and the healthcare system, worsening prognosis, negatively impacting QoL, and increasing healthcare utilization. The aim of this paper is to draw attention, according to the perspective of the participants of this study, to the lack of awareness of SLE and its consequences in Spain, and to suggest improvements., Patients and Methods: This qualitative, descriptive, observational, multicenter, and cross-sectional study included 40 patients with moderate or severe SLE, recruited during their routine visits in six university hospitals in Spain. The study also included 11 caregivers and 9 HCPs. All participants were individually interviewed. Data from the interviews were coded and analyzed thematically by two anthropologists following a phenomenological perspective., Results: Our study identified a lack of disease awareness among primary care physicians, emergency medicine doctors, and other specialists treating SLE symptomatology. This led to diagnostic delays, which had a clinical and emotional impact on patients. Furthermore, symptom awareness was found to be context dependent. Differences in symptom awareness between HCPs and patients led to a mismatch between the severity evaluation made by doctors and patients. Some HCPs did not consider the limitations of the current severity evaluation of SLE, and therefore attributed symptoms potentially caused by SLE to the unfavorable socioeconomic conditions patients lived in. Finally, a lack of social awareness among friends, family members, and romantic partners led to lower social support, increased isolation, and negative physical and emotional impact for patients. Gender differences in the provision of support were identified., Conclusion: This study highlights the need to increase SLE awareness among patients, HCPs, and the broader public in order to improve patient QoL. Being aware of the clinical and emotional impact of such lack of awareness, as well as the role played by context on the patient experience of SLE, is a crucial step towards achieving this goal., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RRR and CSM are employees of A Piece of Pie and have received research funding from AstraZeneca to conduct this study. JSH, MG, and NBR are employees of AstraZeneca. ERA has received honoraria from GSK. All other authors report no competing interests.

Background: Psoriasis is a chronic inflammatory dermatosis whose clinical and topographic distribution requires differential diagnosis, or the possible association with allergic contact dermatitis (ACD), requiring patch testing (PT) as part of the diagnostic procedure., Objectives: To describe the epidemiological, clinical, and allergic profile of patients with a primary or secondary diagnosis of psoriasis undergoing PT and compare them with patients with a diagnosis of ACD at the end of the diagnostic process., Methods: Cross-sectional study with data from REIDAC from 2018 through 2023 of selected patients with a diagnosis of psoriasis and/or ACD., Results: A total of 11 502 patients were included, 513 of whom had been diagnosed with primary or secondary psoriasis, 3640 with ACD, and 108 with both diseases. Men were more predominant in the groups of patients with psoriasis, psoriasis+ACD, and lesions were more predominantly seen in the hands with little association with atopic factors vs the ACD group. The rate of positivity in PT to the 2022 Spanish battery of allergens was lower in the group with psoriasis only in 27% of the patients. The most common allergens found in the psoriasis group were also the most common ones found in the overall ACD population., Conclusions: Overall, 36.2% of psoriatic patients tested positive in PT to the 2022 Spanish battery of allergens, which proved that this association is not uncommon. Overall, psoriatic patients had a higher mean age, were more predominantly men, and showed more hand involvement., (Copyright © 2024 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Current frequency and features for positivity to textile dye mix (TDM) in Spain are unknown., Objectives: To study the frequency, clinical features and simultaneous positivity between TDM, para-phenylenediamine (PPD) and specific disperse dyes., Materials and Methods: We analysed all consecutive patients patch-tested with TDM from the Spanish Contact Dermatitis Registry (REIDAC), from 1 January 2019 to 31 December 2022. Within this group, we studied all selected patients patch-tested with a textile dye series., Results: Out of 6128 patients analysed, 3.3% were positive to the TDM and in 34% of them, the sensitization was considered currently relevant. TDM positivity was associated with working as a hairdresser/beautician and scalp, neck/trunk and arm/forearm dermatitis. From TDM-positive patients, 57% were positive to PPD. One hundred and sixty-four patients were patch-tested with the textile dye series. Disperse Orange 3 was the most frequent positive dye (16%). One of every six cases positive to any dye from the textile dye series would have been missed if patch-tested with the TDM alone., Conclusions: Positivity to TDM is common in Spain and often associated with PPD sensitization. TDM is a valuable marker of disperse dyes allergy that should be part of the Spanish and European standard series., (© 2024 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

The study aimed to assess the impact of an attachment-based intervention on adolescent adaptation to parental divorce. The Adolescent Adjustment Pilot Program to Parental Divorce (AAPPD) employed an experimental group format, targeting improvements in various adaptation indicators (life satisfaction, positive affect, and negative affect). The sample comprised 30 Chilean adolescents aged 12 to 16 (M = 13.6, SD = 1.35), with 60% females and 40% males. After the intervention, the adolescents showed a decrease in negative affect at 6 and 12 months. However, no differences were identified in other dimensions of subjective well-being considered as indicators of divorce adaptation. The findings prompt discussion on theoretical and clinical implications., (© 2024. The Author(s).)

