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Abstract Inflammation is relevant in the pathogenesis and progression of heart failure (HF). Previous studies have shown that elevated high-sensitivity C-reactive protein (hsCRP) are associated with greater severity and may be associated with adverse outcomes. In this study, we sought to evaluate the prognostic role of hsCRP in a non-selected cohort of patients with acute HF. We prospectively included a multicenter cohort of 3,395 patients following an admission for acute HF. HsCRP levels were evaluated during the first 24 h following admission. Study endpoints were the risks of all-cause mortality, CV-mortality, and total HF readmissions. The mean age was 74.2 ± 11.2 years and 1,826 (53.8%) showed a left ventricular ejection fraction (LVEF) ≥ 50%. Median hsCRP was 12.9 mg/L (5.4–30 mg/L). Over a median follow-up of 1.8 (0.6–4.1) years, 1,574 (46.4%) patients died, and 1,341 (39.5%) patients were readmitted for worsening HF. After multivariable adjustment, hsCRP values were significantly and positively associated with a higher risk of all-cause and CV mortality (p = 0.003 and p = 0.001, respectively), as well as a higher risk of recurrent HF admissions (p

Abstract The exploration of metal–insulator transitions to produce field-induced reversible resistive switching effects has been a longstanding pursuit in materials science. Although the resistive switching effect in strongly correlated oxides is often associated with the creation or annihilation of oxygen vacancies, the underlying mechanisms behind this phenomenon are complex and, in many cases, still not clear. This study focuses on the analysis of the superconducting performance of cuprate YBa2Cu3O7−δ (YBCO) devices switched to different resistive states through gate voltage pulses. The goal is to evaluate the effect of field-induced oxygen diffusion on the magnetic field and angular dependence of the critical current density and identify the role of induced defects in the switching performance. Transition electron microscopy measurements indicate that field-induced transition to high resistance states occurs through the generation of YBa2Cu4O7 (Y124) intergrowths with a large amount of oxygen vacancies, in agreement with the obtained critical current density dependences. These results have significant implications for better understanding the mechanisms of field-induced oxygen doping in cuprate superconductors and their role on the superconducting performance.

Abstract Circulating antigen carbohydrate 125 (CA125) has emerged as a proxy of fluid overload in heart failure. This study aimed to evaluate the effect of dapagliflozin on short-term CA125 levels in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effects on peak oxygen consumption (peakVO2). This study is a post-hoc sub-analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin or placebo to evaluate change in peakVO2 (NCT04197635). We used linear mixed regression analysis to compare changes in the natural logarithm of CA125 (logCA125) and percent changes from baseline (Δ%CA125). We used the “rwrmed” package to perform mediation analyses. CA125 was available in 87 patients (96.7%). LogCA125 significantly decreased in patients on treatment with dapagliflozin [1-month: Δ − 0.18, (CI 95% = − 0.33 to − 0.22) and 3-month: Δ − 0.23, (CI 95% = − 0.38 to − 0.07); omnibus p-value = 0.012]. Δ%CA125 decreased by 18.4% and 31.4% at 1 and 3-month, respectively (omnibus p-value = 0.026). Changes in logCA125 mediated the effect on peakVO2 by 20.4% at 1 month (p

BackgroundColonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection.Methods and findingsThis open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases ConclusionsIn this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs.Trial registrationThis trial was registered with ClinicalTrials.gov (NCT02567045).

Los cuidados invisibles se engloban en la práctica de los cuidados y se relacionan con la parte emocional, la humanización y la trascendencia. Es la parte no técnica, pero que acompaña a los diferentes procedimientos y técnicas de unos cuidados profesionalizados. Objetivo. Analizar los cuidados que realizan los profesionales de enfermería sobre las dimensiones de los cuidados invisibles para un mayor conocimiento y reconocimiento de estos, por los profesionales y la institución. Metodología. Se trata de una investigación mixta. Una parte, con un diseño cualitativo fenomenológico, y otra, con un diseño observacional descriptivo y transversal. Los participantes implicados serán los pacientes y los profesionales de enfermería de las diferentes unidades y servicios del Hospital Universitario Son Espases. Para la recogida de los datos cualitativos se utilizará la entrevista grupal para explorar la percepción de los cuidados invisibles. Para la recogida de los datos cuantitativos se utilizará la herramienta Microsoft Forms 365® para la recogida de las respuestas del cuestionario de percepción del cuidado invisible de enfermería (PCIE, dirigido a los pacientes), y el cuestionario Care-Q que evalúa las dimensiones de los cuidados invisibles y el cuestionario ad hoc para identificar acciones de cuidados invisibles (dirigidos a los profesionales). Posteriormente, se implantará en el programa Millennium® para el registro de los cuidados invisibles en los planes de cuidados y visibilizar el valor que representan en el cuidado global y el tiempo dedicado en la jornada laboral. Abstract Invisible care is included in the practice of care and is related to the emotional part, humanization and transcendence. It is the non-technical part, but it accompanies the different procedures and techniques of professionalized care. Objective. Analyze the care provided by nursing professionals on the dimensions of invisible care for greater knowledge and recognition of these, by professionals and the institution. Methodology. It is a mixed investigation. One part, with a qualitative phenomenological design, and another, with a descriptive and cross-sectional observational design. The participants involved will be the patients and nurses from the different units and services of the Son Espases University Hospital (HUSE). For the collection of qualitative data, the group interview will be used to explore the perception of invisible care. For the collection of quantitative data, the Microsoft Forms 365® tool will be used to collect the responses to the perception questionnaire of invisible nursing care (PCIE, aimed at patients), and the Care-Q questionnaire that evaluates the dimensions of invisible care and the ad hoc questionnaire to identify invisible care actions (aimed at nurses). Later, it will be implemented in the Millennium® program to record invisible care in care plans and make visible the value they represent in global care and the time spent during the workday.

Background Despite being the treatment of choice for phobic disorders, in vivo exposure treatment (IVET) presents some important limitations related mainly to low acceptance and high drop-out rates. Augmented reality (AR) technologies can help to overcome these limitations. Evidence supports the use of AR in exposure treatment for small animal phobia. A new projection-based AR exposure treatment system (P-ARET) that offers the possibility of projecting the animals in a natural and non-intrusive environment has been developed. There are no randomised controlled trials (RCTs) available that have tested the efficacy of this system in cockroach phobia. This paper aims to present the protocol of an RCT that evaluates the efficacy of the P-ARET, versus an IVET group and a waiting list control group (WL), in carrying out exposure treatment for cockroach phobia.Methods/design Participants will be randomly allocated to one of three conditions: (1) P-ARET, (2) IVET and (3) WL. Both treatment conditions will follow the ‘one-session treatment’ guidelines. As a diagnostic measure, the Anxiety Disorders Interview Schedule for Diagnostic and Statistical Manual for Mental Health Disorders-Version 5 will be used. The Behavioral Avoidance Test will be used as the primary outcome measure. Secondary outcome measures will include an attentional biases task (measured using eye-tracking technology), the Fear of Cockroaches Questionnaire, Cockroach Phobia Beliefs Questionnaire, Fear and Avoidance Scales, Beck Depression Inventory second edition, Disgust Propensity and Sensitivity Scale-Revised-12, State-Trait Anxiety Inventory, Clinician Severity Scale, and Expectation and Satisfaction with the Treatment Scale. The evaluation protocol will include pretreatment and post-treatment evaluations and 1, 6 and 12 months of follow-ups. Intention-to-treat and per-protocol analyses will be performed.Ethics and dissemination This study has been approved by the Ethics Committee of Universitat Jaume I (Castellón, Spain; 13 December 2019). The results of the presented RCT will be disseminated in presentations at international scientific meetings and peer-reviewed scientific journals.Trial registration number NCT04563390.

Introduction In vivo exposure is the treatment of choice for specific phobia (SP), but this technique presents limitations related to access and acceptability. Augmented reality (AR) offers advantages like maximising strategies such as ‘variability’ (varying stimuli, durations, levels of intensity or the order of the items), control by the therapist, or ‘exposure to multiple contexts’, which can produce positive effects in terms of fear renewal and generalisation of the results. The aim of this study is to test the efficacy of varying the phobic stimuli during treatment with AR: using multiple stimuli (MS) versus a single stimulus (SS) in participants with SP.Methods and analysis Participants (N=80) with a diagnosis of an SP of cockroaches will be randomised into two conditions: (1) projection-based AR exposure therapy with MS (P-ARET MS); (2) P-ARET with an SS (P-ARET SS). The measures are related to the efficacy results (fear, avoidance and negative thoughts, performance on the behavioural avoidance test (BAT) and preferences). The primary outcome measure is the BAT, and the secondary outcome measures are the BAT through AR, Fear of Cockroaches Questionnaire, Cockroach Phobia Beliefs Questionnaire, Fear and Avoidance Scales Patient’s Improvement Scale, and Beck Depression Inventory Second Edition. Five evaluation moments will be included: preintervention, postintervention, and 1-month, 6-month, and 12-month follow-ups. The treatment will follow the guidelines of the ‘one-session treatment’. Student’s t-tests to compare the two groups on the post-test will be applied. In addition, two-way analysis of variances with repeated measures in one of the two factors (pretest, post-test and follow-ups) will be carried out to compare intragroup differences.Ethics and dissemination The Universitat Jaume I Ethics Committee (Castellón, Spain) granted approval for the study (CD/64/2019). Dissemination will include publications and presentations at national and international conferences.Trial registration number NCT04563403.

The objectives of this review were to identify the population groups most frequently studied, to determine the methods and techniques most commonly used to show health inequities, and to identify the most frequent socioeconomic and health indicators used in the studies on health inequities due to socioeconomic inequalities that have been carried out on the Spanish healthcare system. A scoping review was carried out of the studies conducted in the Spanish State and published in literature since 2004, after the publication of the Law of Cohesion and Quality of the National Health System. The PRISMA extension for scoping reviews was followed. The methodological quality of the studies was assessed using the critical reading guides of the Joanna Briggs Institute and an adaptation of the STROBE guide for ecological studies. A total of 58 articles out of 811 articles were included. Most of the articles were (77.59%, n = 45) cross-sectional studies, followed by ecological studies (13.8%, n = 8). The population group used was uneven, while the main geographical area under investigation was the whole state (51.7%, n = 30) compared to other territorial distributions (48.3%, n = 28). The studies used a multitude of health and socioeconomic indicators, highlighting self-perception of health (31.03%, n = 19) and social class (50%, n = 29). The relationship between better health and better socioeconomic status is evident. However, there is variability in the populations, methods, and indicators used to study health equity in Spain. Future health research and policies require greater systematization by public institutions and greater cooperation among researchers from disciplines such as sociology, economics, and health.

Abstract We aimed to assess the association between CA125 and the long-term risk of total acute heart failure (AHF) admissions in patients with an index hospitalization with AHF and preserved ejection fraction (HFpEF). We prospectively included 2369 patients between 2008 and 2019 in three centers. CA125 and NT-proBNP were measured during early hospitalization and evaluated as continuous and categorized in quartiles (Q). Negative binomial regressions were used to assess the association with the risk of recurrent AHF admission. The mean age of the sample patients was 76.7 ± 9.5 years and 1443 (60.9%) were women. Median values of CA125 and NT-proBNP were 38.3 (19.0–90.0) U/mL, and 2924 (1590–5447) pg/mL, respectively. During a median follow-up of 2.2 (0.8–4.6) years, 1200 (50.6%) patients died, and 2084 AHF admissions occurred in 1029 (43.4%) patients. After a multivariate adjustment, CA125, but not NT-proBNP, was positively and non-linearly associated with the risk of cumulative AHF-readmission (p

Objetivo principal: Valorar los conocimientos, actitudes y motivaciones de los profesionales de enfermería en el Hospital Universitario Son Espases (HUSE) y Evaluar la actividad de la Unidad de Investigación de Enfermería (UINE) y su impacto en los profesionales de enfermería hacia la investigación Metodología: Diseño cuasi-experimental de grupos no equivalentes. Participarán una muestra estimada de 118 enfermeros/as del HUSE que cumplan unos criterios de selección. Los participantes contestarán a un cuestionario validado sobre conocimientos y motivaciones hacia la investigación enfermera. Se llevará a cabo mediante enlace google forms que se les enviará al correo corporativo. Las respuestas serán registradas automáticamente. Los datos recogidos serán analizados para obtener los resultados, presentar en congresos y elaborar posibles publicaciones. Resultados principales: se pretende que los resultados confirmen la hipótesis planteada y por tanto, se cumplan los objetivos planteados. Conclusión principal: Los/as enfermeros/as del HUSE adquirirán mayor conciencia, conocimientos y actitudes hacia la investigación enfermera. Esto provocará un cambio que fomentará que la práctica asistencial de los cuidados se fundamente en la evidencia científica la cual permita aproximarse a la excelencia de los cuidados. Palabras clave: cambio, cuidados, enfermera, investigación, hospital

For some decades now, theories on learning methodologies have advocated collaborative learning due to its good results in terms of effectiveness and learning types and its promotion of educational and social values. This means that teachers need to be able to apply different criteria when forming heterogeneous groups of students and to use automated techniques to assist them. In this study, we have created an approach based on complex network theory to design an algorithm called Minimum Entropy Collaborative Groupings (MECG) in order to form these heterogeneous groups more effectively. The algorithm was tested firstly under a synthetic framework and secondly in a real situation. In the first case, we generated 30 synthetic classrooms of different sizes and compared our approach with a genetic algorithm and a random grouping. In the latter case, the approach was tested on a group of 200 students on two subjects of a master's degree in teacher training. For each subject there were 4 large groups of 50 students each, in which collaborative groups of 4 students were created. Two of these large groups were used as random groups, another group used the CHAEA test and the fourth group used the LML test. The results showed that the groups created with MECG were more effective, had less uncertainty and were more interrelated and mature. It was observed that the randomized groups did not obtain significantly better LML results and that this cannot be related to any emotional or motivational effect because the students performed the test as a placebo measure. In terms of learning styles, the results were significantly better with LML than with CHAEA, whereas no significant difference was observed in the randomized groups.

