- Statistics, Mathematics, Econometrics, Applied Mathematics, Epidemiology, Applied Statistics, and 11 moreClinical Trials, Randomization, Computer Science, Education, Information Technology, Research Methodology, Teacher Education, Medicine, Database Systems, Biotechnology, and Clinical Pharmacologyedit
IntroductionEven using well-established technology assessment processes, the basis of the decisions on drug price and reimbursement are sometimes perceived as poorly informed and sometimes may be seen as disconnected from value. The... more
IntroductionEven using well-established technology assessment processes, the basis of the decisions on drug price and reimbursement are sometimes perceived as poorly informed and sometimes may be seen as disconnected from value. The literature remains inconclusive about how Health Technology Assessment Bodies (HTAb) should report the determinants of their decisions. This study evaluates the relationship between oncology and hematology drug list prices and structured value parameters at the time of reimbursement decision in Spain.MethodsThe study includes all new onco-hematological products (22), with a first indication authorized between January 2017 and December 2019 in Spain and pricing decisions published up until October 2022. For each product, 56 contextual and non-contextual indicators reflecting the structured multiple criteria decision analysis (MCDA) – Evidence-based Decision-Making (EVIDEM) framework were measured. The relationship between prices and the MCDA-EVIDEM framew...
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Research Interests: Carbon Dioxide, Health Services Research, Adolescent, Medicine, Humans, and 15 moreHospitalization, Female, Male, Invasive and noninvasive ventilation, Clinical Sciences, Ambulatory, Aged, Middle Aged, Neuromuscular Disease, Mechanical Ventilation, Cost Benefit Analysis, Comparative Effectiveness Research, Health Care Costs, noninvasive ventilation, and Cardiovascular medicine and haematology
Research Interests: Quality of life, Medicine, Population, Humans, Female, and 15 moreMale, Follow-up studies, Health Status, Clinical Sciences, Aged, Middle Aged, Adult, Time Factors, Ards, Chest, X ray Computed Tomography, Critical Illness, Case Control Studies, Nottingham Health Profile, and Respiratory function tests
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Research Interests: Obstetrics, Clinical Trial, Medicine, Prevention, Pregnancy, and 15 moreProgesterone, Humans, Medicina, Female, Clinical Sciences, Gestational Age, Gestation, Clinical Protocols, Pessaries, Progestins, Predictive value of tests, Cervix, Premature Birth, Cervical pessary, and Cardiovascular medicine and haematology
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Psychotropics are increasingly used in pediatrics, often as off-label medicines. The guarantees of safety and efficacy are not always granted in clinical practice compared to adult authorised indications. A retrospective observational... more
Psychotropics are increasingly used in pediatrics, often as off-label medicines. The guarantees of safety and efficacy are not always granted in clinical practice compared to adult authorised indications. A retrospective observational study was done to estimate the prevalence of psychotropic use in pediatric subjects of Catalonia (Spain). Anonymised data on dispensation of psychotropics to pediatric patients, demography and other related data were obtained by the local healthcare management for the period 2008–2017. Estimation of off-label use was done through description of drug dispensations with no authorised use related to age range. The prevalence of psychotropics was 40.8–64.2 per 1,000 pediatric inhabitants. Hydroxyzine-only represented two-thirds of dispensations, and when removed, the prevalence dropped to 26.4–32.2 per 1,000 pediatric inhabitants. Adolescents and boys were more likely to receive a psychotropic. Psychostimulants had the highest exposure rate, mainly due to ...
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Sustained virological response (SVR) to direct‐acting antivirals ameliorates portal hypertension, improves hepatic function and may reverse the procoagulant state observed in patients with cirrhosis. However, an unexpected incidence of... more
Sustained virological response (SVR) to direct‐acting antivirals ameliorates portal hypertension, improves hepatic function and may reverse the procoagulant state observed in patients with cirrhosis. However, an unexpected incidence of portal vein thrombosis (PVT) immediately after antiviral therapy has recently been reported. Therefore, we analysed the long‐term impact of SVR on the development of non‐tumoural PVT.
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Randomized clinical trials are the gold standard when experimental designs are feasible. Randomization allows the handling of allocation bias for known and unknown confounders. Specific tools such as blocking, stratification, and dynamic... more
Randomized clinical trials are the gold standard when experimental designs are feasible. Randomization allows the handling of allocation bias for known and unknown confounders. Specific tools such as blocking, stratification, and dynamic allocation provide additional guarantees to simple randomization. When an experimental design is not feasible, the propensity score (PS) has been shown to produce greater benefit than traditional methods (i.e., restriction, stratification, matching and adjusting). There appears to be a hierarchy in terms of the effectiveness of balancing for PS techniques: matching or weighting above stratification above covariate adjustment (which is discouraged due to its drawbacks). Instrumental variable analysis and its variants might provide added value because they aim to balance for unknown confounders as well, thus mimicking randomization, but at present, are considered more useful for sensitivity rather than primary analyses.