Background: Current frequency and risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in Spain are not well known., Objectives: To study the frequency of sensitization, risk factors and simultaneous sensitization between the four isothiazolinones., Materials and Methods: We analysed all 2019-2021 consecutive patients patch-tested with MI (0.2% aq.), MCI/MI (0.02% aq.), BIT (0.1% pet.) and OIT (0.1% pet) within the Spanish Contact Dermatitis Registry (REIDAC)., Results: A total of 2511 patients were analysed. Frequencies of sensitization were: any isothiazolinone 15.7%, MI 6.8%, MCI/MI 4.8%, BIT 3.5% and OIT 0.5%. MI and MCI/MI sensitization was associated with being occupationally active, hand dermatitis, detergents and age over 40. BIT sensitization was associated with leg dermatitis and age over 40. About one in nine MI-positive patients were positive to BIT, whereas one in five BIT-positive patients were positive to MI., Conclusions: Sensitization to MI, MCI/MI and BIT is still common in Spain, while sensitization to OIT is rare. Currently, sensitization to MI and MCI/MI seems to be occupationally related. Although its origin is unknown, sensitization to BIT is more frequent in patients aged over 40 years. Simultaneous sensitization between MI and BIT is uncommon., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Objective: To explore the experiences of people with persistent COVID in the Basque Country more than a year after the start of the pandemic, in order to understand the health and social impact it has, as well as to detect possible areas for improvement in the care that these people receive in order to develop health programms to support their recovery., Method: Qualitative phenomenological study. In-depth interviews will be carried out as a data collection technique until saturation of the discourse. Patients of legal age who present persistent COVID symptomatology with an evolution time of more than 12 weeks were included. Contact with the patients was made through the Basque Long COVID Collective. The interviews were carried out and recorded through the ZOOM application. After the literal transcription of the interviews, the thematic analysis will be carried out, identifying the first units of meaning and assigning codes that will later be grouped into the different categories., Results: 20 patients participated. A total of three main categories emerged from the analysis of the discourses: 1) affecting/impacting patients' quality of life; 2) identifying improvements in healthcare; and 3) comforting aspects., Conclusions: This study shows the significant impact on the quality of life suffered by these people. It is necessary to design health policies that favour a personalised, comprehensive and multidisciplinary approach to these patients., (Copyright © 2022 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)

Defined as the unpleasant sensation that causes the desire to scratch, pruritus is the most common skin symptom associated with uremia and appears in almost half of patients with advanced chronic kidney disease (CKD). Beyond its direct impact on quality of life, CKD-associated pruritus (CKD-aP) is an independent predictor of mortality that also has a synergistic effect with other quality of life-related symptoms, such as insomnia, depression, and anxiety. Although different mechanisms have been proposed to explain the origin of Pa-ERC, its etiopathogenesis is still not fully understood. Since new therapeutic targets have been identified and several clinical trials have recently shown promising results, our current understanding of the interrelationships has expanded significantly and the pathophysiological mechanisms underlying CKD-aP are now considered to be multifactorial. The potential triggers of pruritus in patients with CKD are discussed in this review, including hypotheses about skin xerosis, accumulation of uremic toxins, dysregulation of the immune system and systemic inflammation, uremic neuropathy, and imbalances in the endogenous opioid system. Other non-uremic causes of pruritus are also discussed, with the aim of guiding the physicians to apply an adequate aetiopathogenic approach to CKD-aP in their day-to-day clinical practice., (Copyright © 2022 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

