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Immunotherapy; Phase 1 trials; Prognostic model Inmunoterapia; Ensayos de fase 1; Modelo pronóstico Immunoteràpia; Assajos de fase 1; Model pronòstic Purpose Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. Methods Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. Results We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%). Conclusions PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/. The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK).

[Background and purpose] Screening for and treatment of latent tuberculosis (TB) in patients with end-stage kidney disease (ESKD) are recommended. However, there is limited evidence on safety and treatment completion in this population. The objective of the study is to evaluate three short-course rifamycin-based regimens for the treatment of latent TB in ESKD patients., [Methods] Study design and setting. This is a prospective, open label, randomized clinical trial, that will be conducted at seven teaching hospitals in Spain. Study population, randomization, and interventions. Consecutive adult patients with ESKD requiring treatment for a latent TB infection will be randomly allocated (1:1:1) to receive one of the three treatment regimens of the study: three months of daily isoniazid plus rifampicin (3HR); three months of once-weekly isoniazid plus rifapentine (3HP); or four months of daily rifampicin (4R). Participants will be followed regularly through pre-established visits and a blood test schedule from enrolment to a month after finishing the assigned treatment. Outcomes. The primary outcome will be treatment completion, while the secondary outcomes will be discontinuation of the assigned treatment due to adverse events, related or unrelated to the study treatment; definitive discontinuation of the assigned treatment because of adverse events related to the treatment of the study, and death. Sample size. Two hundred and twenty-five subjects (75 per arm) will be enrolled, which will enable the demonstration, if it exists, of an increase of 0.16 in treatment completion rates either in the 3HP or 4R arm with respect to the 3HR arm., [Discussion] Results of this clinical trial will contribute to evidence-based recommendations on the management of latent TB infection in ESKD patients., [Trial registration] ClinicalTrials.gov identifier: NCT05021731., This study is funded by the Instituto de Salud Carlos III through the grant “21/004444” (co-funded by the European Regional Development Fund/European Social Fund, “Investing in Your Future”).

Introduction: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. Methods: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician. Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation). We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). Ethics and dissemination: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.

Purpose Pylorus-preserving pancreatoduodenectomy (PPPD) has been the gold standard for pancreatic head lesion resection for several years. Some studies have noted that it involves more delayed gastric emptying (DGE) than classical Whipple (i.e., pancreatoduodenectomy with antrectomy). Our working hypothesis was that the classical Whipple has a lower incidence of DGE. We aimed to compare the incidence of DGE among pancreatoduodenectomy techniques. Methods This pragmatic, randomized, open-label, single-center clinical trial involved patients who underwent classical Whipple (study group) or PPPD (control group). Gastric emptying was clinically evaluated using scintigraphy. DGE was defined according to the International Study Group of Pancreatic Surgery (ISGPS) criteria. The secondary endpoints were postoperative morbidity, length of hospital stay, anthropometric measurements, and nutritional status. Results A total of 84 patients were randomized (42 per group). DGE incidence was 50% (20/40, 95% confidence interval (95% CI): 35–65%) in the study group and 62% (24/39, 95% CI: 46–75%) in the control group (p = 0.260). No differences were observed between both groups regarding postoperative morbidity or length of hospital stay. Anthropometric measurements at 6 months post-surgery: triceps fold measurements were 12 mm and 16 mm (p = 0.021). At 5 weeks post-surgery, triceps fold measurements were 13 mm and 16 mm (p = 0.020) and upper arm circumferences were 26 cm and 28 cm (p = 0.030). No significant differences were observed in nutritional status. Conclusion DGE incidence and severity did not differ between classical Whipple and PPPD. Some anthropometric measurements may indicate a better recovery with PPPD. Trial registration ClinicalTrials.gov Identifier: NCT03984734.

Background Multiple health behaviour change (MHBC) interventions that promote healthy lifestyles may be an efficient approach in the prevention or treatment of chronic diseases in primary care. This study aims to evaluate the cost-utility and cost-effectiveness of the health promotion EIRA intervention in terms of MHBC and cardiovascular reduction. Methods An economic evaluation alongside a 12-month cluster-randomised (1:1) controlled trial conducted between 2017 and 2018 in 25 primary healthcare centres from seven Spanish regions. The study took societal and healthcare provider perspectives. Patients included were between 45 and 75 years old and had any two of these three behaviours: smoking, insufficient physical activity or low adherence to Mediterranean dietary pattern. Intervention duration was 12 months and combined three action levels (individual, group and community). MHBC, defined as a change in at least two health risk behaviours, and cardiovascular risk (expressed in % points) were the outcomes used to calculate incremental cost-effectiveness ratios (ICER). Quality-adjusted life-years (QALYs) were estimated and used to calculate incremental cost-utility ratios (ICUR). Missing data was imputed and bootstrapping with 1000 replications was used to handle uncertainty in the modelling results. Results The study included 3062 participants. Intervention costs were €295 higher than usual care costs. Five per-cent additional patients in the intervention group did a MHBC compared to usual care patients. Differences in QALYS or cardiovascular risk between-group were close to 0 (− 0.01 and 0.04 respectively). The ICER was €5598 per extra health behaviour change in one patient and €6926 per one-point reduction in cardiovascular risk from a societal perspective. The cost-utility analysis showed that the intervention increased costs and has no effect, in terms of QALYs, compared to usual care from a societal perspective. Cost-utility planes showed high uncertainty surrounding the ICUR. Sensitivity analysis showed results in line with the main analysis. Conclusion The efficiency of EIRA intervention cannot be fully established and its recommendation should be conditioned by results on medium-long term effects This study was supported by a grant from the “Instituto de Salud Carlos III, Ministerio de Economía y Competitividad” (Institute of Health Carlos III, Ministry of Economy and competitiveness), Spain (FIS PI15–00114 & FIS PI15–00519); a grant from the Department of Health of the government of Catalonia, Spain (SLT002/16/00112); and a grant awarded by the “Pla Estratègic de Recerca i Innovació en Salut” (PERIS) (Strategic Plan for Health Research and Innovation) at the Ministry of Health (Government of Catalonia) (SLT002/16/00190). We thank the CIBERESP (CIBER in Epidemiology and Public Health, CB16/02/00322) the redIAPP “Red de Investigación en Actividades Preventivas y Promoción de la Salud” Research Network Prevention and Health Promotion in Primary Care (RD12/0005/0006 & RD12/0005/0008) and the European Union ERDF funds for support in the development of this study. MRV has a “Miguel Servet” research contract from the Instituto de Salud Carlos III (ISCIII) at the Ministry of Economy and Competitiveness (Spain) (CP19/00029). ASB has a personal grant funded by the PERIS programme (SLT006/17/68), Generalitat de Catalunya (Spain), to partially dedicate his time to research during the time the study was conducted

The COVID-19 pandemic affected millions of people globally with lasting effects on society, patients, investigators and health institutions. Clinical trials, our best tool to improve cancer treatment for patients through testing the clinical value of a new treatment, have been affected by the pandemic. The pandemic footprint represents both a risk of compromising development of new therapies and an opportunity to elicit discussion over a portfolio of broader reforms, applicable irrespective of pandemics, in order to improve the design and implementation of clinical trials in oncology. The administrative load should be reduced, without affecting the quality of research and principles of good clinical practice. Cancer centres are encouraged to adapt their research/operational structures to the requirements of molecular oncology and embrace novel trial designs. Technological and methodological leaps in telemedicine can convert physical to virtual visits while routine examinations may be performed in local institutions (co-research centres), maintaining adherence to good clinical and research practices. The adoption of broader inclusion criteria and clinically significant endpoints (survival, quality of life) should be promoted, co-existing with pathways for fast-track “conditional” drug approvals in areas of unmet need, based on surrogate endpoints that are linked to strict post-approval validation requirements. The utility of Real World Data as part of these validation requirements should be actively investigated. Lessons learnt from the SARS Cov2 pandemic can be developed in order to expand equitable access to clinical trials of a real world population, in a simplified and methodologically robust modus operandi, for the benefit of all our patients.

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients.Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization.Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC.Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19.Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

Background Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe CRS—calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]—and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. Results We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Median (IQR) age was 62 (52–71), patients were predominantly males (68%) and from Europe/North and South America (88%). CRS, within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV (p = 0.417) nor with PaO2/FiO2 (p = 0.100). Females presented lower CRS than males (95% CI of CRS difference between females-males: − 11.8 to − 7.4 mL/cmH2O p CRS was marginal (p = 0.139). Ventilatory management varied across CRS range, resulting in a significant association between CRS and driving pressure (estimated decrease − 0.31 cmH2O/L per mL/cmH20 of CRS, 95% CI − 0.48 to − 0.14, p CRS (+ 10 mL/cm H2O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02–1.28, p = 0.018). Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV. CRS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at https://www.covid-critical.com/study. Trial registration: ACTRN12620000421932.

Pregunta clínica d’investigació: És eficaç la cocontracció de la musculatura abdominal i la del sòl pelvià, en comparació amb programes d’exercicis específics pel sòl pèlvic, per reduir o curar la incontinència urinària d’estrès en gimnastes? Objectius: l’objectiu principal d’aquest estudi es investigar l’eficàcia de la coordinació entre la musculatura abdominal i la del sòl pèlvic pel tractament de la incontinència urinària d’estrès. Per mesurar-ho, s’avaluarà la quantitat de pèrdues d’orina, la força i funcionalitat muscular del sòl pelvià, la coordinació entre els dos grups musculars i la qualitat de vida de les pacients. Metodologia: es realitzarà un assaig clínic aleatoritzat prospectiu i longitudinal amb doble cec, on la mostra s’obtindrà mitjançant un mostreig consecutiu, formant dos grups, un experimental i el control. La població de l’estudi són noies gimnastes d’entre 13 i 17 anys amb símptomes d’incontinència urinària d’estrès. Tant el grup de la intervenció com el control, realitzaran la pauta d’exercicis cada dia que tinguin entrenament. Les valoracions i la presa de dades es faran cada tres setmanes durant un període de 10 mesos. Pregunta de investigación: ¿Es eficaz la cocontracción de la musculatura abdominal y la del suelo pélvico, en comparación con programas de ejercicios específicos para el suelo pélvico, con el objetivo de mejorar o curar la incontinencia urinaria de estrés en gimnastas? Objetivo: el objetivo principal es investigar la eficacia de la coordinación entre la musculatura del suelo pélvico y la abdominal en el tratamiento de la incontinencia urinaria de estrés. Para medirlo, se evaluara las pérdidas de orina, la fuerza y funcionalidad del suelo pélvico, la coordinación entre los dos grupos musculares y la calidad de vida de las pacientes. Metodología: se realizará un ensayo clínico aleatorizado prospectivo y longitudinal con doble ciego, donde la muestra se obtendrá mediante un muestreo consecutivo, formando dos grupos: uno experimental y otro el control. La población del estudio son gimnastas de entre 13 y 17 años con síntomas de incontinencia urinaria de estrés. Tanto el grupo de la intervención como el control, realizaran la pauta de ejercicios cada día que entrenen. Las valoraciones y la toma de datos se harán cada tres semanas durante un período de 10 meses. Clinical research question: Is effective the cocontraction of the abdominal and pelvic floor muscles (PFM) compared with pelvic floor muscle training (PFMT) to improve or heal stress urinary incontinence (SUI) in gymnasts? Objective: the aim is to research the efficacy of the coordination between PFM and abdominal musculature in SUI treatment. In order to measure this goal the following parameters will be assessed: urine loss, strength and functionality of the PFM, coordination between both muscles groups and patients quality of life. Methodology: a prospective double-blind randomized clinical trial will be performed. The sample will be obtained by consecutive sampling. This will lead to the formation of the experimental and control groups. Subject of study are women gymnasts between 13 and 17 years old with SUI symptoms. Both studied groups will perform the exercise guideline every training day. Data collection and assessment will be done every tree weeks during 10 months.

Introducción: Las tendinopatías son una lesión recurrente en el deporte profesional. En el caso de la tendinopatía rotuliana, esta suele ocurrir en deportes que requieren de la realización de bastante volumen de saltos, como es el caso del fútbol. Objetivos: El objetivo de este trabajo es comparar las diferencias que se producen al realizar una recuperación utilizando ejercicio con restricción del flujo sanguíneo (BFR) y ejercicio tradicional. Métodos: El protocolo se diseñó como un ensayo clínico aleatorizado con doble ciego. Para ello, se necesitarán a 32 participantes que sean jugadores de futbol dentro de una categoría federada que se dividirán en dos grupos de 16. Un grupo será el grupo de ejercicio con BFR y el otro será el de ejercicio tradicional. Los ejercicios a efectuar serán sentadillas, zancadas y sentadillas declinadas. El método de valoración será la escala visual analógica (EVA) y la escala Victorian Institute of Sport Assessment – Patella (VISA-P), las cuáles se utilizarán para comparar las diferencias entre ambos grupos. Conclusiones: Se espera que los resultados en el grupo de ejercicio con BFR sean mejores debido a una reducción del dolor y una mejora de la funcionalidad más rápida que la del grupo de ejercicio tradicional. Introducció: Les tendinopaties són una lesió recurrent a l’esport profesional. Al cas de la tendinopatia rotuliana, aquesta sol ocórrer a esports que requereixen de la realització de bastant volum de salts, com es el cas del futbol. Objectius: L’objectiu d’aquest treball es comparar les diferencies que es produeixen al realitzar una recuperación utilitzant exercici amb restricció del flux sanguini (BFR) i exercici tradicional. Mètodes: El protocol es va dissenyar com a un assaig clínic aleatoritzat amb doble cec. Per això, es necessitarà a 32 participants que siguin jugadors de futbol en una categoria federada que es dividiran en dos grups de 16. Un grup serà el grup de exercici amb BFR i l’altre serà el de exercici tradicional. Els exercicis a efectuar seràn esquats, gambades i esquats declinats. El mètode de valoración serà la escala visual analògica (EVA) i la escala Victorian Institute of Sport Assessment – Patella (VISA-P), les quals s’utilitzaran per a comparar les diferencies entre tots dos grups. Conclusions: S’espera que els resultats al grup d’exercici amb BFR siguin millors degut a una reducción del dolor i a una millora de la funcionalitat més ràpida que la del grup d’exercici tradicional. Introduction: Tendinopathies are a recurrent injury in professional sports. In the case of patellar tendinopathy, it usually happens in sports that requires high volume of jumps, as is the case of soccer. Objectives: The objective of this work is to compare the differences in the rehabilitation using Blood Flow Restriction (BFR) exercises and traditional exercises. Methods: The protocol was designed like a double-blind randomized controlled trial. For that, will be needed 32 participants that are soccer players in a federated category that will be divided in two groups of 16. One group will be the BFR execise group and the other will be the traditional exercise group. The exercises that will be performed are squats, lunges and declined squats. The assessment method will be the analogic visual scale (EVA) and the Victorian Institute of Sport Assessment - Patella (VISA-P) scale, which will be utilized to compare the differences between the two groups. Conclusions: The results are expected to be better in the BFR exercise group due to a faster reduction in pain and a faster improvement in functionality compared with traditional exercise group.

Aim To assess the ability of the patient main problem to predict acuity in adults admitted to hospital wards and step‐down units. Background Acuity refers to the categorization of patients based on their required nursing intensity. The relationship between acuity and nurses' clinical judgment on the patient problems, including their prioritization, is an underexplored issue. Method Cross‐sectional, multi‐centre study in a sample of 200,000 adults. Multivariate analysis of main problems potentially associated with acuity levels higher than acute was performed. Distribution of patients and outcome differences among acuity clusters were evaluated. Results The main problems identified are strongly associated with patient acuity. The model exhibits remarkable ability to predict acuity (AUC, 0.814; 95% CI, 0.81–0.816). Most patients (64.8%) match higher than acute categories. Significant differences in terms of mortality, hospital readmission and other outcomes are observed (p

Significance Traditional analysis of clinical trials precludes a mechanistic understanding of drug actions. This is further compounded by the use of outcome measures in clinical trials not directly related to the mechanism of action of the medication under study. Here, we applied structural equation models to the double-blind randomized controlled trial of simvastatin in secondary progressive multiple sclerosis to investigate causal associations that underlie treatment effects. Our results suggest that beneficial effects of simvastatin on reducing the rate of brain atrophy and slowing the deterioration of disability are independent of serum cholesterol reduction. Our work demonstrates that structural models can elucidate the statistical pathways underlying treatment effects in clinical trials of poorly understood neurodegenerative disorders, such as progressive multiple sclerosis., Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = −0.037; 95% credible interval (CI) = −0.075, −0.010]. This suggests that simvastatin’s beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

Cirrhosis; Probiotic; Cognitive function Cirrosis; Probiòtic; Funció cognitiva Cirrosis; Probiótico; Función cognitiva Probiotics can modulate gut microbiota, intestinal permeability, and immune response and could therefore improve cognitive dysfunction and help avoid potential consequences, such as falls, in patients with cirrhosis. The aim of this study was to evaluate the effect of a multistrain probiotic on cognitive function, risk of falls, and inflammatory response in patients with cirrhosis. Consecutive outpatients with cirrhosis and cognitive dysfunction (defined by a Psychometric Hepatic Encephalopathy Score [PHES] < -4) and/or falls in the previous year were randomized to receive either a sachet of a high-concentration multistrain probiotic containing 450 billion bacteria twice daily for 12 weeks or placebo. We evaluated the changes in cognitive function (PHES); risk of falls (Timed Up and Go [TUG] test, gait speed, and incidence of falls); systemic inflammatory response; neutrophil oxidative burst; intestinal barrier integrity (serum fatty acid-binding protein 6 [FABP-6] and 2 [FABP-2] and zonulin and urinary claudin-3); bacterial translocation (lipopolysaccharide-binding protein [LBP]); and fecal microbiota. Thirty-six patients were included. Patients treated with the probiotic (n = 18) showed an improvement in the PHES (P = 0.006), TUG time (P = 0.015) and gait speed (P = 0.02), and a trend toward a lower incidence of falls during follow-up (0% compared with 22.2% in the placebo group [n = 18]; P = 0.10). In the probiotic group, we observed a decrease in C-reactive protein (P = 0.01), tumor necrosis factor alpha (P = 0.01), FABP-6 (P = 0.009), and claudin-3 (P = 0.002), and an increase in poststimulation neutrophil oxidative burst (P = 0.002). Conclusion: The multistrain probiotic improved cognitive function, risk of falls, and inflammatory response in patients with cirrhosis and cognitive dysfunction and/or previous falls.

Despite the negative influence of cannabis use on the development and prognosis of first-episode psychosis (FEP), there is little evidence on effective specific interventions for cannabis use cessation in FEP. The aim of this study was to compare the efficacy of a specific cognitive behavioral therapy (CBT) for cannabis cessation (CBT-CC) with treatment as usual (TAU) in FEP cannabis users. In this single-blind, 1-year randomized controlled trial, 65 participants were randomly assigned to CBT-CC or TAU. The primary outcome was the reduction in cannabis use severity. The CBT-CC group had a greater decrease in cannabis use severity and positive psychotic symptoms over time, and a greater improvement in functioning at post-treatment than TAU. The treatment response was also faster in the CBT-CC group, reducing cannabis use, anxiety, positive and general psychotic symptoms, and improving functioning earlier than TAU in the follow-up. Moreover, patients who stopped and/or reduced cannabis use during the follow-up, decreased psychotic symptoms and increased awareness of disease compared to those who continued using cannabis. Early intervention based on a specific CBT for cannabis cessation, may be effective in reducing cannabis use severity, in addition to improving clinical and functional outcomes of FEP cannabis users. This study was funded by the Spanish Ministry of Economy and Competitiveness through the Carlos III Health Institute (ISCIII) and the European Regional Development Fund (ERDF) (PI13/02252, PI18/01055, PI21/00713, PI19/00569).

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)–based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose–PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee–assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

IntroductionPsychosocial interventions for patients with breast cancer (BC) have demonstrated their effectiveness at reducing emotional distress and improving quality of life. The current digitisation of screening, monitoring and psychosocial treatment presents the opportunity for a revolution that could improve the quality of care and reduce its economic burden. The objectives of this study are, first, to assess the effectiveness of an e-health platform with integrated and stepped psychosocial services compared with usual psychosocial care, and second, to examine its cost–utility.Methods and analysisThis study is a multicentre randomised controlled trial with two parallel groups: E-health intervention with integrated and stepped psychosocial services vs usual psychosocial care. An estimated sample of 338 patients with BC in the acute survival phase will be recruited from three university hospitals in Catalonia (Spain) and will be randomly assigned to one of two groups. All participants will be evaluated at the beginning of the study (T1: recruitment), 3 months from T1 (T2), 6 months from T1 (T3) and 12 months from T1 (T4). Primary outcome measures will include number of clinical cases detected, waiting time from detection to psychosocial intervention and proportion of cases successfully treated in the different steps of the intervention, as well as outcomes related to emotional distress, quality of life, post-traumatic stress and growth, treatment adherence and therapeutic alliance. Secondary outcomes will include the acceptability of the platform, patients’ satisfaction and usability. For the cost–utility analysis, we will assess quality-adjusted life years and costs related to healthcare utilisation, medication use and adherence, work absenteeism and infrastructure-related and transport-related costs.Ethics and disseminationThis study was approved by the Ethics committee of the Institut Català d’Oncologia network in Hospitalet, Spain. Findings will be disseminated through peer-reviewed journals, reports to the funding body, conferences among the scientific community, workshops with patients and media press releases.Trial registration numberOnline Psychosocial Cancer Screening, Monitoring and Stepped Treatment in Cancer Survivors (ICOnnectat-B),NCT04372459.

Introducción. El aumento de la esperanza de vida ha originado el envejecimiento de la población y una mayor prevalencia de enfermedades crónicas. Esto ha generado la necesidad de cuidadores informales de adultos mayores para enfrentar situaciones de cuidado de estos. Por otra parte, se ha evidenciado un cambio en el perfil epidemiológico de los últimos 50 años, donde se observa un descenso de las enfermedades de tipo infeccioso y una mayor prevalencia de enfermedades no trasmisibles de curso crónico, las cuales aumentan la demanda de los cuidadores familiares. El cuidado de un familiar dependiente puede afectar negativamente en la salud del cuidador/a, en su vida afectiva y laboral. Objetivos. Primera fase, el objetivo general es describir las características sociodemográficas de la muestra de estudio, como específicos son: analizar la relación entre nivel de sobrecarga del cuidador y las variables sociodemográficas de los cuidadores principales, analizar la relación entre nivel de sobrecarga del cuidador y las características clínicas del paciente. Segunda fase, determinar la eficacia de la intervención de la enfermera en círculos de diálogo, para reducir el nivel de sobrecarga percibido por los cuidadores principales de pacientes identificados como paciente crónico complejo y enfermedad crónica avanzada. Como específicos son: comparar el nivel de sobrecarga percibido por los cuidadores principales antes y después de la intervención entre el grupo experimental y el grupo control, y grado de satisfacción sobre la intervención enfermera círculos de diálogos. Metodología. Estudio cuantitativo en dos fases. Primera, estudio descriptivo transversal y segunda, un estudio experimental, ensayo clínico aleatorizado con enmascaramiento simple. El estudio se realizará en Cataluña, en las poblaciones del área metropolitana de Barcelona pertenecientes al Servicio de Atención Primaria Baix Llobregat Centre. Abstract Introduction. The increase in life expectancy has led to an aging population and a higher prevalence of chronic diseases. This has generated the need for informal caregivers of the elderly to face caregiving situations. On the other hand, there has been a change in the epidemiological profile of the last 50 years, where there is a decrease in infectious diseases and a higher prevalence of non-communicable diseases of chronic course such as, which increase the demand of caregivers relatives. Caring for a dependent family member can negatively affect the health of the caregiver in their emotional and working life. Objectives. In the first phase, the general objective is to describe the sociodemographic characteristics of the study sample, as specific, to analyze the relationship between the level of caregiver burden and the sociodemographic variables of the main caregivers, to analyze the relationship between the level of caregiver burden and the clinical characteristics of the patient. In a second phase, it is to determine the effectiveness of the dialogue circles nurse intervention, to reduce the level of burden perceived by the main caregivers of patients identified as complex chronic patients and advanced chronic disease. As specific they are, comparing the level of overload perceived by the main caregivers before and after the intervention between the experimental group and the control group and the degree of satisfaction about the intervention nurse dialogue circles. Methodology. Quantitative study in two phases. In the first a descriptive cross-sectional study and in the second an experimental study, a randomized clinical trial with simple masking. The study will be carried out in Catalonia, in the towns of the metropolitan area of ​​Barcelona, ​​belonging to the Baix Llobregat Center Primary Care Service.

Background: Individuals with obesity are known to present cognitive deficits, especially in executive functions. Executive functions play an important role in health and success throughout the whole life and have been related to food decision-making and to the ability to maintain energy balance. It is possible to improve executive functions through targeted training. This would involve brain plasticity changes that could be studied through connectivity MRI. The general hypothesis of this study is that executive functions training in children with obesity can improve food choices and produce cognitive and neuroimaging changes (structural and functional connectivity), as well as improve emotional state and quality of life.Methods: Randomized controlled double-blind trial with 12-month follow-up. Thirty children with obesity will be randomly allocated into “executive training” (Cognifit with adaptive difficulty + Cogmed) or “control task” group (Cognifit without adaptive difficulty). Both groups will attend 30–45 min of individual gamified training (Cogmed and/or Cognifit systems) by iPad, five times per week during 6 weeks. Cogmed and Cognifit software are commercially available from Pearson and Cognifit, respectively. Participants will receive an iPad with both apps installed for a 6-week use. Participants will also receive counseling diet information via presentations sent to the iPad and will wear a Fitbit Flex 2 tracker to monitor daily activity and sleep patterns. Main outcomes will be cognitive, emotional, food decision, and quality-of-life measures, as well as neuroimaging measures. Participants are evaluated at baseline (T0), after treatment (T1), and 12 months since baseline (T2).Discussion: Longitudinal study with active control group and 3 time points: baseline, immediately after treatment, and 1 year after baseline. Threefold treatment: executive function training, psychoeducation, and feedback on activity/sleep tracking. We will evaluate the transfer effects of the intervention, including emotional and functional outcomes, as well as the effects on neural plasticity by connectivity MRI.Trial registration: This project has been registered in ClinicalTrials.gov (trial registration number NCT03615274), August 3, 2018.

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

Fundamentos: La Comisión Europea recomienda asegurar la equidad en el cribado del cáncer. El objetivo de este estudio fue conocer si existían desigualdades en el acceso a los programas de cribado del cáncer en España. Métodos: Se realizó un estudio transversal mediante encuesta dirigida a las personas responsables de los programas de cribado del cáncer de mama, colorrectal (CCR) y cérvix de las diecinueve Comunidades Autónomas (CCAA) del Estado Español en 2013 y 2020. Se recogió información sobre características organizativas, desigualdades de acceso e intervenciones para reducirlas. Se hizo un análisis descriptivo por CCAA y periodo temporal, mediante el cálculo de frecuencias y porcentajes, en función del tipo de programa (mama, CCR y cérvix). Resultados: En 2013 participaron catorce CCAA para el programa de mama, ocho para el de CCR y siete para el de cérvix, y en 2020, catorce, trece y once CCAA, respectivamente. Todos los programas de mama eran poblacionales en ambos periodos (14/14 en 2013 y 14/14 en 2020), así como los de CCR (8/8 en 2013 y 13/13 en 2020), con un aumento en el caso de los programas de cribado del cáncer de cérvix (0/7 en 2013 y 6/11 en 2020). Se identificaron en ambos periodos grupos sociales no incluidos en la población diana y grupos que, estando incluidos, participaban menos, con diferencias según el tipo de programa. Se realizaron un total de cincuenta y tres intervenciones para reducir desigualdades en el acceso (veintisiete en mama, veintidós en CCR y cuatro en cérvix), el 66% de ellas dirigidas a grupos sociales específicos (35/53). Conclusiones: Se identifican desigualdades de acceso a los programas de cribado del cáncer en España, así como intervenciones para reducirlas.

INTRODUCCIÓN: Durante una tendinopatía crónica del aductor largo, los niveles de funcionalidad y de dolor pueden verse comprometidos, afectando a la calidad del tendón. El protocolo de tratamiento de resistencia pesado y lento (HSRT) mejora tanto la sintomatología como la funcionalidad del tendón. PREGUNTA CLÍNICA DE INVESTIGACIÓN: ¿Es más eficaz el protocolo de tratamiento de resistencia pesado y lento (HSRT) que el protocolo de tratamiento excéntrico (Copenhague) para la mejora de la funcionalidad y la reducción del dolor, en pacientes con tendinopatía crónica del aductor largo? OBJETIVO: Valorar la efectividad del protocolo de tratamiento de resistencia pesado y lento (HSRT) en futbolistas profesionales de 18 a 45 años, diagnosticados de tendinopatía crónica del aductor largo, respecto los niveles de dolor y funcionalidad del propio tendón después de 3 meses de tratamiento y de 13 meses de seguimiento. METODOLOGÍA: Ensayo clínico controlado aleatorizado por grupos (ECAG) triple ciego con futbolistas profesionales de 18 a 45 años diagnosticados de tendinopatía crónica del aductor largo. Los futbolistas, serán distribuidos en un grupo control, que recibirá el protocolo de entrenamiento excéntrico (Copenhague); y un grupo experimental, que recibirá el protocolo de entrenamiento de resistencia pesado y lento (HSRT). La duración del tratamiento será de 3 meses, con 2-3 sesiones semanales. Las variables analizadas serán los niveles de funcionalidad y de dolor del tendón. Serán evaluadas en 3 ocasiones: antes de empezar el tratamiento, después del periodo de tratamiento y al finalizar la fase de seguimiento. INTRODUCTION: During chronic adductor longus tendinopathy, functionality and pain levels can be compromised, affecting tendon quality. The heavy and slow resistance treatment (HSRT) protocol improves both symptomatology and tendon functionality. CLINICAL RESEARCH QUESTION: Is the slow heavy resistance treatment protocol (HSRT) more effective than the eccentric treatment protocol (Copenhagen) in improving functionality and reducing pain in patients with chronic adductor longus tendinopathy? OBJECTIVE: To assess the effectiveness of the heavy and slow resistance treatment protocol (HSRT) in professional soccer players aged 18 to 45 years, diagnosed with chronic adductor longus tendinopathy, with respect to pain levels and functionality of the tendon itself after 3 months of treatment and 13 months of follow-up. METHODOLOGY: Triple-blind cluster-randomized controled trial (CRCT) with professional soccer players aged 18 to 45 years diagnosed with chronic adductor longus tendinopathy. The soccer players will be distributed in a control group, which will receive the eccentric training protocol (Copenhagen); and an experimental group, which will receive the heavy slow resistance training protocol (HSRT). The duration of the treatment will be 3 months, with 2-3 weekly sessions. The variables analyzed will be the levels of tendon functionality and pain. They will be evaluated on 3 occasions: before starting treatment, after the treatment period and at the end of the follow-up phase.