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Research Interests: Gastroenterology, Medicine, Humans, Portal hypertension, Female, and 15 moreMale, Recurrence, Clinical Sciences, General Anesthesia, Aged, Middle Aged, Adult, Time Factors, Retrospective Studies, Cirrhosis, Neurosciences, Ascites, Esophageal and gastric varices, Deep sedation, and Paediatrics and reproductive medicine
Research Interests: Pharmacology, Microbiology, Medical Microbiology, Biology, Drug interactions, and 15 moreMitochondria, Cytotoxicity, Medicine, In Vitro, Mitochondrial DNA, Humans, mRna expression levels, Antimicrobial agents, Cell Survival, Adenine, Epithelial Cell Biology, Cytochrome Oxidase II Gene, Lopinavir, Pharmacology and pharmaceutical sciences, and mRNA expression
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Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily... more
Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cancer (CRC) cells that is linked to the acquisition of a fetal phenotype downstream of YAP1, similar to that observed after intestinal damage. CRC cells displaying this fetal phenotype exhibit tumor- initiating activity comparable to untreated cells but superior metastatic capacity. Notably, nuclear YAP1 accumulation, or detection of the fetal signature in tumors predict poor prognosis in CRC patients carrying p53 wildtype tumors. Collectively, our results uncover a potential adverse response of tumor cells to suboptimal chemotherapy, and identify nuclear YAP1 and fetal conversion of colorectal tumors as biomarkers for prognosis and therapy pr...
Research Interests: Oncology, Cancer, Biology, Chemotherapy, Cancer Research, and 3 moreMedicine, Colorectal cancer, and Fetus
Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome... more
Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a usef...
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BACKGROUND & AIMS Prognosis of compensated cirrhosis is good until decompensation. In decompensated cirrhosis, bacterial infections (BIs) are common and increase the risk of death. The incidence and prognostic implications of BIs in... more
BACKGROUND & AIMS Prognosis of compensated cirrhosis is good until decompensation. In decompensated cirrhosis, bacterial infections (BIs) are common and increase the risk of death. The incidence and prognostic implications of BIs in compensated cirrhosis are less characterized. This study aimed to assess whether BIs influence the risk of decompensation and survival in patients with compensated cirrhosis. METHODS This is a cohort study nested to the PREDESCI, a double-blind, multicenter RCT evaluating if β-blockers could prevent decompensation of cirrhosis. Patients with compensated cirrhosis and HVPG ≥10 mmHg were included. Development of BIs during follow-up was prospectively registered. Using a competing-risk time-dependent regression analysis, we investigated whether BIs affect the risk of decompensation and survival. Decompensation was defined as development of ascites, bleeding or overt encephalopathy. RESULTS 201 patients were randomized and followed for a median of 36 months (IQR: 24-47 months). 34 patients (17%) developed BIs, which in 33 cases occurred before decompensation, and 29 (14%) developed ascites. Respiratory and urinary tract infections were the most frequent BIs. Cirrhosis decompensation occurred in 26% patients with BIs vs 16% without BIs. Patients with BIs had higher risk of decompensation (HR=2.93, 95%CI=1.02-8.42; P= 0.047) and of developing ascites (HR=3.55, 95%CI=1.21-10.47; P=0.022) than those without BIs. Risk of death was also higher in patients with BIs (SHR=6.93, 95%CI=2.64-18.18; P< 0.001), although in 71% of such cases decompensation occurred before death. CONCLUSIONS BIs have a marked impact on natural history of compensated cirrhosis, significantly increasing the risk of decompensation, mainly that of ascites, and increasing the risk of death, which usually occurs after decompensation. Our results suggest that BIs may constitute a target to prevent decompensation. LAY SUMMARY In decompensated cirrhosis bacterial infections are common and increase the mortality risk. However, the relevance of bacterial infections in compensated cirrhosis has not been well studied so far. This study shows that in patients with compensated cirrhosis and clinically significant portal hypertension, bacterial infections occur as frequently as the development of ascites, which is the most frequent decompensating event. Most of these infections are from the respiratory or urinary tract. Their development increases the risk of progression to decompensation, mainly by a higher risk of ascites, and also increases the risk of death which in most cases occurs after decompensation. Bacterial infections have a deep impact on the natural history of compensated cirrhosis and may represent a target to prevent decompensation. CLINICALTRIALS. GOV IDENTIFIER NCT01059396.
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Background: We aimed to determine the impact of tocilizumab use in severe COVID-19 pneumonia mortality. Methods: We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain, from March to April 2020.... more
Background: We aimed to determine the impact of tocilizumab use in severe COVID-19 pneumonia mortality. Methods: We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain, from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by Inverse Probability of the Treatment Weights (IPTW). Tocilizumab effect in patients receiving steroids during the 48h following inclusion was analyzed. Results: During the study period, 506 patients with severe COVID-19 fulfilled inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days (IQR 8-14). Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls (16.8% versus 31.5%, HR 0.514 [95CI 0.355-0.744], p<0.001; weighted HR 0.741 [95CI 0.619-0.887], p=0.001). Tocil...
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Research Interests: Rheumatology, Immunology, Cytokines, Medicine, Internal Medicine, and 14 moreMedicina, Clinical Sciences, Spondyloarthropathies, TNF-a inhibitors, Public health systems and services research, Randomized Controlled Trial, Spondyloarthritis, Posology, Adalimumab, Etanercept, Posologia, Adverse effect, Dosing, and Infliximab
Patients admitted with acute variceal bleeding (AVB) and Child Pugh C score (CP-C) or Child Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding and mortality. Preemptive TIPS (p-TIPS) has... more
Patients admitted with acute variceal bleeding (AVB) and Child Pugh C score (CP-C) or Child Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding and mortality. Preemptive TIPS (p-TIPS) has been shown to improve survival in these patients but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. Multicenter, international, observational study including 671 patients from 34 centers admitted for AVB and high-risk of treatment failure. Patients were managed according to current guidelines and use of drugs and endoscopic therapy (D+E) or preemptive TIPS (p-TIPS) was based on individual center policy. p-TIPS in the setting of AVB is associated with a lower mortality in Child C patients compared to D+E (1 year mortality 22% vs 47% in D+E group; P=0.002). Mortality rate in CP-B+AB patients was low and p-T...
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Background: Forecasting the behavior of epidemic outbreaks is vital in public health. This makes it possible to anticipate the planning and organization of the health system, as well as possible restrictive or preventive measures. During... more
Background: Forecasting the behavior of epidemic outbreaks is vital in public health. This makes it possible to anticipate the planning and organization of the health system, as well as possible restrictive or preventive measures. During the COVID-19 pandemic, this need for prediction has been crucial. This paper attempts to characterize the alternative models that were applied in the first wave of this pandemic context, trying to shed light that could help to understand them for future practical applications. Methods: A systematic literature search was performed in standardized bibliographic repertoires, using keywords and Boolean operators to refine the findings, and selecting articles according to the main PRISMA 2020 statement recommendations. Results: After identifying models used throughout the first wave of this pandemic (between March and June 2020), we begin by examining standard data-driven epidemiological models, including studies applying models such as SIR (Susceptible-...
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73 TACIP was a multicentre, double-blind, randomised, parallel trial comparing the efficacy and safety of triflusal (600 mg/od) and ASA (325 mg/od) in patients who had a recent TIA or non disabling stroke. The primary end-point was the... more
73 TACIP was a multicentre, double-blind, randomised, parallel trial comparing the efficacy and safety of triflusal (600 mg/od) and ASA (325 mg/od) in patients who had a recent TIA or non disabling stroke. The primary end-point was the combined occurrence of non-fatal stroke, non-fatal AMI or cardiovascular death. Any of them separately was a secondary end-point, as well as total mortality, major systemic or cerebral hemorrhage and systemic thromboembolism. Forty-three centres in Spain and Portugal participated in the trial. A total of 2108 patients were evaluated with a mean follow-up of 31 months. There were no significant differences between both groups regarding to baseline characteristics. Main results were: The incidence of major and minor hemorrhages were higher in ASA than in triflusal group (24.5% vs 16.4%; p<0.001). Conclusion: Triflusal and low-dose ASA have a similar efficacy in secondary stroke prevention. Major and minor hemorrhages were significantly reduced by tri...
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The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them... more
The approval of a new drug for cancer treatment by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) is based on positive, well-designed randomized phase III clinical trials (RCTs). However, not all of them are analyzed to support the recommendations. For this reason, there are different scales to quantify and evaluate the quality of RCTs and the magnitude of the clinical benefits of new drugs for treating solid tumors. In this review, we discuss the value of the progression-free survival (PFS) as an endpoint in RCTs and the concordance between it and the overall survival (OS) as a measure of the quality of clinical trial designs. We summarize and analyze the different scales to evaluate the clinical benefits of new drugs such as the The American Society of Clinical Oncology value framework (ASCO-VF-NHB16) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the concordance between them, focusing on metastatic ...
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Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association... more
Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1+ cells express activation markers, T DNAM-1+ cells induce immune suppressi...
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RATIONALE & OBJECTIVE Alport syndrome (AS) is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in COL4A3, COL4A4 or COL4A5... more
RATIONALE & OBJECTIVE Alport syndrome (AS) is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in COL4A3, COL4A4 or COL4A5 genes. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. OBSERVATIONS A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families) while 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 years (95% CI, 58-73), without significant differences across sex (P=0.79), causative genes (P=0.55) or types of variant (P=0.99). Microhematuria was the most common kidney manifestation (92.1%) and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of eGFR decline was -1.46 mL/min/1.73 m2 per year (-1.66 to -1.26) for the overall group, with no significant differences between ADAS genes (P=0.24). LIMITATIONS The relatively small size of this series from a single country, potentially limiting generalizability. CONCLUSIONS ADAS patients have a wide spectrum clinical presentations ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.
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Rationale The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials. Aim The CHemical OptImization of Cerebral... more
Rationale The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials. Aim The CHemical OptImization of Cerebral Embolectomy trial aims to establish whether rescue intraarterial thrombolysis is more effective than placebo in improving suboptimal reperfusion scores in patients with large vessel occlusion stroke treated with mechanical thrombectomy. Sample size estimates A sample size of 200 patients allocated 1:1 to intraarterial thrombolysis or intraarterial placebo will have >95% statistical power for achieving the primary outcome (5% in the control versus 60% in the treatment group) for a two-sided (5% alpha, and 5% lost to follow-up). Methods and design We conducted a multicenter, randomized, placebo-controlled, double blind, phase 2b trial. Eligible patients are 18 or older with symptomatic large vessel occlusion treated with mechanical thrombectomy resu...
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Objective: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS).... more
Objective: People living with HIV (PLWH) have an increased cardiovascular risk (CVR) owing to dyslipidemia, insulin resistance, metabolic syndrome, and HIV/combination antiretroviral therapy (cART)-associated lipodystrophy (HALS). Atherosclerosis and inflammation are related to growth differentiation factor-15 (GDF15). The relationship between metabolic disturbances, HALS, and CVR with GDF15 in PLWH is not known. Research design and methods: Circulating GDF15 levels in 152 PLWH (with HALS = 60, without HALS = 43, cART-naïve = 49) and 34 healthy controls were assessed in a cross-sectional study. Correlations with lipids, glucose homeostasis, fat distribution, and CVR were explored. Results: PLWH had increased circulating GDF15 levels relative to controls. The increase was the largest in cART-treated PLWH. Age, homeostatic model assessment of insulin resistance 1 (HOMA1-IR), HALS, dyslipidemia, C-reactive protein, and CVR estimated with the Framingham score correlated with GDF15 level...
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Caridad Pontes (cpontes@tauli.cat) Jordi Gratacós (jgratacosmas@gmail.com) Ferran Torres (ferran.torres@uab.es) Cristina Avendaño (cavendano@salud.madrid.org) Jesús Sanz (jesussanzsanz4@gmail.com) Antoni Vallano... more
Caridad Pontes (cpontes@tauli.cat) Jordi Gratacós (jgratacosmas@gmail.com) Ferran Torres (ferran.torres@uab.es) Cristina Avendaño (cavendano@salud.madrid.org) Jesús Sanz (jesussanzsanz4@gmail.com) Antoni Vallano (avallano@bellvitgehospital.cat) Xavier Juanola (x.juanola@bellvitgehospital.cat) Eugenio de Miguel (eugenio.demiguel@gmail.com) Raimon Sanmartí (SANMARTI@clinic.ub.es) Gonzalo Calvo (gcalvo@clinic.ub.es)
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BackgroundCOVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with... more
BackgroundCOVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes substantial morbidity and mortality. At the time this clinical trial was planned, there were no available vaccine or therapeutic agents with proven efficacy, but the severity of the condition prompted the use of several pharmacological and non-pharmacological interventions.It has long been hypothesized that the use of convalescent plasma (CP) from infected patients who have developed an effective immune response is likely to be an option for the treatment of patients with a variety of severe acute respiratory infections (SARI) of viral etiology. The aim of this study is to assess the efficacy and safety of convalescent plasma in adult patients with severe COVID-19 pneumonia.Methods/DesignThe ConPlas-19 study is a multicenter, randomized, open-label controlled trial. The protocol has been prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional ...