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Purpose: To systematically review and summarize the available literature on (1) postoperative healing rates, meniscal extrusion (ME) and clinical outcomes following lateral (LMPRR) versus medial (MMPRR) root repair and (2) potential correlations between residual ME and healing outcomes., Methods: A comprehensive literature search was conducted using the Scopus, PubMed and Embase databases. Clinical studies evaluating healing status on second-look arthroscopy and magnetic resonance imaging (MRI) after LMPRR and MMPRR were included. Study quality was assessed using the Methodological Index for Non-Randomized Studies criteria and the modified Coleman Methodology Score., Results: Twenty-three studies comprising 871 patients with LMPRR (n = 406) and MMPRR (n = 465) were included. Overall, 223 (54.9% of total) and 149 (32.04% of total) patients underwent second-look arthroscopy in the LMPRR and MMPRR groups, respectively. Complete root healing was observed in 190 (85.2%) patients in the LMPRR group versus 78 (52.3%) in the MMPRR group (p < 0.001). There were six (2.7%) failed repairs in the LMPRR group compared to 21 (14.09%) in the MMPRR group (p < 0.001). On postoperative MRI, 109 (75.7%) root repairs were healed in the LMPRR group compared to 192 (53.3%) in the MMPRR group (p < 0.001). Failure rates were lower after all-inside and transtibial pullout repairs in the LMPRR group but higher in the MMPRR group, with no significant mean difference between preoperative and postoperative ME in the MMPRR group (p = 0.95). Significantly better clinical outcomes were observed in the LMPRR group compared to the MMPRR group. A greater degree of postoperative ME was associated with lower healing rates (R = -0.78, p < 0.0005). Postoperative ME did not influence clinical outcomes (R = 0.28, p = 0.29)., Conclusions: Lateral meniscus posterior root repairs showed higher healing rates compared to MMPRR on both second-look arthroscopy and postoperative MRI. Meniscal extrusion decreased after LMPRR but not after MMPRR. Greater residual ME correlated inversely with healing rates, as more extrusion was associated with lower healing. Postoperative clinical improvement did not affect ME or healing status., Study Design: Systematic review of level III and IV studies., Level of Evidence: Level IV., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: Cardiogenic shock (CS) is a severe myocardial dysfunction secondary to various cardiac conditions including ST-segment elevation acute myocardial infarction (STEMI) and associated with a high risk of death. Little is known on epigenetic determinants in CS. Here, we investigated plasma miRNAs in relation to CS stratification in STEMI-patients., Methods: STEMI-patients (n = 49), with (CS, n = 25) and without CS (non-CS, n = 24) fulfilling inclusion criteria were included from HSCSP-cohort (Derivation-cohort). CS-miRNAs were analysed by Affymetrix-microarray and RT-PCR. Results were validated in a second cohort of CS-patients (CardShock: n = 35) with similar inclusion/exclusion criteria as the derivation cohort. In silico analysis were performed to identify potential miRNA target genes., Results: Of the 5-miRNA signature obtained from microarray analysis, miR-619-5p showed higher levels in CS than in Non-CS patients (p = .003) and discriminating power for CS by ROC (AUC: .752, p = .003). miR-619-5p directly associated with risk scores [GRACE, p = .001; CardShock, p < .001]. Furthermore, miR-619-5p showed discrimination power for death in CS. Thus, miRNA levels were significantly higher in patients with mortality outcome both in the Derivation HSCSP-cohort (p = .02; AUC: .78 ± .095) and the Validation CardShock-cohort (p = .017; AUC: .737 ± .086) By in silico analysis, miR-619-5p target genes and TNF-alpha were involved in the regulation of inflammation. miR-619-5p and TNF-alpha levels discriminated mortality outcome in CS-patients during 30-day follow-up (Validation-Cohort: ROC: .812, p = .002; HR: 9.99, p = .003)., Conclusions: Up-regulation of miR-619-5p is found in the plasma of STEMI-patients with CS and mortality outcome. These findings highlight the specificity of epigenetic regulation of inflammation on the disease severity of MI., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: The COVID-19 pandemic prompted the use of face masks as a social distancing measure. Although evidence supports their effectiveness in preventing infection, it remains unclear why some adolescents choose to continue wearing them postpandemic, even when it is no longer mandatory. This study aims to explore adolescents' experiences of wearing face masks during the COVID-19 pandemic when their use was no longer mandatory., Method: In this exploratory qualitative study, data were collected from 16 adolescents through face-to-face semistructured interviews. The participants were asked about the reasons and feelings associated with continuing to wear masks, as well as the contexts in which they felt safe without a mask. The collected data were analysed using Braun and Clarke's thematic analysis., Results: Three main themes were identified: (1) Navigating complex decision-making: balancing safety and self-image, (2) peer influence dynamics and (3) managing the future: weather dynamics and pandemic evolution., Discussion: The potential implications of withdrawing COVID-19 preventive measures, such as mask-wearing, beyond the pandemic remain understudied. It is crucial to further investigate the perceptions related to wearing masks and its cessation, especially amongst vulnerable individuals., Patient or Public Contribution: Due to methodological constraints associated with participants' age, they were not engaged in the design, data analysis, data interpretation or manuscript preparation phases of the study., (© 2024 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Aims: Sex-specific differences in acute heart failure (AHF) are both relevant and underappreciated. Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately., Methods and Results: We performed a pre-defined sex-specific analysis in AHF patients randomized to a strategy of early intensive and sustained vasodilatation versus usual care in an international, multicentre, open-label, blinded endpoint trial. Inclusion criteria were AHF with increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100 mmHg, and plan for treatment in a general ward. Among 781 eligible patients, 288 (37%) were women. Women were older (median 83 vs. 76 years), had a lower body weight (median 64.5 vs. 77.6 kg) and lower estimated glomerular filtration rate (median 48 vs. 54 ml/min/1.73 m 2 ). The primary endpoint, a composite of all-cause mortality or rehospitalization for AHF at 180 days, showed a significant interaction of treatment strategy and sex (p for interaction = 0.03; hazard ratio adjusted for female sex 1.62, 95% confidence interval 1.05-2.50; p = 0.03). The combined endpoint occurred in 53 women (38%) in the intervention group and in 35 (24%) in the usual care group. The implementation of rapid up-titration of renin-angiotensin-aldosterone system (RAAS) inhibitors was less successful in women versus men in the overall cohort and in patients with heart failure with reduced ejection fraction (median discharge % target dose in patients randomized to intervention: 50% in women vs. 75% in men)., Conclusion: Rapid up-titration of RAAS inhibitors was less successfully implemented in women possibly explaining their higher rate of all-cause mortality and rehospitalization for AHF., Clinical Trial Registration: ClinicalTrials.gov, unique identifier NCT00512759., (© 2023 European Society of Cardiology.)

Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age- and sex-matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better-informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in-depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non-dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life-threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence-based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification., (© 2023 European Society of Cardiology.)

Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence-based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021., (© 2023 European Society of Cardiology.)

Background and Purpose: Mitochondrial dysfunction and inflammation contribute to a myriad of cardiovascular diseases. Deleterious crosstalk of mitochondria and persistent endoplasmic reticulum (ER) stress triggers oxidative stress, which is involved in the development of vascular diseases. This study determined if inhibition of mitochondrial stress reduces aneurysm development in angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE -/- ) mice and its effect on ER stress., Experimental Approach: The mitochondria-targeted tetrapeptide, Szeto-Schiller 31 (SS31), ameliorated mitochondrial dysfunction and the enhanced expression of ER stress markers triggered by Ang II in ApoE -/- mice, and limited plasmatic and vascular reactive oxygen species (ROS) levels. Interestingly, SS31 improved survival, reduced the incidence and severity of abdominal aortic aneurysm (AAA), and the Ang II-induced increase in aortic diameter as evaluated by ultrasonography, resembling the response triggered by the classic ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (PBA)., Key Results: Disorganization of the extracellular matrix, increased expression of metalloproteinases and pro-inflammatory markers and infiltration of immune cells induced by Ang II in the abdominal aorta were effectively reduced by SS31 and ER inhibitors. Further, C/EBP homologous protein (CHOP) deficiency in ApoE -/- mice attenuated Ang II-mediated increase in vascular diameter and incidence of AAA, suggesting its contribution to the favourable response induced by ER stress inhibition., Conclusions and Implications: Our data demonstrate that inhibition of mitochondrial stress by SS31 limits AAA formation and increases survival through a reduction of vascular remodelling, inflammation and ROS, and support that attenuation of ER stress contributes to the favourable response elicited by SS31., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Aims: Asthma is a heterogeneous respiratory disease that encompasses different inflammatory and functional endophenotypes. Many non-invasive biomarkers has been investigated to its pathobiology. Heany et al proposed a clinical algorithm that classifies severe asthmatic patients into likely-eosinophilic phenotypes, based on accessible biomarkers: PBE, current treatment, FeNO, presence of nasal polyps (NP) and age of onset., Materials and Methods: We assessed the concordance between the algorithm proposed by Heany et al. with sputum examination, the gold standard, in 145 asthmatic patients of the MEGA cohort with varying grades of severity., Results: No correlation was found between both classifications 0.025 (CI = 0.013-0.037). Moreover, no relationship was found between sputum eosinophilia and peripheral blood eosinophilia count in the total studied population., Discussion and Conclusion: In conclusion, our results suggest that grouping the biomarkers proposed by Heany et al. are insufficient to diagnose eosinophilic phenotypes in asthmatic patients. Sputum analysis remains the gold standard to assess airway inflammation., Competing Interests: Dr. Betancor is supported by a Rio Hortega Research Contract from Instituto Carlos III, Spanish Ministry of Science. Dr. Valverde has received lecturing fees from GSK and sits on the advisory board for Organon. Dr. Rial reports receiving personal fees from GSK, Allergy Therapeutics, and AstraZeneca outside the submitted work. Dr. González Barcala reports personal fees from ALK, AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Gebro Pharma, GlaxoSmithKline, Laboratorios Esteve, Menarini, Mundipharma, Novartis, Rovi, Roxall, Stallergenes‐Greer, Teva, as well as grants from Mundipharma outside the submitted work. Dr. Quirce reports personal fees from AstraZeneca, Novartis, Sanofi, Boehringer Ingelheim, Teva, ALK, Mundipharma, GSK, Chiesi, and Leti outside the submitted work. Dr. Soto reports non‐financial support from CIBER de Enfermedades Respiratorias (CIBERES) during the conduct of the study; outside of the present work, she reports personal fees from Stallergennes‐Greer, Menarini, and Novartis, personal fees from GSK, Hal Allergy, Allergy Therapeutics, AstraZeneca, and grants from Sociedad Española de Alergología e Inmunología Clínica SEAIC and Sociedad Española de Neumología y Cirugía Torácica SEPAR. Dr. Martinez Rivera reports having received grants and personal fees from AstraZeneca, Teva, GSK, Novartis, and Mundipharma outside the submitted work. Dr. Munoz reports personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Teva, Mundifarma, Chiesi, and Faes outside the submitted work. Dr. Sastre reports grants and personal fees from Sanofi, GSK, Novartis, AstraZeneca, Mundipharma, and Faes Farma outside the submitted work. Dr. Olaguibel reports grants from Sanofi and/or personal fees from AstraZeneca and Mundipharma outside the submitted work. Dr. Plaza reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Chiesi, Novartis, Menarini, and Sanofi outside the submitted work. Dr. Mullol reports personal and other fees from Sanofi‐Genzyme & Regeneron, Novartis, Viatris (Mylan pharma), Uriach group, Mitsubishi‐Tanabe, Menarini, UCB, AstraZeneca, GSK, and MSD outside the submitted work. Dr. del Pozo reports personal and other