Background Fatigue and exercise intolerance are the most common symptoms in patients with long COVID.Aims This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) programme improves maximal functional capacity in patients’ long COVID after a previous admission due to SARS-CoV-2 pneumonia.Methods This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week IMT or usual care alone (NCT05279430). The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention.The primary endpoint was the change in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints.Results The mean age of the sample and time to first visit after discharge were 50.4±12.2 years and 362±105 days, respectively. A total of 11 (42.3%) were female. At baseline, the mean of peakVO2, ventilatory efficiency and CIx were 18.9±5 mL/kg/min, 29.4±5.2 and 0.64±0.19, respectively. The IMT arm improved their peakVO2 significantly compared with usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p

Background: Nowadays, burnout syndrome (BS) symptoms appear to have increased in healthcareworkers, specifically midwives, but there are no studies on burnout among midwives in Catalonia. Thepresent study aimed to assess and describe the prevalence of BS in midwives working in labour rooms.Methods: A cross-sectional descriptive study was conducted on 122 midwives working in 24 maternityhospitals in the Barcelona (region) which were selected using purposive sampling from January toMarch 2017. Data were collected using two questionnaires (demographic information, job burnoutusing Spanish Burnout Inventory with 20 items and four subscales). Data analysis was performedusing SPSS software version 21 and Chi-Square, U Mann-Whitney, and Kruskall-Wallis. p considered statistically significant.Results: None of the participants obtained a critical level of BS. 37 (30.33%) participants scoredmedium burnout and 47 (38.52%) recorded low burnout. Statistically, work stress (P=0.01), maritalstatus (P=0.006), attendance of more than three women per shift (P=0.001), the number of children(P=0.01), parity (P=0.005), health status (P=0.04), and being on sick leave over last year (P=0.04) weresignificantly correlated with medium-high levels of burnout. Burnout scores were higher in midwiveshaving a life partner and those without children.Conclusion: Following the results, no participant obtained a critical level of BS; about one-third ofthem scored medium-high burnout. However, specific interventions are suggested to be conducted tomaintain the midwives’ motivation and prevent burnout development.

Abstract Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.

Abstract Background Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a

Abstract The functional properties of cuprates are strongly determined by the doping state and carrier density. We present an oxygen doping study of YBa2Cu3O7-δ (YBCO) thin films from underdoped to overdoped state, correlating the measured charge carrier density, $${n}_{\mathrm{H}}$$ n H , the hole doping, p, and the critical current density, $${J}_{c}$$ J c . Our results show experimental demonstration of strong increase of $${J}_{c}$$ J c with $${n}_{\mathrm{H}}$$ n H , up to Quantum Critical Point (QCP), due to an increase of the superconducting condensation energy. The ultra-high $${J}_{c}$$ J c achieved, 90 MA cm−2 at 5 K corresponds to about a fifth of the depairing current, i.e. a value among the highest ever reported in YBCO films. The overdoped regime is confirmed by a sudden increase of $${n}_{\mathrm{H}}$$ n H , associated to the reconstruction of the Fermi-surface at the QCP. Overdoping YBCO opens a promising route to extend the current carrying capabilities of rare-earth barium copper oxide (REBCO) coated conductors for applications.

Abstract Background The optimal distribution between physical activity (PA) levels and sedentary behaviour (SB) for the greatest benefits for body composition among older adults with overweight/obesity and chronic health conditions remains unclear. We aimed to determine the prospective association between changes in PA and in SB with concurrent changes in body composition and to examine whether reallocating inactive time into different physical activity levels was associated with 12-month change to body composition in older adults. Methods Longitudinal assessment nested in the PREDIMED-Plus trial. A subsample (n = 1564) of men and women (age 55–75 years) with overweight/obesity and metabolic syndrome from both arms of the PREDIMED-Plus trial was included in the present analysis. Participants were followed up at 6 and 12 months. Physical activity and SB were assessed using validated questionnaires. Out of 1564 participants, 388 wore an accelerometer to objectively measure inactive time and PA over a 7-day period. At each time point, participants’ body composition was measured using dual-energy X-ray absorptiometry (DXA). Standard covariate-adjusted and isotemporal substitution modelling were applied to linear mixed-effects models. Results Increasing 30 min of total PA and moderate-to-vigorous physical activity (MVPA) was associated with significant reductions in body fat (β − 0.07% and − 0.08%) and visceral adipose tissue (VAT) (− 13.9 g, and − 15.6 g) at 12 months (all p values

Abstract Objectives The Brown trout is a salmonid species with a high commercial value in Europe. Life history and spawning behaviour include resident (Salmo trutta m. fario) and migratory (Salmo trutta m. trutta) ecotypes. The main objective is to apply RNA-seq technology in order to obtain a reference transcriptome of two key tissues, brain and muscle, of the riverine trout Salmo trutta m. fario. Having a reference transcriptome of the resident form will complement genomic resources of salmonid species. Data description We generate two cDNA libraries from pooled RNA samples, isolated from muscle and brain tissues of adult individuals of Salmo trutta m. fario, which were sequenced by Illumina technology. Raw reads were subjected to de-novo transcriptome assembly using Trinity, and coding regions were predicted by TransDecoder. A final set of 35,049 non-redundant ORF unigenes were annotated. Tissue differential expression analysis was evaluated by Cuffdiff. A False Discovery Rate (FDR) ≤ 0.01 was considered for significant differential expression, allowing to identify key differentially expressed unigenes. Finally, we have identified SNP variants that will be useful tools for population genomic studies.