We have updated recommendations on 12 controversial topics that were published in the 2013 National Consensus on the diagnosis, risk stratification and treatment of patients with pulmonary embolism (PE). A comprehensive review of the literature was performed for each topic, and each recommendation was evaluated in two teleconferences. For diagnosis, we recommend against using the Pulmonary Embolism Rule Out Criteria (PERC) rule as the only test to rule out PE, and we recommend using a D-dimer cutoff adjusted to age to rule out PE. We suggest using computed tomography pulmonary angiogram as the imaging test of choice for the majority of patients with suspected PE. We recommend using direct oral anticoagulants (over vitamin K antagonists) for the vast majority of patients with acute PE, and we suggest using anticoagulation for patients with isolated subsegmental PE. We recommend against inserting an inferior cava filter for the majority of patients with PE, and we recommend using full-dose systemic thrombolytic therapy for PE patients requiring reperfusion. The decision to stop anticoagulants at 3 months or to treat indefinitely mainly depends on the presence (or absence) and type of risk factor for venous thromboembolism, and we recommend against thrombophilia testing to decide duration of anticoagulation. Finally, we suggest against extensive screening for occult cancer in patients with PE., (Copyright © 2021 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background & Aims: Individuals with non- or minimally verbal autism (nvASD) are primarily characterized by a severe speech production deficit, with speech limited to no or only a few words by school age. Significant unclarity remains over variability in language profiles across the lifespan, the nature of the language impairment seen, and (dis-) associations between linguistic and nonverbal cognitive measures., Methods: To address these questions, we recruited both a school-age and an adult group with nvASD (total N = 49) and investigated relations between expressive and receptive language, and between these and nonverbal intelligence quotient (NVIQ) and sense-making capacities (the ComFor test)., Results: Results revealed limited variation across this sample in receptive language, which in turn predicted expressive language levels. Importantly, an upward trend in verbal mental age (VMA) across increasing chronological age was seen in the youngsters (only). A radical dissociation between NVIQ and both expressive and receptive language transpired as well, and a subset of individuals with normal NVIQ were comparable in terms of any other cognitive aspect. Sense-making reached symbolic levels in 62.2% of the sample and loaded on both verbal and nonverbal factors., Conclusions: These patterns inform theories of nvASD by revealing an impairment that is not conceptualizable as one of expressive language only, sharply limits learning opportunities across the lifespan, and cannot be compensated for by nonverbal cognition., Implications: These findings stress the need to seize developmental opportunities that may disappear when youngsters turn into adults, via therapies that specifically target language as a central cognitive system comprising both production and comprehension., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Introduction: Studies which focus on the process of acculturation in the lifestyles, nutritional status and health of immigrants from the Community of Portuguese-Speaking Countries (CPLP) in the Iberian Peninsula are still scarce. This study aims to explore the influence of the acculturation process and dietary acculturation on the lifestyle and nutritional and health status of CPLP immigrants in Portugal and Spain, focusing on two Iberian contexts: Lisbon Metropolitan Area and the Basque Country., Methods and Analysis: A mixed methods sequential explanatory design, combining cross-sectional studies and semistructured interviews. Official data will also be analysed. Primary data will be collected through a questionnaire and assessment of nutritional status and body composition. The estimated samples sizes are 1061 adults (≥18 years old) in the Lisbon Metropolitan Area and 573 in the Basque Country. Time-location sampling will be used for the quantitative component and non-probabilistic sampling for the qualitative component. If safety conditions are not guaranteed due to the COVID-19 pandemic, online studies will be conducted. The semistructured interviews will complement the questionnaire data and extend knowledge about the process of acculturation of CPLP immigrants and their relationship with eating habits and physical activity. Thematic analysis will be used for qualitative data. Triangulation of data derived from different methods will be carried out. An integrative approach will be used to address potential discrepancies in findings and limitations inherent to the study design. As inter-method discrepancies may occur, triangulation protocol will be used, elaborating a 'convergence coding matrix' to display findings emerging from each component of the study., Ethics and Dissemination: Ethical approval was obtained through the IHMT Ethics Council (Doc No 20/2020), Portugal, and it was submitted to the Ethics Committee of the UPV/EHU (Doc No under revision), Spain., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Standard patch test series must be updated using objective data on allergen sensitization. The Spanish standard series was last updated in 2016 and the European series in 2019, and the inclusion of several emerging allergens needs to be evaluated., Material and Methods: We conducted a prospective, observational, multicenter study of consecutive patients from the registry of the Spanish Contact Dermatitis and Skin Allergy Research Group (GEIDAC) who were patch tested in 2019 and 2020 with linalool hydroperoxide, limonene hydroperoxide, 2-hydroxyethyl-methacrylate, benzisothiazolinone, octylisothiazolinone, textile dye mix (TDM), sodium metabisulfite, propolis, bronopol, Compositae mix II, diazolidinyl urea, imidazolidinyl urea, decyl glucoside, and lauryl glucoside., Results: We analyzed data for 4654 patients tested with diazolidinyl urea, imidazolidinyl urea, and bronopol, and 1890 tested with the other allergens. The values for the MOAHLFA index components were 30% for male, 18% for occupational dermatitis, 15% for atopic dermatitis, 29% for hand, 6.5% for leg, 23% for face, and 68% for age > 40 years. Sensitization rates above 1% were observed for 7 allergens: linalool hydroperoxide, 2-hydroxyethyl-methacrylate, benzisothiazolinone, limonene hydroperoxide, TDM, sodium metabisulfite, and propolis. Three allergens had a current relevance rate of over 1%: linalool hydroperoxide, 2-hydroxyethyl-methacrylat, and limonene hydroperoxide. Benzisothiazolinone and TDM had a relevance rate of between 0.9% and 1%., Conclusions: Our results indicate that 7 new allergens should be considered when extending the Spanish standard patch test series. The data from our series could be helpful for guiding the next extension of the European baseline series., (Copyright © 2021 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Importance: Studies on the prognostic role of hyperthermic intraperitoneal chemotherapy (HIPEC) in pseudomyxoma peritonei (PMP) are currently not available., Objectives: To evaluate outcomes after cytoreductive surgery (CRS) and HIPEC compared with CRS alone in patients with PMP., Design, Setting, and Participants: This cohort study analyzed data from the Peritoneal Surface Oncology Group International (PSOGI) registry, including 1924 patients with histologically confirmed PMP due to an appendiceal mucinous neoplasm. Eligible patients were treated with CRS with or without HIPEC from February 1, 1993, to December 31, 2017, and had complete information on the main prognostic factors and intraperitoneal treatments. Inverse probability treatment weights based on the propensity score for HIPEC treatment containing the main prognostic factors were applied to all models to balance comparisons between the CRS-HIPEC vs CRS-alone groups in the entire series and in the following subsets: optimal cytoreduction, suboptimal cytoreduction, high- and low-grade histologic findings, and different HIPEC drug regimens. Data were analyzed from March 1 to June 1, 2018., Interventions: HIPEC including oxaliplatin plus combined fluorouracil-leucovorin, cisplatin plus mitomycin, mitomycin, and other oxaliplatin-based regimens., Main Outcomes and Measures: Overall survival, severe morbidity (determined using the National Cancer Institute Common Terminology for Adverse Events, version 3.0), return to operating room, and 30- and 90-day mortality. Differences in overall survival were compared using weighted Kaplan-Meier curves, log-rank tests, and Cox proportional hazards multivariable models. A sensitivity analysis was based on the E-value from the results of the main Cox proportional hazards model. Differences in surgical outcomes were compared using weighted multivariable logistic models., Results: Of the 1924 patients included in the analysis (997 [51.8%] men; median age, 56 [interquartile range extremes (IQRE), 45-65] years), 376 were in the CRS-alone group and 1548 in the CRS-HIPEC group. Patients with CRS alone were older (median age, 60 [IQRE, 48-70] vs 54 [IQRE, 44-63] years), had less lymph node involvement (14 [3.7%] vs 119 [7.7%]), received more preoperative systemic chemotherapy (198 [52.7%] vs 529 [34.2%]), and had higher proportions of high-grade disease (179 [47.6%] vs 492 [31.8%]) and suboptimal cytoreduction residual disease (grade 3, 175 [46.5%] vs 117 [7.6%]). HIPEC was not associated with a higher risk of worse surgical outcomes except with mitomycin, with higher odds of morbidity (1.99; 95% CI, 1.25-3.19; P = .004). HIPEC was associated with a significantly better overall survival in all subsets (adjusted hazard ratios [HRs], 0.60-0.68, with 95% CIs not crossing 1.00). The weighted 5-year overall survival was 57.8% (95% CI, 50.8%-65.7%) vs 46.2% (95% CI, 40.3%-52.8%) for CRS-HIPEC and CRS alone, respectively (weighted HR, 0.65; 95% CI, 0.50-0.83; P < .001; E-value, 2.03). Such prognostic advantage was associated with oxaliplatin plus fluorouracil-leucovorin (HR, 0.42; 95% CI, 0.19-0.93; P = .03) and cisplatin plus mitomycin (HR, 0.57; 95% CI, 0.42-0.78; P = .001) schedules., Conclusions and Relevance: In this cohort study, HIPEC was associated with better overall survival when performed after CRS in PMP, generally without adverse effects on surgical outcomes.

Objective: To estimate the incidence and analyze any cancer-associated factors in patients with systemic lupus erythematosus (SLE), differentiating between hormone-sensitive (HS) and non-HS cancers., Methods: This was a retrospective multicenter study of a patient cohort from the Systemic Lupus Erythematosus Registry of the Spanish Society of Rheumatology. Included were the first cancer post-SLE diagnosis, clinical and sociodemographic information, cumulative damage, severity, comorbidities, treatments, and refractoriness. Cancers were classified as HS (prostate, breast, endometrium, and ovarian) and non-HS (the remainder). The standardized incidence ratio (SIR) was calculated and logistic regression models were built., Results: A total of 3,539 patients (90.4% women) were included, 154 of whom had cancer (91% female), and 44 had HS cancer (100% female). The cancer SIR was 1.37 (95% confidence interval [95% CI] 1.15-1.59), with higher values in women age <65 years (SIR 2.38 [95% CI 1.84-2.91]). The SIR in women with HS versus non-HS cancer was 1.02 (95% CI 0.13-1.91) and 1.93 (95% CI 0.98-2.89). In HS versus non-HS cancers, SLE diagnostic age (odds ratio [OR] 1.04 [P = 0.002] versus 1.04 [P = 0.019]), and period of disease evolution (OR 1.01 [P < 0.001] versus 1.00 [P = 0.029]) were associated with cancer. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (OR 1.27 [P = 0.022]) and angiotensin-converting enzyme (ACE) inhibitor prescriptions (OR 2.87 [P = 0.048]) were associated with non-HS cancers., Conclusion: Cancer incidence in patients with SLE was higher than in the Spanish population, particularly among young women. This increase might be due to non-HS cancers, which would be associated with SLE involving greater cumulative damage where more ACE inhibitors are prescribed., (© 2019, American College of Rheumatology.)

MUC5B rs35705950 (G/T) is strongly associated with idiopathic pulmonary fibrosis (IPF) and also contributes to the risk of interstitial lung disease (ILD) in rheumatoid arthritis (RA-ILD) and chronic hypersensitivity pneumonitis (CHP). Due to this, we evaluated the implication of MUC5B rs35705950 in antisynthetase syndrome (ASSD), a pathology characterised by a high ILD incidence. 160 patients with ASSD (142 with ILD associated with ASSD [ASSD-ILD+]), 232 with ILD unrelated to ASSD (comprising 161 IPF, 27 RA-ILD and 44 CHP) and 534 healthy controls were genotyped. MUC5B rs35705950 frequency did not significantly differ between ASSD-ILD+ patients and healthy controls nor when ASSD patients were stratified according to the presence/absence of anti Jo-1 antibodies or ILD. No significant differences in MUC5B rs35705950 were also observed in ASSD-ILD+ patients with a usual interstitial pneumonia (UIP) pattern when compared to those with a non-UIP pattern. However, a statistically significant decrease of MUC5B rs35705950 GT, TT and T frequencies in ASSD-ILD+ patients compared to patients with ILD unrelated to ASSD was observed. In summary, our study does not support a role of MUC5B rs35705950 in ASSD. It also indicates that there are genetic differences between ILD associated with and that unrelated to ASSD.

We assembled genome-wide data from 271 ancient Iberians, of whom 176 are from the largely unsampled period after 2000 BCE, thereby providing a high-resolution time transect of the Iberian Peninsula. We document high genetic substructure between northwestern and southeastern hunter-gatherers before the spread of farming. We reveal sporadic contacts between Iberia and North Africa by ~2500 BCE and, by ~2000 BCE, the replacement of 40% of Iberia's ancestry and nearly 100% of its Y-chromosomes by people with Steppe ancestry. We show that, in the Iron Age, Steppe ancestry had spread not only into Indo-European-speaking regions but also into non-Indo-European-speaking ones, and we reveal that present-day Basques are best described as a typical Iron Age population without the admixture events that later affected the rest of Iberia. Additionally, we document how, beginning at least in the Roman period, the ancestry of the peninsula was transformed by gene flow from North Africa and the eastern Mediterranean., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To assess the efficacy of the ProMIC, multidisciplinary program for patients admitted at hospital because of heart failure (HF) programme, in reducing the HF-related readmission rate., Desing: Quasi-experimental research with control group., Settings: Twelve primary health care centres and 3 hospitals from the Basque Country., Participants: Aged 40 years old or above patients admitted for HF with a New York Heart Association functional class II to IV., Interventions: Patients in the intervention group carried out the ProMIC programme, a structured clinical intervention based on clinical guidelines and on the chronic care model. Control group received usual care., Main Measurements: The rate of readmission for HF and health-related quality of life RESULTS: One hundred fifty five patients were included in ProMIC group and 129 in control group. 45 rehospitalisation due to heart failure happened in ProMIC versus 75 in control group (adjusted hazard ratio=0.59, CI 95%: 0.36-0.98; P=.049). There were significant differences in specific quality of life al 6 months. No significant differences were found in rehospitalisation due to all causes, due to cardiovascular causes, visits to emergency room, mortality, the combined variable of these events, the functional capacity or quality of life at 12 months of follow up., Conclusions: ProMIC reduces significantly heart failure rehospitalisation and improve quality of life al 6 months of follow up. No significant differences were found in the rests of variables., (Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

When listeners misperceive words in noise, do they report words that are more common? Lexical frequency differences between misperceived and target words in English and Spanish were examined for five masker types. Misperceptions had a higher lexical frequency in the presence of pure energetic maskers, but frequency effects were reduced or absent for informational maskers. The tendency to report more common words increased with the degree of energetic masking, suggesting that uncertainty about segment identity provides a role for lexical frequency. However, acoustic-phonetic information from an informational masker may additionally constrain lexical choice.

Objective: To assess the impact of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain on endometriosis-associated pelvic pain., Study Design: Multicenter, open-label, non-comparative clinical trial in a representative sample of women with endometriosis-associated pelvic pain., Results: In total, 398 patients with a mean age of 34.6 ± 7.2 years were treated with a combination of N-acetyl cysteine, alpha lipoic acid and bromelain for 6 months. At baseline, 92.7% of the patients had pain intensity > 4 on the visual analogue scale (VAS); at 3 months of treatment, this percentage decreased to 87.2% (p = 0.074) and at 6 months the percentage was 82.7% (p < 0.05)., Conclusions: Women with endometriosis who wish to become pregnant and are treated with a preparation containing N-acetyl cysteine, alpha lipoic acid and bromelain experienced a significant improvement in endometriosis-associated pelvic pain and required lower intake of rescue analgesics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cochlea-scaled entropy (CSE) was proposed as a signal-based metric for automatic detection of speech regions most important for intelligibility, but its proposed superiority over traditional linguistic and psychoacoustical characterisations was not subsequently confirmed. This paper shows that the CSE concept is closely related to intensity and as such captures similar speech regions. However, a slight but significant advantage of a CSE over an intensity-based characterisation was observed, associated with a time difference between the two metrics, suggesting that the CSE index may capture dynamical properties of the speech signal crucial for intelligibility.

Speakers adjust their voice when talking in noise (known as Lombard speech), facilitating speech comprehension. Recent neurobiological models of speech perception emphasize the role of amplitude modulations in speech-in-noise comprehension, helping neural oscillators to "track" the attended speech. This study tested whether talkers produce more pronounced amplitude modulations in noise. Across four different corpora, modulation spectra showed greater power in amplitude modulations below 4 Hz in Lombard speech compared to matching plain speech. This suggests that noise-induced speech contains more pronounced amplitude modulations, potentially helping the listening brain to entrain to the attended talker, aiding comprehension.

Objective: Despite cautions by professional associations, benzodiazepines (BZD) and Z hypnotics (BZD/Z) are widely prescribed to older adults who are particularly susceptible to insomnia and anxiety, but who are also more sensitive to drugs adverse events. In this study, we assessed the prescription of BZD/Z drugs in a sample of older adults (≥65) who presented for emergency care after a fall., Methods: We collected the type, number and dose of BZD/Z drugs prescribed and explored gender differences in the prescription., Results: BZD/Z drugs were prescribed to 43.6% of the sample (n=654) and more frequently to women; 78.4% of prescriptions were for BZD/Z drugs with a short half-life. The majority of patients (83.5%) were prescribed only one type of BZD/Z, but 16.5% had been prescribed multiple BZD/Z drugs, with no gender difference. Doses higher than those recommended for older adults were prescribed to 58% of patients, being the doses significantly higher for men compared to women (70.0% vs 53.1%)., Conclusions: Over 40% of older adults presenting for emergency care after a fall had previously been prescribed BZD/Z drugs. Some important gender differences in the prescription of BZD/Z drugs were seen, especially prescription above the recommended dose and of drugs with a long-half life., (Copyright © 2017 SEP y SEPB. Publicado por Elsevier España, S.L.U. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Evidence from longitudinal studies has reported contradictory results regarding the association between OSA and hypertension. In a previous analysis of the Vitoria Sleep Cohort, the relationship between OSA and the risk of developing hypertension was evaluated and no independent association after adjustment for confounding factors was found. In the present study, a post hoc analysis to assess the association between OSA and incident stage 2 hypertension (systolic BP ≥ 160 mm Hg and/or diastolic BP ≥ 100 mm Hg) was made on the basis of sex differences., Methods: A prospective study was performed over 7.5 ± 0.8 years on a middle-aged general population, which included 1,155 normotensive subjects (43.7% men) who completed the follow-up. BP measurements (at baseline and follow-up) and polygraphy at baseline were performed. Logistic regression models were used to determine the association between the respiratory disturbance index (RDI) and stage 2 hypertension and a recursive partitioning method was used to determine the variables related to the incidence of stage 2 hypertension. The RDI was divided into subgroups (0-2.9, 3-6.9, 7-13.9, and ≥ 14), using the first subgroup as reference., Results: For men, an RDI ≥ 14 was associated with a significantly increased OR for stage 2 hypertension (OR, 2.54 [95% CI, 1.09-5.95], P = .032). This association was not statistically significant among women (P = .371)., Conclusions: The results suggest an association between moderate and severe OSA, and the incidence of more severe forms of hypertension occurring in men but not in women. However, because this is a community-based study, the women's population characteristics may differ from women usually seen in sleep-disorders clinics., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

We evaluated the impact of a workplace 'sit less, move more' programme (Walk@WorkSpain, W@WS, 19-week) on self-reported activity-related energy expenditure (AREE) in Spanish office employees (n = 264; 42 ± 10 years; 171 female) randomly assigned to Intervention (IG; used W@WS; n = 129) or comparison groups (CGs; n = 135). A linear mixed model assessed changes in METs-min/wk of total, vigorous, moderate and light physical activity (IPAQ short form) between baseline and 2 months follow-up. Over the CG, IG significantly increased light intensity AREE (P = 0.027). W@WS secured sustained increases on AREE-but not on achieving PA recommendations-providing translational evidence that active living in office employees can be increased., (© The Author 2017. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Objective: To understand the barriers to implementing nursing research findings into practice, as perceived by the nurses working in Osakidetza and to analyze if the workplace factor and time worked affect the perception of these barriers., Methods: Cross-sectional study. BARRIERS Scale questionnaire was given to a representative sample of 1,572 Basque Health Service nurses, stratified and randomized, according to scope of work and job responsibility (response rate: 43.76%)., Results: According to the research results, the first important barrier was "insufficient time on the job to implement new ideas". Nurses have perceived the organizational factor as the most important barrier in their practice. Nurses in "Special hospital departments" perceived more barriers in the "quality of research" factor than those working in "Primary Care". Years of service showed a slight influence., Conclusions: The nurses stated that external factors related to the organization principally interfered in implementing results into clinical practice. They placed lack of critical reading training second. Working environment and seniority mark differences in the perception of barriers. This study may help to develop strategies for planning training programs to facilitate the use of research in clinical practice, in order to provide quality care., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Algorithmic modifications to the durational structure of speech designed to avoid intervals of intense masking lead to increases in intelligibility, but the basis for such gains is not clear. The current study addressed the possibility that the reduced information load produced by speech rate slowing might explain some or all of the benefits of durational modifications. The study also investigated the influence of masker stationarity on the effectiveness of durational changes. Listeners identified keywords in sentences that had undergone linear and nonlinear speech rate changes resulting in overall temporal lengthening in the presence of stationary and fluctuating maskers. Relative to unmodified speech, a slower speech rate produced no intelligibility gains for the stationary masker, suggesting that a reduction in information rate does not underlie intelligibility benefits of durationally modified speech. However, both linear and nonlinear modifications led to substantial intelligibility increases in fluctuating noise. One possibility is that overall increases in speech duration provide no new phonetic information in stationary masking conditions, but that temporal fluctuations in the background increase the likelihood of glimpsing additional salient speech cues. Alternatively, listeners may have benefitted from an increase in the difference in speech rates between the target and background.

This work attempts to study the way higher music graduate students segment a contemporary music work, Itinerant, and to understand the influence of musical feature on segmentation. It attempts to test the theory stating that saliences contribute to organising the music surface. The 42 students listened to the work several times and, in real time, they were requested to indicate the places on the score where they perceived structural boundaries. This work is characterised by its linearity, which could hinder identification of saliences and thereby, the establishment of structural boundaries. The participants show stability in the points of segmentation chosen. The results show significant coincidences among the participants in strategic places of the work, which leads us to conclude, in line with other researches, although in a work with different characteristics, that listeners can find a structural organisation in contemporary music that could allow them to understand it.

Objectives: The main objective of this study was to compare two cold water immersion protocols, continuous or intermittent, on recovery in basketball players., Methods: Ten male basketball players (age: 14 ± 0.4 years, body mass: 65.4 ± 9.1 kg, height: 175 ± 7.3 cm, body fat %: 10.3 ± 4) were included in the study. After three 90-minute training sessions (avg. heart rate 158 ± 11.92, 156 ± 7.06 and 151 ± 10.44 bpm), participants were grouped into a continuous immersion (12 min at 12 ± 0.4°C) group, intermittent immersion (4 x 2 min immersion at 12 ± 0.4 °C + 1 min out of water) group and a control group (CG). Countermovement jump (CMJ), muscle pain and thigh volume were measured., Results: Both cold water immersion protocols were effective in reducing the pain 24 and 48 hours after training compared with the CG (F (3.54) = 2.91, p = 0.016, η p 2  = .24). Concerning CMJ change, % differences occurred at 24 (Z = 11.04, p = 0.004) and 48 hours (Z = 14.01, p < 0.001) in comparison with the CG. Regarding the muscle volume, the statistical analysis did not report a significant interaction (F (3.54) = 2.42, p = 0.058)., Conclusion: Both cold water immersion CWI protocols are effective in improving recovery in basketball players.

Introduction: Since its approval by the European Medicines Agency, a great number of patients born small for gestational date have received recombinant growth hormone treatment in Spain. The aim of this study is to analyse its outcome in the setting of ordinary clinical practice., Methods: Information was gathered from the registers of the assessment boards that authorise all growth hormone treatments prescribed in public hospitals in six autonomic communities (regions)., Results: Valid data from 974 patients was obtained. All of them complied with criteria established by the European Medicines Agency. Patients in the sample were smaller in length than weight at birth, with their median target height being below 1 standard deviation (SD), and 23% of them had been delivered prematurely. Treatment was started at 7.2±2.8 years (mean±SD). The mean patient height at start was -3.1±0.8 SD. They gained 0.7±0.2 SD in the first year, and 1.2±0.8 SD after two years. Final height was attained by 8% of the sample, reaching -1.4±0.7 SD., Conclusions: These results are similar to other Spanish and international published studies, and are representative of the current practice in Spain. Despite treatment being started at a late age, adequate growth is observed in the short term and in the final height. Up to a 24% of patients show a poor response in the first year., (Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

For decades, human activities have gradually destroyed the natural habitats of wild grapevine, Vitis vinifera L. subsp. sylvestris (Gmelin) Hegi, and nowadays this species is endangered in southern Europe. In this paper, 94 populations of this species have been localized and characterized in the Andalusian region in the Iberian Peninsula between 1989 and 2013. Location, ecological aspects, and sanitary characteristics are described. Must properties and in vitro tolerance to calcareous conditions were also checked. The paper also contains a global description of female and male individuals. Two hundred individuals from six river basin populations have been sampled, and their genetic structure analyzed by using 25 nuclear microsatellites loci to investigate the gene diversity of wild grape populations in Andalusia at two levels: total individuals and at river basin populations. Also, the genetic relationship of wild and cultivated accessions has been tested. Wild grapevine is considered the ancestor of the cultivated varieties and should be preserved as this material could be used to start breeding programs of cultivated varieties and also to restore riverbank forests, which constitute one of the worst preserved ecosystems in the area., (Copyright © 2017 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.)

The metastasis suppressor KISS1 is reported to be involved in the progression of several solid neoplasias, making it a promising molecular target for controlling their metastasis. The KISS1 sequence contains an N-terminal secretion signal and several dibasic sequences that are proposed to be the proteolytic cleavage sites. We present the first structural characterization of KISS1 by circular dichroism, multi-angle light scattering, small angle X-Ray scattering and NMR spectroscopy. An analysis of the KISS1 backbone NMR chemical shifts does not reveal any preferential conformation and deviation from a random coil ensemble. The backbone 15N transverse relaxation times indicate a mildly reduced mobility for two regions that are rich in bulky residues. The small angle X-ray scattering curve of KISS1 is likewise consistent with a predominantly random coil ensemble, although an ensemble optimization analysis indicates some preference for more extended conformations possibly due to positive charge repulsion between the abundant basic residues. Our results support the hypothesis that KISS1 mostly samples a random coil conformational space, which is consistent with its high susceptibility to proteolysis and the generation of Kisspeptin fragments.

Introduction: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination., Methodology: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV)., Results: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk., (Copyright © 2016 SEP y SEPB. Published by Elsevier España. All rights reserved.)

Objective: To evaluate the effects of an intensive postoperative physiotherapy program focused on respiratory exercises in patients undergoing lobectomy by open thoracotomy., Design: Quasi-experimental study., Setting: Tertiary referral academic hospital., Participants: 208 patients undergoing lobectomy by open thoracotomy., Interventions: Control group patients (n=102) received standard medical/nursing care, and experimental group patients (n=106) added to the standard clinical pathway a daily physiotherapy program focused on respiratory exercises until discharge., Outcomes: Analyzed outcomes were the frequency of postoperative pulmonary complications (PPCs) more amenable to physiotherapy (pneumonia, atelectasis and respiratory insufficiency) and length of hospital stay (LOS)., Results: Both groups were comparable regarding preoperative and surgical characteristics. Incidence of PPCs was 20.6% in control and 6.6% in experimental group (P=.003). Median (IQR) LOS in control group was 14 (7) days (Huber M estimator 14.21) and 12 (6) days (Huber M estimator 12.81) in experimental. Logistic regression model identified the evaluated physiotherapy program (P=.017; EXP [B] 95% CI 0.081-0.780) and % FEV1 (P=.042; EXP [B] 95% CI 0.941-0.999) as protective factors for the development of PPCs in patients undergoing lobectomy., Conclusions: Implementing a postoperative intensive physiotherapy program focused on respiratory exercises reduces the risk of PPCs and resultant LOS on patients undergoing lobectomy., (Copyright © 2016 SEPAR. Published by Elsevier Espana. All rights reserved.)

Landscapes and features of the everyday world were scarcely represented in Paleolithic art, especially those features associated with the human landscape (huts and campsites). On the contrary, other figurative motifs (especially animals) and signs, traditionally linked to the magic or religious conceptions of these hunter-gatherer societies, are the predominant themes of Upper Paleolithic art. This paper seeks to present an engraved schist slab recently found in the Molí del Salt site (North-eastern Iberia) and dated at the end of the Upper Paleolithic, ca. 13,800 years ago. This slab displays seven semicircular motifs that may be interpreted as the representation of dome-shaped huts. The analysis of individual motifs and the composition, as well as the ethnographic and archeological contextualization, suggests that this engraving is a naturalistic depiction of a hunter-gatherer campsite. Campsites can be considered the first human landscape, the first area of land whose visible features were entirely constructed by humans. Given the social meaning of campsites in hunter-gatherer life-styles, this engraving may be considered one of the first representations of the domestic and social space of a human group.

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnaneX receptors). Although parti provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described., (Copyright © 2014 SEP y SEPB. Published by Elsevier España. All rights reserved.)