Autobiographical memory (AM) has been largely investigated as the ability to recollect specific events that belong to an individual's past. However, how we retrieve real-life routine episodes and how the retrieval of these episodes changes with the passage of time remain unclear. Here, we asked participants to use a wearable camera that automatically captured pictures to record instances during a week of their routine life and implemented a deep neural network-based algorithm to identify picture sequences that represented episodic events. We then asked each participant to return to the lab to retrieve AMs for single episodes cued by the selected pictures 1 week, 2 weeks and 6–14 months after encoding while scalp electroencephalographic (EEG) activity was recorded. We found that participants were more accurate in recognizing pictured scenes depicting their own past than pictured scenes encoded in the lab, and that memory recollection of personally experienced events rapidly decreased with the passing of time. We also found that the retrieval of real-life picture cues elicited a strong and positive ‘ERP old/new effect’ over frontal regions and that the magnitude of this ERP effect was similar throughout memory tests over time. However, we observed that recognition memory induced a frontal theta power decrease and that this effect was mostly seen when memories were tested after 1 and 2 weeks but not after 6–14 months from encoding. Altogether, we discuss the implications for neuroscientific accounts of episodic retrieval and the potential benefits of developing individual-based AM exploration strategies at the clinical level., This work was supported by Ministerio de Ciencia e Innovación, which is part of Agencia Estatal de Investigación, through the project PSI2016-80489-P and PID2019-111199GB-I00 (Co-funded by European Regional Development Fund. ERDF, a way to build Europe) and by ICREA Academia, to L.F. P.R. is supported by TIN2018-095232-B-C21, SGR-2017 1742, Greenhabit EIT Digital program. We thank CERCA Programme/Generalitat de Catalunya for institutional support. We thank the Editor and two anonymous reviewers for their constructive criticisms, remarks and advices.

Importance: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. Methods: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). Results: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] mu m in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] mu m [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. Conclusions and Relevance: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study.

Background The diagnosis of coeliac disease (CD) in individuals that have started a gluten-free diet (GFD) without an adequate previous diagnostic work-out is a challenge. Several immunological assays such as IFN-γ ELISPOT have been developed to avoid the need of prolonged gluten challenge to induce the intestinal damage. We aimed to evaluate the diagnostic accuracy of activated gut-homing CD8+ and TCRγδ+ T cells in blood after a 3-day gluten challenge and to compare it with the performance of IFN-γ ELISPOT in a HLA-DQ2.5 subsample. Methods A total of 22 CD patients and 48 non-CD subjects, all of them following a GFD, underwent a 3-day 10-g gluten challenge. The percentage of two T cell subsets (CD8+ CD103+ β7hi CD38+/total CD8+ and TCRγδ+ CD103+ β7hi CD38+/total TCRγδ+) in fresh peripheral blood drawn baseline and 6 days after the challenge was determined by flow cytometry. IFN-γ ELISPOT assays were also performed in HLA-DQ2.5 participants. ROC curve analysis was used to assess the diagnostic performance of the CD8+ T cell response and IFN-γ ELISPOT. Results Significant differences between the percentage of the two studied subsets of CD8+ and TCRγδ+ cells at days 0 and 6 were found only when considering CD patients (p < 10−3 vs. non-CD subjects). Measuring activated CD8+ T cells provided accurate CD diagnosis with 95% specificity and 97% sensitivity, offering similar results than IFN-γ ELISPOT. Conclusions The results provide a highly accurate blood test for CD diagnosis in patients on a GFD of easy implementation in daily clinical practice.

Background Undiagnosed sinus or atrioventricular node dysfunction may bias estimation of the real efficacy of cardiac pacing in preventing vasovagal reflex syncope. We assessed this hypothesis in the BIOSync CLS trial which showed that dual-chamber pacing with closed loop stimulation (CLS) remarkably reduced recurrences of syncope. Methods and results In the study patients aged 40 years or older with ≥2 episodes of loss of consciousness in the last year and an asystolic response to Tilt-Table test were randomized to pacing ON (DDD-CLS mode) or pacing OFF (ODO mode). We utilized the available pacemaker diagnostic data in a total of 103 patients (52 pacing ON, 51 pacing OFF) to generate cumulative distribution charts for heart rate (HR) and percentage of pacing. At 12 months, we did not find evidence of suspected sinus or atrioventricular node dysfunction. Beats were similarly distributed between groups (p = 0.96), with an average HR of 76 ± 8 bpm (pacing ON) versus 77 ± 7 bpm (pacing OFF). In the active group, the median percentage of atrial and ventricular pacing was 47% and 0%, respectively. Intolerance to high pacing rates was reported in only one patient (1.6%) and was easily resolved by reprogramming the maximum CLS pacing rate. Conclusions We did not find evidence of suspected sinus or atrioventricular node dysfunction in the BIOSync CLS patients. The benefit of pacing should be ascribed to pacing prevention of pure vasovagal episodes. CLS algorithm modulated pacing rates over a wide frequency range, consistently competing with sinus node.

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson’s disease patients (Parkinson’s Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson’s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson’s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor–patient contacts will be analysed. The noninferiority of the Parkinson’s Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson’s Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022. Trial registration NCT04176302;https://clinicaltrials.gov/show/NCT04176302

Estudi no aleatoritzat; Malaltia rara; Revisió sistemàtica Estudio no aleatorizado; Enfermedad rara; Revisión sistemática Nonrandomized study; Rare disease; Systematic review Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases.

The identification of variables that can modulate the efficacy of cue exposure using virtual reality (VR) is crucial. This study aimed to explore determinant variables of cue-elicited alcohol craving and perceived realism (PR) of environments and alcoholic beverages during a VR cue-exposure session among alcohol use disorder (AUD) outpatients. A prospective cohort study was conducted amongst 72 outpatients with AUD from a clinical setting. Alcohol craving experienced during VR exposure and PR of virtual environments and alcoholic drinks were evaluated after a VR session of exposure to alcohol-related contexts and cues. Sociodemographic, psychological and consumption characteristics were examined as possible predicting variables. Multiple linear regression analyses showed that the AUD severity and PR of beverages were predictors of cue-elicited alcohol craving. Educational level, PR of beverages and age were predictors of the PR of VR environments. In relation to the PR of VR beverages, cue-elicited alcohol craving and the PR of environments were predictors. A simple mediational model was also performed to analyze the influence of the PR of beverages on the relationship between the AUD severity and alcohol craving experienced during VR exposure: an indirect or mediational effect was found. PR of alcoholic beverages was (1) a key predictor of the PR of VR environments (and vice versa) and the alcohol craving (and vice versa) experienced during VR cue-exposure sessions using ALCO-VR software among AUD patients and (2) a mediator between AUD severity and cue-elicited alcohol craving.

Background: Cemented hip arthroplasty requires applying a layer of polymethylmethacrylate (cement) in the space between the bone and the prosthetic stem. This can be achieved using 2 techniques: the thick-layer technique (requires a layer of at least 2 mm to surround an undersized prosthetic stem), and the thin-layer technique (requires a thin layer of cement, so that the prosthetic stem fills the femoral medullary canal). Both approaches have excellent long-term clinical and radiological outcomes, although an implant's insertion into the bone generates inevitable bone mass and bone metabolic changes around it. Combination of single photon emission computed tomography and computed tomography scan (SPECT-CT) imaging combines the single photon emission computed tomography's ability to provide detailed bone metabolism assessment with the computed tomography scan's capacity to provide a meticulous anatomical study. Methods: This is a single center, open label, randomized clinical trial, performed in the premises of the Bellvitge University Hospital. Participants will be randomly assigned to the Thick-layer technique group (Exeter V40 Cemented Femoral Stem) or to the French paradox technique group (Müller Straight Stem). All participants will have a SPECT-CT scan study at 3, 6, 12, and 24 months after the surgery. Discussion: Surgical distress itself and the implant's insertion into the bone may cause microvascular changes that alter periprosthetic bone mass and bone metabolism. To the best of our knowledge, there are no studies using SPECT-CT to compare bone metabolism evolution in the postoperative period between these 2 surgical cementation techniques. We aim to provide information in this regard that could help decision making in complicated implant cases and, maybe, pave the way for larger, and methodologically improved studies. Trial registration: NCT05010733 (August 18, 2021).

Pregunta d’investigació Resulta ser efectiva la teràpia Basic Body Awareness Therapy (BBAT) per millorar la simptomatologia dels pacients diagnosticats de la síndrome de l’intestí irritable (SII) en comparació amb el grup control? Objectiu L’objectiu principal és comprovar l’efectivitat de BBAT en la millora de la simptomatologia en pacients diagnosticats de la SII en comparació amb tractament usual que reben aquests pacients durant dotze setmanes i un seguiment posterior (sis mesos) després de la finalització de la intervenció. Els objectius secundaris establerts són la millora del dolor, la severitat de la SII, la disminució del nombre de fàrmacs i ansietat, la millora en la gestió de l’estrès i també en la qualitat del moviment i la qualitat de vida relacionada amb la salut. L’objectiu indirecte és donar a conèixer aquest tipus d’abordatge fisioterapèutic de l’especialització en salut mental en els experts sanitaris. Metodologia: És planteja un assaig clínic controlat aleatoritzat amb avaluador cec. La mostra calculada és de 236 participants (18 a 65 anys), diagnosticats de la SII que formin part del part del Consorci Sanitari de l’Anoia. Els participants es dividiran en dos grups: l’experimental (sessions de BBAT i sessions d’assessorament i seguiment de les mesures higièniques i dietètiques) i el grup control (únicament tractament dietètic) durant 3 mesos. S’elaborarà un registre de mesures per escriure els valors dels qüestionaris avaluats en diversos períodes (T0, T1, T2) i posteriorment una anàlisis estadística d’aquestes. Research question: Is Basic Body Awareness Therapy (BBAT) effective to improve the symptomatology of irritable bowel syndrome (IBS) patients compared the control group? Objective: The aim of this study is to know the effectivity that BBAT has in improving the symptomatology of IBS patients compared to the usual treatment during 12 weeks and a following up in 6 months after the end of the intervention. Other objectives are to relieve pain, diminish IBS severity, decrease in the number of medicines and anxiety and also to improve the quality of movement and life related to health. Finally to make the physiotherapeutic approach of mental health in IBS patients known. Methodology: The study we have proposed is a randomized clinical trial with a blind evaluator. The sample studied is of 236 participants with ages ranging from 18 to 65. All the patients are diagnosed with IBS and are part of the Consorci Sanitari de l’Anoia. The patients will be divided in 2 groups: experimental group (BBAT sessions and advice and monitoring of hygienic and dietary sessions) and a control group (only dietary treatment). All the intervention will last 3 months. Meanwhile, the questionaries results will be registered and evaluated three times (T0, T1, T2), later on a statistical analysis of the results will be obtained.

Antecedentes: La esclerosis múltiple es la enfermedad neurológica discapacitante que más afecta a adultos jóvenes, especialmente a mujeres. Su sintomatología es muy variada y puede cursar de manera diferente en cada individuo; sin embargo, la fatiga parece ser la manifestación más común, y también la más persistente, llegando a afectar al 80% de los pacientes. Numerosos estudios han demostrado que técnicas de conciencia corporal como el yoga o el taichi resultan efectivas en la disminución de la fatiga en personas con esclerosis múltiple, mientras que Basic Body Awareness Therapy (BBAT), también ha mostrado buenos resultados con respecto a la fatiga en patologías como la fibromialgia. Pregunta de investigación: ¿Resulta efectivo Basic Body Awareness Therapy (BBAT) en la mejora de la sintomatología de pacientes con esclerosis múltiple que reciben tratamiento farmacológico? Objetivo: Evaluar la efectividad de BBAT sobre la mejora de la fatiga en pacientes con esclerosis múltiple, y evaluar, de manera secundaria, la efectividad sobre otros síntomas como la depresión y la ansiedad, la discapacidad generalizada, el dolor físico, el equilibrio y la calidad de movimiento. Metodología: El presente proyecto corresponde a un protocolo de ensayo clínico controlado aleatorizado sin cegar. La muestra estará conformada por personas de entre 18 y 55 años que padezcan esclerosis múltiple y estén registradas en el Hospital Arnau de Vilanova de Lleida. Los participantes serán divididos aleatoriamente en dos grupos, en el grupo experimental se combinará BBAT con el tratamiento farmacológico habitual, mientras que el grupo control sólo recibirá tratamiento farmacológico. Se realizarán dos sesiones semanales durante doce semanas, evaluando las variables al inicio, a mitad, al finalizar y tres meses después de la intervención. Dichas variables serán evaluadas mediante el Inventario Multidimensional de Fatiga (MFI), la Escala Expandida de Estado de Discapacidad (EDSS), la Escala Hospitalaria de Ansiedad y Depresión (HADS), el Balance Evaluation Systems Test (BEST Test), la Escala Analógica Visual (EVA) y la Body Awareness Rating Scale-Movement Quality and Experience (BARS-MQE). La duración total del estudio será de quince meses. Background: Multiple sclerosis is the most disabling neurological disease that affects young adults, especially women. Although its symptoms vary widely from person to person, fatigue seems to be the most common manifestation, and also the most persisten, affecting 80% of patients. Numerous studies have shown that body awareness techniques such as yoga or tai chi are successful in reducing fatigue in people with multiple sclerosis, while Basic Body Awareness Therapy (BBAT) has also shown good results in respect to fatigue in pathologies such as fibromyalgia. Research question: Is Basic Body Awareness Therapy (BBAT) effective in improving the symptoms of patients with multiple sclerosis receiving drug treatment? Objective: To evaluate the effeciency of BBAT on the improvement of fatigue in patients with multiple sclerosis and, in addition, to assess its effectiveness in relieving other symptoms such as depression and anxiety, generalized disability, physical pain, balance and quality of movement. Methodology: The present project corresponds to an unblinded randomized controlled clinical trial protocol. The sample will be made up of X people between 18 and 55 years of age who suffer from multiple sclerosis and are registered at the Arnau de Vilanova Hospital in Lleida. The participants will be randomly divided into two groups: in the experimental grupo, BBAT will be combined with the usual pharmacological treatment, while the control group will only receive pharmacological tratment. Two weekly sessions will be held for twelve weeks, evaluating the variables at the beginning, in the middle, at the end and at three months after the intervention. These variables will be evaluated using the Multidimensional Fatigue Inventory (MFI), Expanded Disability Status Scale (EDSS), Hospital Anxiety and Depression Scale (HADS), Balance Evaluation Systems Test (BEST Test), Visual Analogue Scale (VAS) and Body Awareness Rating Scale-Movement Quality and Experience (BARS MQUE). The total duration of the study will be fifteen months.

Pregunta clínica d’investigació: És eficaç la combinació de l’exercici aeròbic amb oscil·lacions de tronc en llit elàstic amb la fisioteràpia respiratòria, en comparació a la fisioteràpia respiratòria exclusiva, en la millora de la simptomatologia i l’augment d’expectoració i adherència en població infantil amb fibrosi quística? Objectiu: Analitzar l’efectivitat de la combinació de l’exercici en llit elàstic amb la fisioteràpia respiratòria pel que fa a la simptomatologia, l’expectoració i l’adherència. Per aquest motiu, s’analitza el pes de l’esput, la FEV1, la saturació d’oxigen, la tolerància a l’exercici, l’adherència i la qualitat de vida relacionada amb la salut. Metodologia: Es realitza un assaig clínic creuat aleatoritzat, longitudinal prospectiu, amb avaluació cega per tercers. Es formen dos grups per estudiar la intervenció control, fisioteràpia respiratòria i, la intervenció d’interès, combinació de llit elàstic amb fisioteràpia respiratòria; els subjectes se sotmeten a les dues intervencions en períodes diferents. Aquests són infants de 5 a 10 anys amb fibrosi quística i mutació Phe508del, amb un percentil IMC>50, un peak flow>270 L/min i sense exacerbacions respiratòries, hemoptisis, sinusitis i/o otitis. El grup control realitza en una primera part jocs per bufar i en una segona fa ús del dispositiu Acapella. El grup d’intervenció d’interès, realitza 20 minuts de llit elàstic i posteriorment fa la mateixa intervenció que el control. Es realitza quatre valoracions fora de sessió i varies durant la sessió. Cada intervenció consisteix en 36 sessions i es realitza un període de blanqueig d’un mes entre ambdues intervencions. Clinical research question: Is the combination of aerobic exercise with trunk oscillations in a trampoline with respiratory physiotherapy effective, compared to exclusive respiratory physiotherapy, in the improvement of symptomatology and increased expectoration and adherence in children with cystic fibrosis? Objective: To analyze the effectiveness of the combination of exercise in trampoline with respiratory physiotherapy in terms of symptoms, expectoration and adherence. For this reason, sputum weight, FEV1, oxygen saturation, exercise tolerance, adherence and health-related quality of life are analyzed. Methodology: A randomized, prospective longitudinal cross-sectional clinical trial with blinded third-party evaluation is performed. Two groups are formed to study the control intervention, respiratory physiotherapy and, the intervention of interest, combination of trampoline with respiratory physiotherapy; subjects undergo both interventions at different periods. These are children aged 5 to 10 years with cystic fibrosis and Phe508del mutation, with a BMI percentile >50, a peak flow >270 L/min and without respiratory exacerbations, hemoptysis, sinusitis and/or otitis. The control group plays blowing games in the first part and uses the Acapella device in the second. The interested intervention group performs 20 minutes of trampoline and then performs the same intervention as the control. Four out-of-session assessments are performed and several during the session. Each intervention consists of 36 sessions and a one-month whitening period is performed between the two interventions.

BackgroundThe CAPRICE trial was designed to specifically evaluate neoadjuvant pegylated liposomal doxorubicin (PLD) in elderly patients or in those with other cardiovascular risk factors in whom conventional doxorubicin was contraindicated. The primary analysis of the study showed a pathological complete response (pCR) of 32% and no significant decreases in LVEF during chemotherapy. Here, we report important secondary study objectives: 5-year cardiac safety, disease-free survival (DFS), overall survival (OS) and breast cancer specific survival (BCSS).MethodsIn this multicentre, single-arm, phase II trial, elderly patients or those prone to cardiotoxicity and high risk stage II-IIIB breast cancer received PLD (35 mg/m2) plus cyclophosphamide (600 mg/m2) every 4 weeks for 4 cycles, followed by paclitaxel for 12 weeks as neoadjuvant chemotherapy (NAC). Left ventricular ejection fraction (LVEF) monitorization, electrocardiograms and cardiac questionnaires were performed at baseline, during treatment and at 9, 16, 28 and 40 weeks thereafter. The primary endpoint was pCR and 5-year cardiac safety, DFS, BCSS and OS were also analyzed.ResultsBetween Oct 2007, and Jun 2010, 50 eligible patients were included. Median age was 73 (35-84) years, 84% were older than 65; 64% of patients suffered from hypertension, and 10% had prior cardiac disease. Most of tumors (88%) were triple negative. No significant decreases in LVEF were observed. The mean baseline LVEF was 66.6% (52-86) and after a median follow-up of 5 years, mean LVEF was 66 (54.5-73). For intention to treat population, 5-year DFS was 50% (95% CI 40.2-68.1) and 5-year OS was 56% (95%CI 41.2-68.4). There were 8 non-cancer related deaths, achieving a 5 years BCSS of 67.74% (CI 95%:54.31%- 81.18%).ConclusionAt 5-year follow-up, this PLD-based NAC regimen continued to be cardiac-safe and effective in a population of very high-risk breast cancer patients. This scheme should be considered as an option in elderly patients or in those with other risks of developing cardiotoxicity.Trial Registration NumberClinicalTrials.gov reference NCT00563953.

[EN]Abstract Background: Residual motor deficits of the upper limb in patients with chronic stroke are common and have a negative impact on autonomy, participation and quality of life. Music-Supported Therapy (MST) is an effective intervention to enhance motor and cognitive function, emotional well-being and quality of life in chronic stroke patients. We have adapted the original MST training protocol to a home-based intervention, which incorporates increased training intensity and variability, group sessions, and optimisation of learning to promote autonomy and motivation. Methods: A randomised controlled trial will be conducted to test the effectiveness of this enriched MST (eMST) protocol in improving motor functions, cognition, emotional well-being and quality of life of chronic stroke patients when compared to a program of home-based exercises utilizing the Graded Repetitive Arm Supplementary Program (GRASP). Sixty stroke patients will be recruited and randomly allocated to an eMST group (n = 30) or a control GRASP intervention group (n = 30). Patients will be evaluated before and after a 10-week intervention, as well as at 3-month follow-up. The primary outcome of the study is the functionality of the paretic upper limb measured with the Action Research Arm Test. Secondary outcomes include other motor and cognitive functions, emotional well-being and quality of life measures as well as self-regulation and self-efficacy outcomes. Discussion: We hypothesize that patients treated with eMST will show larger improvements in their motor and cognitive functions, emotional well-being and quality of life than patients treated with a home-based GRASP intervention. Trial registration: The trial has been registered at ClinicalTrials.gov and identified as NCT04507542 on 8 August 2020, This work was supported by the Ministerio de Ciencia, Innovación y Universidades (ref. PGC2018-099859-B-I00) to A.R.F, by 2017-SGR-172 from Generalitat de Catalunya to J.L.A. Study resulting from the 201729.30 project, funded by La Marató de TV3. We thank CERCA Programme / Generalitat de Catalunya for institutional support.

Temporal expectations critically influence perception and action. Previous research reports contradictory results in children’s ability to endogenously orient attention in time as well as the developmental course. To reconcile this seemingly conflicting evidence, we put forward the hypothesis that expectancy violations—through the use of invalid trials—are the source of the mixed evidence reported in the literature. With the aim of offering new results that could reconcile previous findings, we tested a group of young children (4- to 7-year-olds), an older group (8- to 12-year-olds), and a group of adults. Temporal cues provided expectations about target onset time, and invalid trials were used such that the target appeared at the unexpected time in 25% of the trials. In both experiments, the younger children responded faster in valid trials than in invalid trials, showing that they benefited from the temporal cue. These results show that young children rely on temporal expectations to orient attention in time endogenously. Importantly, younger children exhibited greater validity effects than older children and adults, and these effects correlated positively with participants’ performance in the invalid (unexpected) trials. We interpret the reduction of validity effects with age as an index of better adaptation to the invalid (unexpected) condition. By using invalid trials and testing three age groups, we demonstrate that previous findings are not inconsistent. Rather, evidence converges when considering the presence of expectancy violations that require executive control mechanisms, which develop progressively during childhood. We propose a distinction between rigid and flexible mechanisms of temporal orienting to accommodate all findings.

This observational, longitudinal retrospective, noncomparative study was designed to assess the persistence and effectiveness of golimumab as a second anti-tumor necrosis factor (TNF) drug in patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug.Data were collected retrospectively for all patients with axial spondyloarthritis or psoriatic arthritis from 20 rheumatology clinics in Spain who started golimumab as a second anti-TNF drug between January 2013 and December 2015. Golimumab persistence was assessed with Kaplan-Meier survival analysis, and associated factors were assessed with Cox regression analysis.210 patients started golimumab as a second anti-TNF drug: 131 with axial spondyloarthritis and 79 with psoriatic arthritis. In axial spondyloarthritis patients, the mean (standard deviation) Bath Ankylosing Spondylitis Disease Activity Index score at baseline was 5.5 (2.1), decreasing to 3.9 (2.0) at month 3 and 3.5 (2.0) at year 1, and remaining stable thereafter. In psoriatic arthritis patients, mean (standard deviation) baseline Disease Activity Score was 4.0 (1.3), reducing to 2.5 (1.2) at month 3 and to 2.2 (1.3) at year 1. Corresponding improvements were recorded from baseline in C-reactive protein levels and erythrocyte sedimentation rates. The probability of persistence of treatment with golimumab was 80% at year 1, 70% at year 2 and 65% at years 3 and year 4, and was similar in those who had stopped the first anti-TNF due to loss of efficacy or other reasons. Cox regression analysis showed that the probability of survival with golimumab was higher in patients with higher erythrocyte sedimentation rate, in patients with axial spondyloarthritis than with psoriatic arthritis, and in those who had discontinued adalimumab as first anti-TNF. Seventy-two patients (34.3%) discontinued golimumab during follow-up, 50 of them due to lack of efficacy.In patients with spondyloarthritis requiring discontinuation from a first anti-TNF drug, treatment with golimumab was effective and showed a high probability of persistence up to 4 years of treatment.

Pregunta de investigación: ¿Son efectivas las técnicas de fisioterapia en un equipo interdisciplinar de la unidad de cuidados paliativos en pacientes oncológicos pediátricos? Objetivos: Comprobar la efectividad de las técnicas de fisioterapia en la mejora funcional del paciente pediátrico en un equipo interdisciplinar de cuidados paliativos oncológicos. Metodología: Se trata de un estudio clínico aleatorizado, prospectivo y longitudinal que determinara el papel del fisioterapeuta dentro de un equipo interdisciplinar en la unidad de cuidados paliativos oncológicos pediátricos. Los participantes, residentes en la provincia de Lleida, tendrán edades comprendidas de 0 a 19 años. Una vez obtenida la muestra será aleatorizada y se formaran dos grupos, uno experimental que realizará un programa combinado con técnicas propias de fisioterapia junto con deambulación y cambios posturales adecuado a su evolución, todo ello, estará coordinado con la actuación de otros profesionales de la salud formando así, un equipo interdisciplinar, mientras que el grupo control es sometido a deambulación, cambios posturales y equilibrio junto con terapia de masaje y técnicas de relajación con un fisioterapeuta del servicio de rehabilitación domiciliaria del GSS. Los pacientes serán evaluados a través de cuestionarios entre los días 13 y 17 de cada mes durante los 6 meses que dura la intervención. Research question: Are physiotherapy techniques effective in an interdisciplinary team of the palliative care unit in pediatric cancer patients? Objective: The objective is to verify the effectiveness of physiotherapy techniques in the functional improvement of the pediatric patient in an interdisciplinary team of palliative oncological care. Methods: This is a randomized, prospective and longitudinal clinical study that will determine the role of the physiotherapist within an interdisciplinary team in the pediatric cancer palliative care unit. Participants, residents in the province of Lleida, among 0 and 19 years old. Once the sample is obtained, it will be randomized and two groups will be formed, an experimental one that will execute a combined program with its own physiotherapy techniques together with ambulation and postural changes appropriate to its evolution, all of which will be coordinated with the actions of other health professionals thus forming an interdisciplinary team, while the control group is subjected to ambulation, postural changes and balance along with massage therapy and relaxation techniques with a physiotherapist from the GSS home rehabilitation service. The patients will be evaluated through questionnaires between the 13th and 17th of each month during the 6 months that the intervention lasts.

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient’s data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44, 95% CI, 0.21–0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient’s survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren’s syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials., Sjögren’s syndrome, a disease that primarily affects women, is poorly understood. Here, the authors combine data from a large cohort of patients and healthy controls to identify biomarkers that distinguish patient subgroups to improve our understanding of the disease and facilitate drug development.

Background: Adolescence, when the most complex behaviors are refined to adult sophistication, represents a major window of opportunity and vulnerability for neuropsychological development. To support and protect this complex and active brain growth, different nutritional components considered essential need to be acquired from the diet. For instance, omega-3 fatty acids are mainly obtained from seafood, seeds, and walnuts. Known for their rich lipid profile, walnuts contain sizable amounts of an essential fatty acid, alpha-linolenic acid (ALA), the vegetable omega-3 fatty acid that is the precursor of two longer-chain omega-3 polyunsaturated fatty acids (omega-3 PUFA): docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. While there is growing evidence of neuropsychological improvements in the young developing brain associated with omega-3 PUFA intake, few studies have examined whether consuming walnuts during adolescence entails similar beneficial effects. There is a need to further explore the ways in which walnuts influence youthful brain function, particularly for the long-term. Thus, we designed the WALNUTs study (WSS), a population-based randomized controlled trial conducted in adolescents in Barcelona, Spain. We hypothesize that walnut intake will increase omega-3 PUFA tissue availability (particularly ALA) to a level that enhances the neuropsychological development during adolescence.Methodology/Design: We conducted a 6-month population-based randomized controlled trial in teenagers (n = 800) and we aimed to determine the effectiveness of the intervention (four walnuts per day, or 30 kernel g, ~1.5g of ALA) in enhancing brain neuropsychological and socio-emotional development compared to a control group with no walnut intervention. Before randomization, different neuropsychological tests were recorded for all participants, and blood samples (in a subsample of participants) were collected to measure omega-3 PUFA levels at baseline, and all again, after randomization and the intervention. The data is now collected and we will conduct linear regression models to assess the effect of the intervention.Discussion: The WALNUTs (WSS) study results will allow us to better understand the role of plant-based omega-3 PUFA intake from regular walnut consumption on neuropsychological development during adolescence. Results could be translated into nutritional public health recommendations targeting teenagers.Trial Registration:ClinicalTrials.gov, U.S. National Library of Medicine, National Institutes of Health # NCT02590848. Retrospectively registered 29/10/2015.

BACKGROUND: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. PATIENTS AND METHODS: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. RESULTS: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P=0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P=0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomitingand appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. CONCLUSION: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. TRIAL REGISTRATION NUMBER: NCT02028507 (ClinTrials.gov). EUDRACT STUDY NUMBER: 2013-003170-27.

Enfermedad de Fabry; Enfermedad renal crónica; Tratamiento enzimático sustitutivo Fabry disease; Chronic kidney disease; Enzyme replacement therapy Malaltia de Fabry; Malaltia renal crònica; Tractament enzimàtic substitutiu Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. Study design: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. Conclusions: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. El objetivo de este estudio es realizar un mapa del tratamiento actual de la enfermedad de Fabry en España, analizando el efecto de diferentes factores en el desarrollo de eventos clínicos a largo plazo. Diseño del estudio: Análisis observacional retrospectivo multicéntrico. Criterios de inclusión: pacientes diagnosticados y tratados de enfermedad de Fabry. Se recogieron datos generales en relación con el diagnóstico, síntomas y tipo mutación, tipo de tratamiento recibido, evolución renal y cardiológica. Durante un tiempo de seguimiento de 60 meses (24-120), se recogió el primer evento clínico tras el inicio de tratamiento sustitutivo enzimático definido como mortalidad, evento renal, cardiológico o neurológico. Resultados: Se incluyeron 69 pacientes (42 H, 27 M) con una edad media de 44,6 ± 13,7 años. A los cinco años de tratamiento, el FGe y la hipertrofia ventricular izquierda se mantuvieron estables, y la albuminuria tiende a disminuir, siendo este descenso más significativo en el grupo de pacientes tratados con beta-galactosidasa (de 242 a 128mg/g (p = 0,05). Veintiún pacientes sufrieron un evento clínico (30%): seis renales, dos neurológicos y 13 cardiológicos (incluidas tres muertes). Los pacientes con ERC (FGe < 60) antes del inicio de tratamiento tuvieron más eventos (log-rank 12.423, p = 0,001), manteniéndose la predicción si excluíamos los eventos renales (log-rank 4.086 (p = 0,043) en hombres y mujeres. La peor función renal al inicio del tratamiento aumentó entre tres y siete veces el riesgo de eventos clínicos en diferentes modelos de Cox ajustados. Conclusiones: La función renal al inicio de tratamiento sustitutivo enzimático es la principal predictora de desarrollo de eventos clínicos a largo plazo, tanto en hombres como mujeres. El inicio de tratamiento sustitutivo enzimático precoz antes del desarrollo de ERC mejoraría el pronóstico. MG, JT, AO, RT are supported by ISCIII RETIC REDINREN, RD016/009 and FEDER funds

Approximately one‐third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high‐risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4–7, enrolled in the ECHELON‐1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first‐line therapy after a median follow‐up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4–7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537–0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4–7 (HR, 0.588; 95% CI, 0.386–0.894; p = 0.012). The most common adverse events (AEs) in A + AVD‐treated versus ABVD‐treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4–7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high‐risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON‐1 shows a favorable benefit‐risk balance in high‐risk patients.