Abstract Abnormalities in actin cytoskeleton have been linked to Friedreich’s ataxia (FRDA), an inherited peripheral neuropathy characterised by an early loss of neurons in dorsal root ganglia (DRG) among other clinical symptoms. Despite all efforts to date, we still do not fully understand the molecular events that contribute to the lack of sensory neurons in FRDA. We studied the adult neuronal growth cone (GC) at the cellular and molecular level to decipher the connection between frataxin and actin cytoskeleton in DRG neurons of the well-characterised YG8R Friedreich’s ataxia mouse model. Immunofluorescence studies in primary cultures of DRG from YG8R mice showed neurons with fewer and smaller GCs than controls, associated with an inhibition of neurite growth. In frataxin-deficient neurons, we also observed an increase in the filamentous (F)-actin/monomeric (G)-actin ratio (F/G-actin ratio) in axons and GCs linked to dysregulation of two crucial modulators of filamentous actin turnover, cofilin-1 and the actin-related protein (ARP) 2/3 complex. We show how the activation of cofilin is due to the increase in chronophin (CIN), a cofilin-activating phosphatase. Thus cofilin emerges, for the first time, as a link between frataxin deficiency and actin cytoskeleton alterations.

Introduction Exercise intolerance and fatigue are the most common symptoms in patients with chronic COVID-19 after hospital discharge. Supervised exercise training programmes improve symptoms, but scarce research has been done on home-based exercise programmes on the maximal functional capacity for discharged symptomatic COVID-19 patients. This study evaluates whether a home-based inspiratory muscle training (IMT) programme improves maximal functional capacity in chronic COVID-19 after hospital admission.Methods and analysis This single-centre, assessor-blinded randomised controlled trial, powered for superiority, seeks to evaluate maximal functional capacity as the primary endpoint. A total of 26 eligible patients with a previous admission for acute respiratory syndrome coronavirus 2 pneumonia (>3 months after hospital discharge) will be randomised (1:1) to receive a 12-week programme of IMT versus usual care alone. A blinded assessor will measure outcomes at baseline and after the intervention (12 weeks). An analysis of variance will be used to compare continuous outcomes among the two-intervention groups. As of 21 March 2022, eight patients have been enrolled.Ethics and dissemination The research ethics committee (Comité Ético de Investigación con Medicamentos de l'Hospital Clínic Universitari de València) approved the protocol following the principles of the Declaration of Helsinki and national regulations (Approval Number: 021/226). Findings will be published in peer-reviewed journals and conference publications.Trial registration number NCT05279430.

Cancer is the leading cause of death in dogs, yet there are no established screening paradigms for early detection. Liquid biopsy methods that interrogate cancer-derived genomic alterations in cell-free DNA in blood are being adopted for multi-cancer early detection in human medicine and are now available for veterinary use. The CANcer Detection in Dogs (CANDiD) study is an international, multi-center clinical study designed to validate the performance of a novel multi-cancer early detection “liquid biopsy” test developed for noninvasive detection and characterization of cancer in dogs using next-generation sequencing (NGS) of blood-derived DNA; study results are reported here. In total, 1,358 cancer-diagnosed and presumably cancer-free dogs were enrolled in the study, representing the range of breeds, weights, ages, and cancer types seen in routine clinical practice; 1,100 subjects met inclusion criteria for analysis and were used in the validation of the test. Overall, the liquid biopsy test demonstrated a 54.7% (95% CI: 49.3–60.0%) sensitivity and a 98.5% (95% CI: 97.0–99.3%) specificity. For three of the most aggressive canine cancers (lymphoma, hemangiosarcoma, osteosarcoma), the detection rate was 85.4% (95% CI: 78.4–90.9%); and for eight of the most common canine cancers (lymphoma, hemangiosarcoma, osteosarcoma, soft tissue sarcoma, mast cell tumor, mammary gland carcinoma, anal sac adenocarcinoma, malignant melanoma), the detection rate was 61.9% (95% CI: 55.3–68.1%). The test detected cancer signal in patients representing 30 distinct cancer types and provided a Cancer Signal Origin prediction for a subset of patients with hematological malignancies. Furthermore, the test accurately detected cancer signal in four presumably cancer-free subjects before the onset of clinical signs, further supporting the utility of liquid biopsy as an early detection test. Taken together, these findings demonstrate that NGS-based liquid biopsy can offer a novel option for noninvasive multi-cancer detection in dogs.

BackgroundPreterm newborns can be exposed early to significant perinatal stress, and this stress can increase the risk of altered socioemotional development. Sustained social withdrawal in infants is an early indicator of emotional distress which is expressed by low reactivity to the environment, and if persistent, is frequently associated with altered psychological development. Infants born prematurely have a higher probability of developing sustained social withdrawal (adjusted odds ratio 1.84, 95% CI 1.04-3.26) than infants born full term, and there is a correlation between weight at birth and sustained social withdrawal at 12 months of age. ObjectiveThe aims of this study are to compare the effect of the interactive guidance intervention to that of routine pediatric care on sustained social withdrawal in infants born moderately or late preterm and to explore the relationship between sustained social withdrawal in these infants and factors such as neonatal intensive care unit hospitalization variables, parental depression, and posttraumatic stress symptoms. MethodsThis study is designed as a multicenter randomized controlled trial. Moderate and late preterm newborns and their parents were recruited and randomized (1:1 allocation ratio) to control and experimental groups. During neonatal intensive care unit hospitalization, daily duration of skin-to-skin contact, breastfeeding, and parental visits were recorded. Also, a daily score for neonatal pain and painful invasive procedures were recorded. After discharge from neonatal intensive care, for the duration of the study, both groups will attend follow-up consultations with neonatologists at 2, 6, and 12 months of age (corrected for gestational age) and will receive routine pediatric care. Every consultation will be recorded and assessed with the Alarm Distress Baby Scale to detect sustained social withdrawal (indicated by a score of 5 or higher). The neonatologists will perform an interactive guidance intervention if an infant in the intervention group exhibits sustained social withdrawal. In each follow-up consultation, parents will fill out the Edinburgh Postnatal Depression Scale, the modified Perinatal Posttraumatic Stress Disorder Questionnaire, and the Impact of Event Scale–revised. ResultsRecruitment for this trial started in September 2017. As of May 2020, we have completed enrollment (N=110 infants born moderately or late preterm). We aim to publish the results by mid-2021. ConclusionsThis is the first randomized controlled trial with a sample of infants born moderately or late preterm infants who will attend pediatric follow-up consultations during their first year (corrected for gestational age at birth) with neonatologists trained in the Alarm Distress Baby Scale and who will receive this interactive guidance intervention. If successful, this early intervention will show significant potential to be implemented in both public and private health care, given its low cost of training staff and that the intervention takes place during routine pediatric follow-up. Trial RegistrationClinicalTrials.gov NCT03212547; https://clinicaltrials.gov/ct2/show/NCT03212547. International Registered Report Identifier (IRRID)DERR1-10.2196/17943

Newcastle Disease (ND) is a viral disease spread worldwide with a high impact on economy and animal welfare. Vaccination against Newcastle Disease is one of the main control measures in countries such as Germany with endemic occurrence of Newcastle Disease virus in the free ranging bird population. The German Standing Veterinary Committee on Immunization (StIKo Vet) recommends to revaccinate chickens at intervals of six weeks against Newcastle Disease with attenuated live vaccines via drinking water or spray in line with the SPCs (Summary of Product Characteristics) of current vaccines. However, it is still common practice to revaccinate only every twelve weeks because the SPCs of former vaccines proposed a revaccination after checking the antibody titer which based on practical knowledge was typically sufficient for twelve weeks. The aim of this study was to evaluate if a vaccination interval of twelve weeks against Newcastle Disease under field conditions results in sufficient seroconversion to protect flocks. Antibody titers of 810 blood samples from 27 backyard flocks of chickens were analyzed by ELISA- and HI-tests between 69 and 111 days after vaccination of the flocks with attenuated live vaccines of the ND strain Clone 30. Furthermore, data on the flocks such as breed, sex and age were collected through a questionnaire. In this study a sufficient antibody titer was found in 26 of these flocks. Therefore, a vaccination interval of every twelve weeks with the live vaccines tested is suitable for a vaccination protocol against Newcastle Disease. The lack of seroconversion of one flock also emphasizes the need for regular vaccination monitoring by serological testing and re-evaluation of the vaccination process if needed.

In Spain, systematic reporting of pulmonary infections with nontuberculous mycobacteria is not mandatory. Therefore, to determine trends, we retrospectively identified cases for January 1994–December 2014 in Catalonia. Over the 21 years, prevalence increased and was associated with being male. Mycobacterium avium complex and M. abscessus prevalence increased; M. kansasii prevalence decreased.

Abstract Atherosclerosis arises from leukocyte infiltration and thickening of the artery walls and constitutes a major component of vascular disease pathology, but the molecular events underpinning this process are not fully understood. Proteins containing an Asn-Gly-Arg (NGR) motif readily undergo deamidation of asparagine to generate isoDGR structures that bind to integrin αvβ3 on circulating leukocytes. Here we report the identification of isoDGR motifs in human atherosclerotic plaque components including extracellular matrix (ECM) proteins fibronectin and tenascin C, which have been strongly implicated in human atherosclerosis. We further demonstrate that deamidation of NGR motifs in fibronectin and tenascin C leads to increased adhesion of the monocytic cell line U937 and enhanced binding of primary human monocytes, except in the presence of a αvβ3-blocking antibody or the αv-selective inhibitor cilengitide. In contrast, under the same deamidating conditions monocyte-macrophages displayed only weak binding to the alternative ECM component vitronectin which lacks NGR motifs. Together, these findings confirm a critical role for isoDGR motifs in mediating leukocyte adhesion to the ECM via integrin αvβ3 and suggest that protein deamidation may promote the pathological progression of human atherosclerosis by enhancing monocyte recruitment to developing plaques.

Abstract Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.

Abstract Superconductivity and ferromagnetism are two antagonistic phenomena that combined can lead to a rich phenomenology of interactions, resulting in novel physical properties and unique functionalities. Here we propose an original hybrid system formed by a high-temperature superconducting film, patterned with antidots, and with ferromagnetic nano-rods grown inside them. This particular structure exhibits the synergic influence of superconductor (SC) - ferromagnetic (FM) stray fields, in both the superconducting behaviour of the film and the three-dimensional (3D) magnetic structure of nano-rods. We show that FM stray fields directly influence the critical current density of the superconducting film. Additional functionalities appear due to the interaction of SC stray fields, associated to supercurrent loops, with the non-trivial 3D remanent magnetic structure of FM nano-rods. This work unravels the importance of addressing quantitatively the effect of stray magnetic fields from both, the superconductor and the ferromagnet in hybrid magnetic nano-devices based on high temperature superconductors.

ObjectiveThe aims of this study were as follows. First, we sought to compare the in vitro susceptibility of liposomal amphotericin B (LAmB) and anidulafungin on Candida albicans and Candida glabrata biofilms growing on silicone discs. Second, we sought to compare the activity of LAmB versus anidulafungin for the treatment of experimental catheter-related C. albicans and C. glabrata infections with the antifungal lock technique in a rabbit model.MethodsTwo C. albicans and two C. glabrata clinical strains were used. The minimum biofilm eradication concentration for 90% eradication (MBEC90) values were determined after 48h of treatment with LAmB and anidulafungin. Confocal microscopy was used to visualize the morphology and viability of yeasts growing in biofilms. Central venous catheters were inserted into New Zealand rabbits, which were inoculated of each strain of C. albicans and C. glabrata. Then, catheters were treated for 48h with saline or with antifungal lock technique using either LAmB (5mg/mL) or anidulafungin (3.33mg/mL).ResultsIn vitro: anidulafungin showed greater activity than LAmB against C. albicans and C. glabrata strains. For C. albicans: MBEC90 of anidulafungin versus LAmB: CA176, 0.03 vs. 128 mg/L; CA180, 0.5 vs. 64 mg/L. For C. glabrata: MBEC90 of anidulafungin versus LAmB: CG171, 0.5 vs. 64 mg/L; CG334, 2 vs. 32 mg/L. In vivo: for C. albicans species, LAmB and anidulafungin achieved significant reductions relative to growth control of log10 cfu recovered from the catheter tips (CA176: 3.6±0.3 log10 CFU, p≤0.0001; CA180: 3.8±0.1 log10 CFU, p≤0.01). For C. glabrata, anidulafungin lock therapy achieved significant reductions relative to the other treatments (CG171: 4.8 log10 CFU, p≤0.0001; CG334: 5.1 log10 CFU, p≤0.0001).ConclusionsFor the C. albicans strains, both LAmB and anidulafungin may be promising antifungal lock technique for long-term catheter-related infections; however, anidulafungin showed significantly higher activity than LAmB against the C. glabrata strains.

Helicobacter pylori is a common pathogen associated with several severe digestive diseases. Although multiple virulence factors have been described, it is still unclear the role of virulence factors on H. pylori pathogenesis and disease progression. Whole genome sequencing could help to find genetic markers of virulence strains. In this work, we analyzed three complete genomes from isolates obtained at the same point in time from a stomach of a patient with adenocarcinoma, using multiple available bioinformatics tools. The genome analysis of the strains B508A-S1, B508A-T2A and B508A-T4 revealed that they were cagA, babA and sabB/hopO negative. The differences among the three genomes were mainly related to outer membrane proteins, methylases, restriction modification systems and flagellar biosynthesis proteins. The strain B508A-T2A was the only one presenting the genotype vacA s1, and had the most distinct genome as it exhibited fewer shared genes, higher number of unique genes, and more polymorphisms were found in this genome. With all the accumulated information, no significant differences were found among the isolates regarding virulence and origin of the isolates. Nevertheless, some B508A-T2A genome characteristics could be linked to the pathogenicity of H. pylori.