fees from Sanofi, AstraZeneca, and GSK outside the submitted work. All other authors have no conflicts of interest., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: The Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument has been developed to inform the methodology, reporting and appraisal of clinical practice guidelines. Evidence suggests that the quality of surgical guidelines can be improved, and the structure and content of AGREE II can be modified to help enhance the quality of guidelines of surgical interventions., Objective: To develop an extension of AGREE II specifically designed for guidelines of surgical interventions., Methods: In the tripartite Guideline Assessment Project (GAP) funded by United European Gastroenterology and the European Association for Endoscopic Surgery, (i) we assessed the quality of surgical guidelines and we identified factors associated with higher quality (GAP I); (ii) we applied correlation analysis, factor analysis and the item response theory to inform an adaption of AGREE II for the purposes of surgical guidelines (GAP II); and (iii) we developed an AGREE II extension for surgical interventions, informed by the results of GAP I, GAP II, and a Delphi process of stakeholders, including representation from interventional and surgical disciplines; the Guideline International Network (GIN); the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group; the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) initiative; and representation of surgical journal editors and patient/public., Results: We developed AGREE-S, an AGREE II extension for surgical interventions, which comprises 24 items organized in 6 domains; Scope and purpose, Stakeholders, Evidence synthesis, Development of recommendations, Editorial independence, and Implementation and update. The panel of stakeholders proposed 3 additional items: development of a guideline protocol, consideration of practice variability and surgical/interventional expertise in different settings, and specification of infrastructures required to implement the recommendations. Three of the existing items were amended, 7 items were rearranged among the domains, and one item was removed. The domain Rigour of Development was divided into domains on Evidence Synthesis and Development of Recommendations. The new domain Development of Recommendations incorporates items from the original AGREE II domain Clarity of Presentation., Conclusion: AGREE-S is an evidence-based and stakeholder-informed extension of the AGREE II instrument, that can be used as a guide for the development and adaption of guidelines on surgical interventions., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Despite the success of automated pattern recognition methods in problems of human brain tumor diagnostic classification, limited attention has been paid to the issue of automated data quality assessment in the field of MRS for neuro-oncology. Beyond some early attempts to address this issue, the current standard in practice is MRS quality control through human (expert-based) assessment. One aspect of automatic quality control is the problem of detecting artefacts in MRS data. Artefacts, whose variety has already been reviewed in some detail and some of which may even escape human quality control, have a negative influence in pattern recognition methods attempting to assist tumor characterization. The automatic detection of MRS artefacts should be beneficial for radiology as it guarantees more reliable tumor characterizations, as well as the development of more robust pattern recognition-based tumor classifiers and more trustable MRS data processing and analysis pipelines. Feature extraction methods have previously been used to help distinguishing between good and bad quality spectra to apply subsequent supervised pattern recognition techniques. In this study, we apply feature extraction differently and use a variant of a method for blind source separation, namely Convex Non-Negative Matrix Factorization, to unveil MRS signal sources in a completely unsupervised way. We hypothesize that, while most sources will correspond to the different tumor patterns, some of them will reflect signal artefacts. The experimental work reported in this paper, analyzing a combined short and long echo time 1 H-MRS database of more than 2000 spectra acquired at 1.5T and corresponding to different tumor types and other anomalous masses, provides a first proof of concept that points to the possible validity of this approach., (© 2019 John Wiley & Sons, Ltd.)

Rare diseases (RDs) as a whole affect a huge number of individuals although each specific condition comprises a low number of individuals. As a consequence, funds allocated to expand research to all conditions are often limited. Several initiatives have emerged to invest more resources for research in RDs, but patients express unmet needs regarding educational initiatives, awareness support, and psychosocial resources. We developed an educational training program in the format of weekly sessions covering basic medical scientific knowledge and psychosocial aspects of RDs. The aim of this initiative was to assess its overall impact regarding knowledge, psychological issues, and participant satisfaction. Items were evaluated through surveys before and after the sessions. Here, we report the experience and impact of two editions of this initiative with a total of 37 participants. Our results show improvements in knowledge and better management of the psychological impact. Moreover, participants were able to exchange experiences and concerns, most of which were shared even though the RDs were different. Overall, the program was evaluated by the participants as a highly beneficial experience and all of them were interested in attending advanced editions., (© 2020 National Society of Genetic Counselors.)

Introduction: The MEGA (MEchanism underlying the Genesis and evolution of Asthma) project is a multicenter cohort study carried out in eight Spanish hospitals, gathering clinical, physiological, and molecular data from patients with asthma and multimorbidities in order to gain insight into the different physiopathological mechanisms involved in this disorder., Material and Methods: We report the baseline clinical and physiological characteristics and biomarker measures of adult participants in the project with the aim of better understanding the natural history and underlying mechanisms of asthma as well as the associated multimorbidities across different levels of severity. We carried out a detailed clinical examination, pulmonary function testing, measurement of fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick tests, chest computed tomography scan, asthma questionnaires, and multimorbidity assessment in 512 asthmatic patients., Results: When compared to patients with milder disease, severe asthmatic patients showed greater presence of symptoms, more exacerbations, lower asthma control, increased airflow obstruction, and higher frequency of chronic rhinosinusitis with nasal polyps, severe rhinitis, anxiety and depression, gastroesophageal reflux, and bronchiectasis., Conclusion: The MEGA project succeeded in recruiting a high number of asthma patients, especially those with severe disease, who showed lower control and higher frequency of multimorbidities., (© 2021 The Authors. Clinical and Translational Allergy published by John Wiley and Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Clinical coordination mechanisms (CCMs) have become key tools in healthcare networks for improving coordination between primary care (PC) and secondary care (SC) and are particularly relevant in health systems with highly fragmented healthcare provision. However, their implementation has been little studied to date in Latin America and particularly in Colombia. This study analyses the level of knowledge and use of CCMs between care levels and their changes between 2015 and 2017 in two public healthcare networks in Bogotá, Colombia. Comparison of two cross-sectional studies based on surveys among PC and SC doctors working in their networks (174 doctors per network/year). The COORDENA questionnaire was used for measuring knowledge concerning CCMs and the frequency of use and difficulties involved in using referral/reply letters (R/RLs) and hospital discharge reports (HDRs). Descriptive bivariate analysis and Poisson regression models with robust variance were used for analysing differences between networks and years. The results for both networks and years revealed greater knowledge and use of information coordination mechanisms than those regarding clinical management coordination (though their knowledge increased in 2017). Although widely known and used, significant problems regarding infrequent and late receipt of RLs and HDRs in PC as well as the poor quality of their contents limits their effective use, which may affect the quality of care. Strategies are required to improve CCMs use., (© 2020 John Wiley & Sons Ltd.)

A distinctive new indirect immunofluorescence pattern in liver tissue has been associated with anti-HMGCR autoantibodies. It is known as HALIP (HMGCR Associated Liver Immunofluorescence Pattern). In this study, we furthered the original studies to demonstrate the association of anti-HMGCR antibodies with the HALIP. Human anti-HMGCR antibodies from patients' sera were purified and incubated with rat triple tissue (kidney/stomach/liver). A characteristic HALIP was observed. Additionally, a colocalization assay of human anti-HMGCR antibodies with rabbit polyclonal anti-HMGCR antibodies showed colocalization of both immunofluorescence patterns. This study confirms that the HALIP is due to human anti-HMGCR antibodies., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2020 Andrés Baucells et al.)

Background: Loop ileostomy reduces the rates of morbidity due to colorectal anastomotic dehiscence. For its part, ileostomy closure is associated with low mortality (0-4%) but substantial morbidity (11-37%). Incisional surgical site infection (SSI) is one of the most frequent complications (2-40%)., Methods: A single-center, prospective, randomized controlled clinical trial of two study groups: control (conventional primary skin closure) and experimental (primary skin closure with a contralateral Penrose ® drain)., Results: Seventy patients undergoing loop ileostomy closure between April 2013 and June 2017 were included (35 per branch). Four were later removed from the study. Six of the remaining 66 patients (per protocol analysis) were diagnosed with incisional SSI (9.1%); there were no statistically significant differences between the two groups (control group: 9.7%; experimental group: 8.6%) or between the risk factors associated with incisional SSI. Rates of overall and relevant morbidity (Clavien ≥ III) were considerable (28.1% and 9.1%, respectively), and there were no statistically significant differences between the two groups. No patients died., Conclusion: Contralateral drainage does not significantly affect the results of primary ileostomy closure. The rate of incisional SSI was similar in the drainage and non-drainage groups, and the overall rate of 9.1% was in the low range of those reported in the literature. The absence of mortality (0%) and the non-negligible rates of overall and relevant morbidity (28.1% and 9.1%, respectively) in our series suggest that loop ileostomy is a safe procedure. However, the bowel reconstruction involves risks that must be borne in mind., Clinical Trial Registration: The study was registered and approved by the clinical research ethics committee of the study center (reference number 2012076). Clinical trial was registered in ClinicalTrial.gov (identification number NCT02574702 and reference: ILEOS-ISS&#95;2013).

We present the case of a 34-year-old male patient employed for 8 years in a company manufacturing and packaging animal feed. The patient developed occupational asthma to dry Gammarus powder. The diagnosis was confirmed by specific bronchial provocation test. The determination of specific IgE antibodies was positive for Pen m 4, a sarcoplasmic calcium binding protein, with a level of 6.7 ISU-E. The sensitization to Pen m 4 described here may identify a new allergen causing occupational asthma in these workers.

Aryl-alcohol oxidase (AAO) plays a fundamental role in the fungal ligninolytic secretome, acting as a supplier of H 2 O 2 . Despite its highly selective mechanism of action, the presence of this flavooxidase in different biotechnological settings has hitherto been hampered by the lack of appropriate heterologous expression systems. We recently described the functional expression of the AAO from Pleurotus eryngii in Saccharomyces cerevisiae by fusing a chimeric signal peptide (preαproK) and applying structure-guided evolution. Here, we have obtained an AAO secretion variant that is readily expressed in S. cerevisiae and overproduced in Pichia pastoris. First, the functional expression of AAO in S. cerevisiae was enhanced through the in vivo shuffling of a panel of secretion variants, followed by the focused evolution of the preαproK peptide. The outcome of this evolutionary campaign-an expression variant that accumulated 4 mutations in the chimeric signal peptide, plus two mutations in the mature protein- showed 350-fold improved secretion (4.5 mg/L) and was stable. This secretion mutant was cloned into P. pastoris and fermented in a fed-batch bioreactor to enhance production to 25 mg/L. While both recombinant AAO from S. cerevisiae and P. pastoris were subjected to the same N-terminal processing and had a similar pH activity profile, they differed in their kinetic parameters and thermostability. The strong glycosylation observed in the evolved AAO from S. cerevisiae underpinned this effect, since when the mutant was produced in the glycosylation-deficient S. cerevisiae strain Δkre2, its kinetic parameters and thermostability were comparable to its poorly glycosylated P. pastoris recombinant counterpart., (© 2018 Wiley Periodicals, Inc.)

Background: The objective of this study was to estimate the association between sleep quality (SQ) and improvements in low back pain (LBP) and disability, among patients treated for LBP in routine practice., Methods: This prospective cohort study included 461 subacute and chronic LBP patients treated in 11 specialized centres, 14 primary care centres and eight physical therapy practices across 12 Spanish regions. LBP, leg pain, disability, catastrophizing, depression and SQ were assessed through validated questionnaires upon recruitment and 3 months later. Logistic regression models were developed to assess: (1) the association between the baseline score for SQ and improvements in LBP and disability at 3 months, and (2) the association between improvement in SQ and improvements in LBP and disability during the follow-up period., Results: Seventy-three per cent of patients were subacute. Median scores at baseline were four points for both pain and disability, as assessed with a visual analog scale and the Roland-Morris Questionnaire, respectively. Regression models showed (OR [95% CI]) that baseline SQ was not associated with improvements in LBP (0.99 [0.94; 1.06]) or in disability (0.99 [0.93; 1.05]), although associations existed between 'improvement in SQ' and 'improvement in LBP' (4.34 [2.21; 8.51]), and 'improvement in SQ' and 'improvement in disability' (4.60 [2.29; 9.27])., Conclusions: Improvement in SQ is associated with improvements in LBP and in disability at 3-month follow-up, suggesting that they may reflect or be influenced by common factors. However, baseline SQ does not predict improvements in pain or disability., Significance: In clinical practice, sleep quality, low back pain and disability are associated. However, sleep quality at baseline does not predict improvement in pain and disability., (© 2017 European Pain Federation - EFIC®.)

Huntington's disease (HD) is a neurodegenerative disorder which is primarily associated with striatal degeneration. However, the alterations in connectivity of this structure in HD have been underinvestigated. In this study, we analyzed the functional and structural connectivity of the left putamen, while participants performed a finger-tapping task. Using fMRI and DW-MRI, 30 HD gene expansion carriers (HDGEC) and 29 healthy participants were scanned. Psychophysiological interaction analysis and DTI-based tractography were employed to examine functional and structural connectivity, respectively. Manifest HDGEC exhibited a reduced functional connectivity of the left putamen with the left and the right primary sensorimotor areas (SM1). Based on this result, the inhibitory functional connectivity between the left SM1 and the right SM1 was explored, appearing to be also decreased. In addition, the tract connecting these areas (motor corpus callosum), and the tract connecting the left putamen with the left SM1 appeared disrupted in HDGEC compared to controls. Significant correlations were found between measures of functional and structural connectivity of the motor corpus callosum, showing a coupling of both types of alterations in this tract. The observed reduction of functional and structural connectivity was associated with worse motor scores, which highlights the clinical relevance of these results. Hum Brain Mapp 39:54-71, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Objective: The objective was to determine the effect of frailty on risk of 30-day mortality in nonseverely disabled older patients with acute heart failure (AHF) attended in emergency departments (EDs)., Methodology: The Frailty-AHF Study is a retrospective analysis of a multicenter, observational, prospective, cohort study (Older-AHF Register). This study included consecutive patients ≥ 65 years of age without severe functional dependence or dementia attended for AHF in three Spanish EDs for 4 months. Frailty was defined by frailty phenotype as the presence of three or more domains. Baseline and episode characteristics and 30-day mortality were collected in all the patients., Results: A total of 465 patients with a mean (±SD) age of 82 (±7) years were included, 283 (61.0%) being female and 225 (51.3%) with severe comorbidity (Charlson index ≥ 3). Frailty was present in 169 (36.3%). The rate of 30-day mortality was 7.3%. Frailty adjusted for potential confounding factors was an independent factor associated with 30-day mortality (adjusted hazard ratio = 2.5; 95% confidence interval = 1.0 to 6.0; p = 0.047)., Conclusion: The presence of frailty is an independent risk factor of 30-day mortality in nonsevere dependent older patients attended with AHF in EDs., (© 2016 by the Society for Academic Emergency Medicine.)

Aims: Prevention of hospital readmissions is one of the main objectives in the management of patients with heart failure (HF). Most of the models predicting readmissions are based on data extracted from hospitalized patients rather than from outpatients. Our objective was to develop a validated score predicting 1-month and 1-year risk of readmission for worsening of HF in ambulatory patients., Methods and Results: A cohort of 2507 ambulatory patients with chronic HF was prospectively followed for a median of 3.3 years. Clinical, echocardiographic, ECG, and biochemical variables were used in a competing risk regression analysis to construct a risk score for readmissions due to worsening of HF. Thereafter, the score was externally validated using a different cohort of 992 patients with chronic HF (MUSIC registry). Predictors of 1-month readmission were the presence of elevated natriuretic peptides, left ventricular (LV) HF signs, and estimated glomerular filtration rate (eGFR) <60 mL/min/m(2) . Predictors of 1-year readmission were elevated natriuretic peptides, anaemia, left atrial size >26 mm/m(2) , heart rate >70 b.p.m., LV HF signs, and eGFR <60 mL/min/m(2) . The C-statistics for the models were 0.72 and 0.66, respectively. The cumulative incidence function distinguished low-risk (<1% event rate) and high-risk groups (>5% event rate) for 1-month HF readmission. Likewise, low-risk (7.8%), intermediate-risk (15.6%) and high-risk groups (26.1%) were identified for 1-year HF readmission risk. The C-statistics remained consistent after the external validation (<5% loss of discrimination)., Conclusion: The Redin-SCORE predicts early and late readmission for worsening of HF using proven prognostic variables that are routinely collected in outpatient management of chronic HF., (© 2015 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: There is evidence supporting the effectiveness of psychoeducation (PE) in patients with symptoms of depression in primary care (PC), but very few studies have assessed this intervention in antidepressant-naïve patients. The aim of this study is to assess the effectiveness of a PE program in these patients, since the use of antidepressant (AD) medication may interfere with the effects of the intervention., Methods: 106 participants were included, 50 from the PE program (12 weekly 1.5-hour sessions) and 56 from the control group (CG) that received the usual care. Patients were assessed at baseline and at 3, 6, and 9 months. The main outcome measures were the Beck Depression Inventory (BDI) and remission based on the BDI. The analysis was carried out on an intention-to-treat basis., Results: The PE program group showed remission of symptoms of 40% (P = 0.001) posttreatment and 42% (P = 0.012) at 6 months. The analysis only showed significant differences in the BDI score posttreatment (P = 0.008; effect size Cohen's d' = 0.55)., Conclusions: The PE intervention is an effective treatment in the depressive population not treated with AD medication. Before taking an AD, psychoeducational intervention should be considered.

Objective: Suffering frequently occurs in the context of chronic and progressive medical illnesses and emerges with great intensity at end-of-life. A review of the literature on suffering and distress-related factors was conducted to illustrate the integrative nature of suffering in this context. We hope it will result in a comprehensive approach, centered in the patient-family unit, which will alleviate or eliminate unnecessary suffering and provide well-being, when possible., Methods: An extensive search of the literature on suffering and distress in end-of-life patients was conducted. While the present review is not a systematic one, an in-depth search using the terms 'Suffering', 'Distress', End-of-Life', 'Palliative Care', and 'Terminal illness' was conducted using search engines such as PubMed, PsycINFO, MEDLINE, EBSCO-Host, OVID, and SciELO., Results: Taking into account the comprehensive and integrative nature of suffering, factors related to the physical, psychological, spiritual, and social human dimensions are described. As well, some treatment considerations in the palliative care context are briefly discussed., Conclusions: Suffering is individual, unique, and inherent to each person. Assessment processes require keeping in mind the complexity, multi-dimensionality, and subjectivity of symptoms and experiences. Optimal palliative care is based on continuous and multidimensional evaluation and treatment of symptoms and syndromes. It should take place in a clinical context where the psychological, spiritual, and socio-cultural needs of the patient-family unit are taken care of simultaneously. A deep knowledge of the nature of suffering and its associated factors is central to alleviate unnecessary suffering., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: The aim of this study was to ascertain the outcome of liver transplantation (LT) due to hepatocellular carcinoma (HCC) in patients who had undergone previous liver resection (LR) for HCC., Methods: A case-control study (1:2) was designed to compare patients who underwent LT due to HCC recurrence with a previous LR for HCC (study group) with those who underwent LT for primary HCC but without previous LR (control group)., Results: From January 1990 to December 2007, a total of 303 cirrhotic patients with primary HCC were evaluated for surgery. Primary LT was performed in 191 and LR in 100. When HCC recurrence was diagnosed after LR (69/100), 17 of the 69 (25%) patients underwent LT (study group). The median follow-up was 70 months (12.7-203.0 months). Disease-free survivals at 1, 3, and 5 years in the study group versus the control group were 86%, 68%, 58% vs. 97%, 93%, 89%, respectively (p < 0.04). The 1-, 3-, and 5-year actuarial patient survivals in the study group versus the control group were 59%, 52%, 52% vs. 85%, 76%, 65%, respectively (p = NS). Patients of the study group were divided into two groups according to the time to recurrence after LR: group 1 was <1 year, and group 2 was >1 year. Recurrence after LT was 75% in group 1 vs. 15.4% in group 2 (p < 0.03). The 1-, 3-, and 5-year actuarial patient survivals were 25%, 0%, 0% in group 1 and 69%, 69%, 69% in group 2, p < 0.02)., Conclusions: Liver transplantation can be safely performed after a previous LR for HCC. Patients with recurrence during the first year after hepatectomy have a poor prognosis after LT.

The role of a hemiparasitic life-style in plant resistance to toxic trace elements in polluted soils is unclear. Restriction of metal uptake by the host, restriction of metal transfer from host to parasite, or transformation of metals into a less toxic form may play a role. This study analysed the transfer of selected mineral elements from soil to host (Cistus spp.) and from host to hemiparasite (Odontites lutea) at locations with different metal burdens: a Cu-rich serpentine site, Pb-Ba mine spoil and an unpolluted soil. Highest soil-to-host transfer factors for K, Mg, Ca, Zn, Cu and Pb were observed on the unpolluted soil. Statistically significant differences among locations of host-to-parasite transfer factors were only found for Ca and Pb. Restriction of transfer of unfavourable Ca/Mg ratios, characteristic at the serpentine site, and of high Pb and Zn concentrations at the Pb-Ba mine occurred mainly at the soil-host, and not at the host-parasite, level. Odontites lutea was able to withstand enhanced Zn and Pb concentrations and low Fe/Cu ratios in shoot tissue without developing toxicity symptoms. This could be caused by specific metal resistance mechanisms in this hemiparasite and/or the transformation and transfer of these metals into a less toxic form by the metal-tolerant host.

This article examines the relation between dieting and non-dieting adolescent girls and body mass index (BMI), eating attitudes and the influence of the aesthetic body shape model. Three hundred forty-nine Spanish adolescent girls in their second year of secondary education were selected. The research design was a cross-sectional ex post facto study and validated measures were used to assess the main variables. Fourteen per cent of the sample was on a diet. Of this group, 69% were overweight, 70% had disordered eating attitudes and 70% were influenced by the current aesthetic body shape model. In all situations, the scores for dieters were significantly higher than those for non-dieters. Although there is not yet any clear consensus with regards to how adolescents interpret the term 'diet', the results indicate major differences between dieters and non-dieters and that those who self-report that they are on a diet present elements of the risk of developing eating and weight disorders., ((c) 2007 John Wiley & Sons, Ltd and Eating Disorders Association)

Background: Clinical studies suggest that tramadol-induced analgesia is partially antagonized by ondansetron., Aims: To investigate the type of interaction between tramadol and two anti-emetics on antinociception and gastrointestinal transit in mice., Methods: We assessed the antinociceptive (acetic acid writhing test, plantar test) and antitransit (charcoal meal) effects of tramadol individually, and combined with ondansetron or droperidol in female Swiss CD-1 mice. Isobolograms and analysis of variance were used to determine the type of interaction., Results: In the writhing test, tramadol, ondansetron and droperidol, each induced dose-related inhibition of nociception. The ED(50)'s were: tramadol 4.2+/-0.33 mg kg(-1); ondansetron 1.03+/-0.05 mg kg(-1), and droperidol 1.00+/-0.14 mg kg(-1). Dose-response curves were also obtained with tramadol combined with ondansetron or droperidol at 1:1 fixed ratios. The isobolographic analysis demonstrated antagonism for both combinations. In the plantar test, the ED(50) for tramadol was 51.4+/-2.3 mg kg(-1), but no dose-response curves could be obtained with ondansetron or droperidol individually. The interaction was assessed from dose-response curves to tramadol in the presence of a fixed dose of ondansetron (0.1 mg kg(-1)) or droperidol (0.05 mg kg(-1)). The results show antagonism between tramadol-ondansetron (p<0.05) and no interaction for the tramadol-droperidol combination. Both anti-emetics antagonized the antitransit effects of tramadol., Conclusions: The interaction of tramadol with ondansetron or droperidol on antinociception can be antagonistic or additive, depending on the type of stimuli. Both anti-emetics antagonize the anti-transit effects of tramadol. The results demonstrate antagonism between tramadol and the two anti-emetics for analgesia and inhibition of gastrointestinal transit, supporting previous clinical studies.

Alcoholic fermentation under Saccharomyces cerevisiae yeasts is governed largely by glucose uptake, biomass formation, ethanol and glycerin production, and acidification. In this work, PLS calibration models were developed with a view to determining these analytical parameters from near infrared spectra and analytical data provided by the corresponding reference methods. The models were applied to a set of samples obtained from various fermentation processes. The glucose, ethanol, and biomass values predicted by the models exhibited a high correlation with those provided by the reference method., ((c) 2004 Wiley Periodicals, Inc)

Liver transplantation (LT) for malignant tumors should be accepted if, with adequate case selection, long-term results are similar to those in patients transplanted for benign diseases. The aim of the present study was to reexamine selection criteria for LT in malignant diseases with particular emphasis on hepatocellular carcinoma (HCC) in cirrhosis. One hundred-three of 369 patients transplanted in our unit had HCC in cirrhosis (28%), 15 of which were incidental tumors, and 234 patients underwent LT for non-cholestatic cirrhosis. Pretransplant arterial chemoembolization(TACE) was performed in 36 cases (41%) of known HCC. Only early,well-delimited tumors in advanced cirrhosis with no extrahepatic disease were accepted for LT. Hepatocellular carcinoma characteristics included mean tumor size (3.1 cm), multiple (59%), bilobular involvement (31%), and vascular invasion (9.2%). Postoperative mortality was 4%. Median follow-up was 67.5 months. Tumor recurrence rate was 14.5%, 33% (5/15) in incidental tumors and 11.4% (10/88) in known HCC and by tumor stage (pTNM): 7.7% (1/13) in stage I, 16.7%(5/30) in stage II, 15% (3/20) in stage III, and 17% (6/35) in stage IV. Mean time for recurrence was 20.6 months. Tumoral vascular invasion, tumor differentiation, and satellite tumors were significant factors for tumor recurrence in univariate analysis, whereas tumor vascular invasion was the only significant factor for tumor recurrence in multivariate analysis. Actuarial survival rates at 1, 3, and 5 years were 81%, 66%, 58%, respectively, in patients with HCC and were similar to those of cirrhotic patients 76%, 67%, 63%, respectively. In conclusion, patients with early HCC in cirrhosis are good candidates for LT; results are similar when compared with those of cirrhotic patients without tumor. Liver transplantation for other malignancies is admitted only in fibrolamellar hepatoma, hepatoblastoma, epithelioid hemangioendothelioma without extrahepatic disease, and in metastases from carcinoid tumors.

Percutaneous washes of the guttural pouches were obtained from two groups of 15 clinically normal horses, one lightly exercised and the other heavily exercised. Microbiological and cytological studies showed a wide variation in the differential cell counts. The cytological pattern of the normal lavages (< 5 per cent neutrophils) was characterised by a large proportion of ciliated columnar epithelial cells, a few non-ciliated cuboidal epithelial cells, and less than 1 per cent monocytes, lymphocytes, and eosinophils. Abnormal lavages (with more than 5 per cent neutrophils) had higher levels of bacterial growth than normal lavages. There were significant differences between the bacterial growth and total cell count, and also between the neutrophil contents of the lavages from the two groups of horses.

Background: Pain, one of the most frequent symptoms of lung cancer, is difficult to control at times, not only because of the many structures involved but also because of the paths through which the pain is conveyed., Methods: When usual analgesic treatment did not alleviate pain after chemotherapy in a patient with lung adenocarcinoma, long-term interpleural analgesia was begun. A DuPen epidural catheter was inserted between the pleura parietalis and visceralis for the administration of bupivacaine in a bolus regimen every 6 hours., Results: Thoracic pain thus was controlled until the patient died 130 days after placement., Conclusions: The long-term tunneled interpleural placement of DuPen catheters constitutes an alternative to systemic and spinal treatments for thoracic pain due to cancer.

Twenty-five untreated patients with extensive stage small cell lung cancer (ESSCLC) were treated with carboplatin (CBDCA) (500 mg/m2) given as a 24-hour infusion every 21 days. Thirteen patients responded for an overall response rate of 52% (95% confidence limits, 32% to 72%) with 3 complete responses (CR) (12%; 95% confidence limits, 0% to 25%). The median duration of response was 4.5 months. The median survival time was 8 months with three long-term survivors (12%) at 27, 33, and 43 months from the start of CBDCA treatment. Ninety-two courses of CBDCA were administered and one treatment-related death occurred. The main toxicity was myelosuppression. Grade 3 or 4 hematologic toxicity (hemoglobin level, less than 8 g/dl; granulocyte count, less than 1900/microliters; and platelet count, less than 49,000/microliters) was observed as follows: neutropenia in 7 courses (8%) and in 7 patients (28%), decreased hemoglobin level in 13 courses (15%) and in 7 patients (28%), and decreased platelet count in 10 courses (11%) all Grade 3 and in 8 patients (32%). This study demonstrates that at this dose and schedule CBDCA is a highly active drug in ESSCLC and it has tolerable toxicity.

Fourteen patients with malignant ovarian germ cell tumors were treated postoperatively with a short-term, sequential regimen combining cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, etoposide, Adriamycin (Adria Laboratories, Columbus, OH), and vinblastine (POMB/ACE/PAV). Two patients had Stage I disease, Five had Stage II, five had Stage III, and two had Stage IV. The histologic diagnosis was immature teratoma in five cases (two cases were Grade 2 and three cases were Grade 3) endodermal sinus tumor in two cases, dysgerminoma in three cases, and mixed germ cell tumors in four cases. The chemotherapy regimen appeared to be highly effective against all histologic types, including advanced stages, with 12 of 14 (86%) overall sustained remissions. The median duration of treatment was 5 months. The toxicity of the regimen, which contained low total doses of cisplatin and bleomycin, was only moderate. After a median follow-up of 53+ months, 13 patients were alive without evidence of disease. The results and toxicity obtained were compared with those from other currently used regimens. Also, some comments on initial surgery and second-look surgery are given.

The reversal of acute alcohol intoxication by naloxone is controversial. Naloxone increases cortisol secretion but there are no reports of this effect during acute alcohol intoxication. This study examines the effect of 20 mg naloxone on alcohol-induced intoxication using a balanced placebo design to investigate the role of cortisol, participant expectancy of treatment, and possible pharmacokinetic interactions during intoxication. Our results show differences in the time course of subjective self-evaluation of drunkenness in the presence of naloxone. Also, changes are observed in naloxone pharmacokinetic parameters with the ingestion of alcohol, specifically a decrease in plasma clearance. Whereas the cortisol response induced by naloxone was greater in the subgroup of participants with positive expectancy, in the presence of alcohol the naloxone effect on cortisol response was not observed. These observations may help explain the observed reversal of alcohol-induced coma by naloxone in a subgroup of patients.

A 48-year-old man became erythrodermatous after intramuscular administration of ribostamycin, an aminoglycoside antibiotic in the same family as neomycin. Patch tests were positive to ribostamycin and neomycin, as well as to mercurials. There was no mercurial preservative in the injection solution. A lymphocyte transformation test was positive for ribostamycin and tobramycin, but not for gentamycin. Diagnostic and structure-activity relationship aspects of the case are discussed.