Frataxin (FXN) deficiency causes Friedreich’s ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

Despite the great efforts devoted to research on Helicobacter pylori, the prevalence of single-strain infection or H. pylori mixed infection and its implications in the mode of transmission of this bacterium are still controversial. In this study, we explored the usefulness of housekeeping gene amplicon sequencing in the detection of H. pylori microevolution and multiple infections. DNA was extracted from five gastric biopsies from four patients infected with distinct histopathological diagnoses. PCR amplification of six H. pylori-specific housekeeping genes was then assessed on each sample. Optimal results were obtained for the cgt and luxS genes, which were selected for amplicon sequencing. A total of 11,833 cgt and 403 luxS amplicon sequences were obtained, 2042 and 112 of which were unique sequences, respectively. All cgt and luxS sequences were clustered at 97% to 9 and 13 operational taxonomic units (OTUs), respectively. For each sample from a different patient, a single OTU comprised the majority of sequences in both genes, but more than one OTU was detected in all samples. These results suggest that multiple infections with a predominant strain together with other minority strains are the main way by which H. pylori colonizes the human stomach.

Dispersal is a critical determinant of animal distribution and population dynamics, and is essential information for management planning. We studied the movement patterns and the influence of habitat and biotic factors on Mediterranean brown trout (Salmo trutta) by mark-recapture methods in three headwater streams of the Ebro Basin (NE Iberian Peninsula). Fish were sampled by electrofishing on five occasions over 18–24 months and movements of over 3,000 individually tagged trout (age 1+ onwards) were recorded. Most of the tagged fish exhibited limited movement and were recaptured within 100 m from the initial capture section. Small seasonal differences in the movement pattern were observed, but in two of the streams, displacement distances increased prior the spawning period in autumn. The frequency distributions of dispersal distances were highly leptokurtic and skewed to the right and fitted well to a two-group exponential model, thus trout populations were composed of mobile and stationary individuals, the latter being the predominant component in the populations (71.1–87.5% of individuals). The mean dispersal distances, for fish captured at least in three sampling events, ranged 20.7–45.4 m for the stationary group and 229.4–540.5 m for the mobile group. Moving brown trout were larger than non-moving individuals and exhibited higher growth rates in two of the streams. Habitat features were not consistently linked to movement rates, but there were some interaction effects between stream and habitat characteristics such as depth, cover and water velocity.

Gut microbial structure in animals depends on the host, dietary habits and local environment. A random event, dietary change or antibiotic treatment may alter the gut environment with possible repercussions for the bacterial community composition and functionality and ultimately host fitness. The present study was focused on the composition, structure and functionality of gut microbiota in Reticulitermes grassei and the data obtained was compared with sequence surveys of three other Reticulitermes species. Each Reticulitermes species had a significantly different bacterial gut microbiota (pairwise significance tests using the Kolmogorov-Smirnov test), but a similar pattern of distribution (P-test in weighted Unifrac). The core gut microbiota from the analyzed Reticulitermes species contained 16 bacterial operational taxonomic units. Enzymes (KO) were detected from 14 pathways related to carbohydrate metabolism. R. grassei and R. hesperus, based on relative abundance of KO, had the most similar carbohydrate pathway patterns. In addition, we described the gut microbiota and functionality pathways in R. grassei after a 7-day dietary shift and antibiotic (ciprofloxacin) treatment. Both factors, but above all the antibiotic, altered the relative abundance of certain microbial groups, although the changes were not statistically significant (P-test in weighted Unifrac). The cellulose diet enhanced the carbohydrate pathways related to propanoate, butanoate, ascorbate, and glyoxylate metabolism. The antibiotic treatment affected galactose metabolism, the citrate cycle and inositol phosphate metabolism. Those functional changes may be related to changes in the abundance of several bacterial groups. Our findings provide insights into the stability of the gut microbiota in R. grassei and a resilience response to dietary shift or antibiotic treatment disturbance after 7 days.

[This corrects the article DOI: 10.1371/journal.pone.0197254.].

OBJECTIVE:Bariatric surgery is considered the most efficient treatment for morbid obesity and its related diseases. However, its role as a metabolic modifier is not well understood. We aimed to determine biosignatures of response to bariatric surgery and elucidate short-term metabolic adaptations. METHODS:We used a LC- and FIA-ESI-MS/MS approach to quantify acylcarnitines, (lyso)phosphatidylcholines, sphingomyelins, amino acids, biogenic amines and hexoses in serum samples of subjects with morbid obesity (n = 39) before and 1, 3 and 6 months after bariatric surgery. K-means cluster analysis allowed to distinguish metabotypes of response to bariatric surgery. RESULTS:For the first time, global metabolic changes following bariatric surgery independent of the baseline health status of the subjects have been revealed. We identify two metabolic phenotypes (metabotypes) at the interval 6 months-baseline after surgery, which presented differences in the levels of compounds of urea metabolism, gluconeogenic precursors and (lyso)phospholipid particles. Clinically, metabotypes were different in terms of the degree of improvement in insulin resistance, cholesterol, low-density lipoproteins and uric acid independent of the magnitude of weight loss. CONCLUSIONS:This study opens new perspectives and new hypotheses on the metabolic benefits of bariatric surgery and understanding of the biology of obesity and its associated diseases.

Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker.