Spanish Clinical Research Network

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

<h3>Importance</h3> Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. <h3>Objective</h3> To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. <h3>Evidence Review</h3> We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. <h3>Findings</h3> In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). <h3>Conclusions and Relevance</h3> The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

The aim of this study was to clarify which cognitive mechanisms underlie Trail Making Test (TMT) direct and derived scores. A comprehensive review of the literature on the topic was carried out to clarify which cognitive factors had been related to TMT performance. Following the review, we explored the relative contribution from working memory, inhibition/interference control, task-switching ability, and visuomotor speed to TMT performance. Forty-one healthy old subjects participated in the study and performed a battery of neuropsychological tests including the TMT, the Digit Symbol subtest [Wechsler Adult Intelligence Scale (Third Version) (WAIS-III)], a Finger Tapping Test, the Digits Forward and Backward subtests (WAIS-III), Stroop Test, and a task-switching paradigm inspired in the Wisconsin Card Sorting Test. Correlation and regression analyses were used in order to clarify the joint and unique contributions from different cognitive factors to the prediction of TMT scores. The results suggest that TMT-A requires mainly visuoperceptual abilities, TMT-B reflects primarily working memory and secondarily task-switching ability, while B-A minimizes visuoperceptual and working memory demands, providing a relatively pure indicator of executive control abilities.

To standardize outcome reporting in clinical trials of patients with nonspecific low back pain, an international multidisciplinary panel recommended physical functioning, pain intensity, and health-related quality of life (HRQoL) as core outcome domains. Given the lack of a consensus on measurement instruments for these 3 domains in patients with low back pain, this study aimed to generate such consensus. The measurement properties of 17 patient-reported outcome measures for physical functioning, 3 for pain intensity, and 5 for HRQoL were appraised in 3 systematic reviews following the COSMIN methodology. Researchers, clinicians, and patients (n = 207) were invited in a 2-round Delphi survey to generate consensus (≥67% agreement among participants) on which instruments to endorse. Response rates were 44% and 41%, respectively. In round 1, consensus was achieved on the Oswestry Disability Index version 2.1a for physical functioning (78% agreement) and the Numeric Rating Scale (NRS) for pain intensity (75% agreement). No consensus was achieved on any HRQoL instrument, although the Short Form 12 (SF12) approached the consensus threshold (64% agreement). In round 2, a consensus was reached on an NRS version with a 1-week recall period (96% agreement). Various participants requested 1 free-to-use instrument per domain. Considering all issues together, recommendations on core instruments were formulated: Oswestry Disability Index version 2.1a or 24-item Roland-Morris Disability Questionnaire for physical functioning, NRS for pain intensity, and SF12 or 10-item PROMIS Global Health form for HRQoL. Further studies need to fill the evidence gaps on the measurement properties of these and other instruments.

Rates of spontaneous mutation critically determine the genetic diversity and evolution of RNA viruses. Although these rates have been characterized in vitro and in cell culture models, they have seldom been determined in vivo for human viruses. Here, we use the intrapatient frequency of premature stop codons to quantify the HIV-1 genome-wide rate of spontaneous mutation in DNA sequences from peripheral blood mononuclear cells. This reveals an extremely high mutation rate of (4.1 ± 1.7) × 10-3 per base per cell, the highest reported for any biological entity. Sequencing of plasma-derived sequences yielded a mutation frequency 44 times lower, indicating that a large fraction of viral genomes are lethally mutated and fail to reach plasma. We show that the HIV-1 reverse transcriptase contributes only 2% of mutations, whereas 98% result from editing by host cytidine deaminases of the A3 family. Hypermutated viral sequences are less abundant in patients showing rapid disease progression compared to normal progressors, highlighting the antiviral role of A3 proteins. However, the amount of A3-mediated editing varies broadly, and we find that low-edited sequences are more abundant among rapid progressors, suggesting that suboptimal A3 activity might enhance HIV-1 genetic diversity and pathogenesis.

OBJECTIVE: Diabetes is a common cause of shortened life expectancy. We aimed to assess the association between diabetes and cause-specific death. RESEARCH DESIGN AND METHODS: We used the pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79 years old. Diabetes status was self-reported or defined as glycemia >125 mg/dL at baseline. Vital status and causes of death were ascertained by medical records review and linkage with the official death registry. The hazard ratios and cumulative mortality function were assessed with two approaches, with and without competing risks: proportional subdistribution hazard (PSH) and cause-specific hazard (CSH), respectively. Multivariate analyses were fitted for cardiovascular, cancer, and noncardiovascular noncancer deaths. RESULTS: We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63-2.52) and PSH = 1.99 (1.60-2.49) in men; and CSH = 2.28 (1.75-2.97) and PSH = 2.23 (1.70-2.91) in women; 2) cancer death, CSH = 1.37 (1.13-1.67) and PSH = 1.35 (1.10-1.65) in men; and CSH = 1.68 (1.29-2.20) and PSH = 1.66 (1.25-2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23-1.91) and PSH = 1.50 (1.20-1.89) in men; and CSH = 1.89 (1.43-2.48) and PSH = 1.84 (1.39-2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes. CONCLUSIONS: Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes. The use of CSH and PSH provides a comprehensive view of mortality dynamics in a population with diabetes.

Importance: Enhanced Recovery After Surgery (ERAS) care has been reported to be associated with improvements in outcomes after colorectal surgery compared with traditional care. Objective: To determine the association between ERAS protocols and outcomes in patients undergoing elective colorectal surgery. Design, Setting, and Participants: The Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol (POWER) Study is a multicenter, prospective cohort study of 2084 consecutive adults scheduled for elective colorectal surgery who received or did not receive care in a self-declared ERAS center. Patients were recruited from 80 Spanish centers between September 15 and December 15, 2017. All patients included in this analysis had 1 month of follow-up. Exposures: Colorectal surgery and perioperative management were the exposures. Twenty-two individual ERAS items were assessed in all patients, regardless of whether they were included in an established ERAS protocol. Main Outcomes and Measures: The primary study outcome was moderate to severe postoperative complications within 30 days after surgery. Secondary outcomes included ERAS adherence, mortality, readmissions, reoperation rates, and hospital length of stay. Results: Between September 15 and December 15, 2017, 2084 patients were included in the study. Of these, 1286 individuals (61.7%) were men; mean age was 68 years (interquartile range [IQR], 59-77). A total of 879 patients (42.2%) presented with postoperative complications and 566 patients (27.2%) developed moderate to severe complications. The number of patients with moderate or severe complications was lower in the ERAS group (25.2% vs 30.3%; odds ratio [OR], 0.77; 95% CI, 0.63-0.94; P = .01). The overall rate of adherence to the ERAS protocol was 63.6% (IQR, 54.5%-77.3%), and the rate for patients from hospitals self-declared as ERAS was 72.7% (IQR, 59.1%-81.8%) vs non-ERAS institutions, which was 59.1% (IQR, 50.0%-63.6%; P < .001). Adherence quartiles among patients receiving the highest and lowest ERAS components showed that the patients with the highest adherence rates had fewer moderate to severe complications (OR, 0.34; 95% CI, 0.25-0.46; P < .001), overall complications (OR, 0.33; 95% CI, 0.26-0.43; P < .001), and mortality (OR, 0.27; 95% CI, 0.07-0.97; P = .06) compared with those who had the lowest adherence rates. Conclusions and Relevance: An increase in ERAS adherence appears to be associated with a decrease in postoperative complications.

PURPOSE: Much of the common practice in paediatric mechanical ventilation is based on personal experiences and what paediatric critical care practitioners have adopted from adult and neonatal experience. This presents a barrier to planning and interpretation of clinical trials on the use of specific and targeted interventions. We aim to establish a European consensus guideline on mechanical ventilation of critically children. METHODS: The European Society for Paediatric and Neonatal Intensive Care initiated a consensus conference of international European experts in paediatric mechanical ventilation to provide recommendations using the Research and Development/University of California, Los Angeles, appropriateness method. An electronic literature search in PubMed and EMBASE was performed using a combination of medical subject heading terms and text words related to mechanical ventilation and disease-specific terms. RESULTS: The Paediatric Mechanical Ventilation Consensus Conference (PEMVECC) consisted of a panel of 15 experts who developed and voted on 152 recommendations related to the following topics: (1) general recommendations, (2) monitoring, (3) targets of oxygenation and ventilation, (4) supportive measures, (5) weaning and extubation readiness, (6) normal lungs, (7) obstructive diseases, (8) restrictive diseases, (9) mixed diseases, (10) chronically ventilated patients, (11) cardiac patients and (12) lung hypoplasia syndromes. There were 142 (93.4%) recommendations with "strong agreement". The final iteration of the recommendations had none with equipoise or disagreement. CONCLUSIONS: These recommendations should help to harmonise the approach to paediatric mechanical ventilation and can be proposed as a standard-of-care applicable in daily clinical practice and clinical research.

The cost of generating a quality-adjusted life year (QALY) within a National Health Service provides an approximation of the average opportunity cost of funding decisions. This information can be used to inform a cost-effectiveness threshold. The aim of this paper is to estimate the cost per QALY at the Spanish National Health Service. We exploit variation across 17 regional health services and the exogenous changes in expenditure that took place as a consequence of the economic crisis over 5 years of data. We conduct fixed effect models and use an instrumental variable approach to test for potential remaining endogeneity. Our results show that health expenditure has a positive and significant effect on population health, with an average spending elasticity of 0.07. This translates into a cost per QALY of between 22,000€ and 25,000€. These values are below the cost-effectiveness threshold figure of 30,000€ commonly cited in Spain.

Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study (Observatorio Nacional de Atherosclerosis en NEFrologia) prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.

OBJECTIVE: To compare the effectiveness of sedation, the time required for weaning, and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol. DESIGN: Open-label, randomized, prospective, phase IV clinical trial. SETTING: Medical and surgical intensive care unit (ICU) in a community hospital. PATIENTS: All ICU admissions (medical, surgical and trauma) requiring mechanical ventilation for > 24 hrs. A total of 108 patients were included in the study. INTERVENTIONS: Patients were randomized to receive midazolam or propofol. The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol. The lowest dose that achieved an adequate patient-ventilator synchrony was infused. All patients received 0.5 mg/kg/24 hrs of morphine chloride. MEASUREMENTS AND MAIN RESULTS: The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started. If sedation could not be achieved by infusing the highest dose of midazolam or propofol, the case was recorded as a therapeutic failure. In the propofol group, serum triglycerides were determined every 72 hrs. Concentrations of > 500 mg/dL were also recorded as a therapeutic failure. When the patient was ready for weaning according to defined criteria, sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured. Cost analysis was performed based on the cost of intensive care in our unit ($54/hr). In the midazolam group (n = 54), 15 (27.8%) patients died; 11 (20.4%) patients had therapeutic failure; and 28 (51.8%) patients were subjected to a T-bridge trial. In the propofol group (n = 54), these proportions were 11 (20.4%), 18 (33.4% [including seven due to inadequate sedation, and 11 due to hypertriglyceridemia]), and 25 (46.2%), respectively. None of these values was significantly different between the two groups. Duration of sedation was 141.7 +/- 89.4 (SD) hrs and 139.7 +/- 84.7 hrs (p = NS), and cost (US dollars) attributed to sedation was $378 +/- 342 and $1,047 +/- 794 (p = .0001) for the midazolam and propofol groups, respectively. In the midazolam group, time from discontinuation of the drug infusion to extubation was 97.9 +/- 54.6 hrs (48.9 +/- 47.2 hrs to the first disconnection, and 49.0 +/- 23.7 hrs to extubation). In the propofol group, time from discontinuation of the drug infusion to extubation was 34.8 +/- 29.4 hrs (4.0 +/- 3.9 hrs to the first disconnection, and 30.8 +/- 29.2 hrs to extubation). The difference between the two groups in the weaning time was 63.1 +/- 12.5 (SEM) hrs (p < .0001). Cost per patient in the midazolam group (including ICU therapy and sedation with midazolam) was $10,828 +/- 5,734. Cost per patient in the propofol group was $9,466 +/- 5,820, $1,362 less than in the midazolam group. CONCLUSIONS: In our population of critically ill patients sedated with midazolam or propofol over prolonged periods, midazolam and propofol were equally effective as sedative agents. However, despite remarkable differences in the cost of sedation with these two agents, the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration.

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

BACKGROUND: The Spanish five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) valuation study was the first to use the EuroQol Valuation Technology protocol, including composite time trade-off (C-TTO) and discrete choice experiments (DCE). In this study, its investigators noticed that some interviewers did not fully explain the C-TTO task to respondents. Evidence from a follow-up study in 2014 confirmed that when interviewers followed the protocol, the distribution of C-TTO responses widened. OBJECTIVES: To handle the data quality issues in the C-TTO responses by estimating a hybrid interval regression model to produce a Spanish EQ-5D-5L value set. METHODS: Four different models were tested. Model 0 integrated C-TTO and DCE responses in a hybrid model and models 1 to 3 altered the interpretation of the C-TTO responses: model 1 allowed for censoring of the C-TTO responses, whereas model 2 incorporated interval responses and model 3 included the interviewer-specific protocol violations. For external validation, the predictions of the four models were compared with those of the follow-up study using the Lin's concordance correlation coefficient. RESULTS: This stepwise approach to modeling C-TTO and DCE responses improved the concordance between the valuation and follow-up studies (concordance correlation coefficient: 0.948 [model 0], 0.958 [model 1], 0.952 [model 2], and 0.989 [model 3]). We recommend the estimates from model 3, because its hybrid interval regression model addresses the data quality issues found in the valuation study. CONCLUSIONS: Protocol violations may occur in any valuation study; handling them in the analysis can improve external validity. The resulting EQ-5D-5L value set (model 3) can be applied to inform Spanish health technology assessments.

BACKGROUND: Nonadherence and medication errors are common among patients with complex drug regimens. Apps for smartphones and tablets are effective for improving adherence, but they have not been tested in elderly patients with complex chronic conditions and who typically have less experience with this type of technology. OBJECTIVE: The objective of this study was to design, implement, and evaluate a medication self-management app (called ALICE) for elderly patients taking multiple medications with the intention of improving adherence and safe medication use. METHODS: A single-blind randomized controlled trial was conducted with a control and an experimental group (N=99) in Spain in 2013. The characteristics of ALICE were specified based on the suggestions of 3 nominal groups with a total of 23 patients and a focus group with 7 professionals. ALICE was designed for Android and iOS to allow for the personalization of prescriptions and medical advice, showing images of each of the medications (the packaging and the medication itself) together with alerts and multiple reminders for each alert. The randomly assigned patients in the control group received oral and written information on the safe use of their medications and the patients in the experimental group used ALICE for 3 months. Pre and post measures included rate of missed doses and medication errors reported by patients, scores from the 4-item Morisky Medication Adherence Scale (MMAS-4), level of independence, self-perceived health status, and biochemical test results. In the experimental group, data were collected on their previous experience with information and communication technologies, their rating of ALICE, and their perception of the level of independence they had achieved. The intergroup intervention effects were calculated by univariate linear models and ANOVA, with the pre to post intervention differences as the dependent variables. RESULTS: Data were obtained from 99 patients (48 and 51 in the control and experimental groups, respectively). Patients in the experimental group obtained better MMAS-4 scores (P<.001) and reported fewer missed doses of medication (P=.02). ALICE only helped to significantly reduce medication errors in patients with an initially higher rate of errors (P<.001). Patients with no experience with information and communication technologies reported better adherence (P<.001), fewer missed doses (P<.001), and fewer medication errors (P=.02). The mean satisfaction score for ALICE was 8.5 out of 10. In all, 45 of 51 patients (88%) felt that ALICE improved their independence in managing their medications. CONCLUSIONS: The ALICE app improves adherence, helps reduce rates of forgetting and of medication errors, and increases perceived independence in managing medication. Elderly patients with no previous experience with information and communication technologies are capable of effectively using an app designed to help them take their medicine more safely. TRIAL REGISTRATION: Clinicaltrials.gov NCT02071498; http://clinicaltrials.gov/ct2/show/NCT02071498.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Epithelial-to-mesenchymal transition (EMT) is a self-regulated physiological process required for tissue repair that, in non-controled conditions may lead to fibrosis, angiogenesis, loss of normal organ function or cancer. Although several molecular pathways involved in EMT regulation have been described, this process does not have any specific treatment. This article introduces a systematic review of effective natural plant compounds and their extract that modulates the pathological EMT or its deleterious effects, through acting on different cellular signal transduction pathways both in vivo and in vitro. Thereby, cryptotanshinone, resveratrol, oxymatrine, ligustrazine, osthole, codonolactone, betanin, tannic acid, gentiopicroside, curcumin, genistein, paeoniflorin, gambogic acid and Cinnamomum cassia extracts inhibit EMT acting on transforming growth factor- (TGF-)/Smads signaling pathways. Gedunin, carnosol, celastrol, black rice anthocyanins, Duchesnea indica, cordycepin and Celastrus orbiculatus extract downregulate vimectin, fibronectin and N-cadherin. Sulforaphane, luteolin, celastrol, curcumin, arctigenin inhibit -catenin signaling pathways. Salvianolic acid-A and plumbagin block oxidative stress, while honokiol, gallic acid, piperlongumine, brusatol and paeoniflorin inhibit EMT transcription factors such as SNAIL, TWIST and ZEB. Plectranthoic acid, resveratrol, genistein, baicalin, polyphyllin I, cairicoside E, luteolin, berberine, nimbolide, curcumin, withaferin-A, jatrophone, ginsenoside-Rb1, honokiol, parthenolide, phoyunnanin-E, epicatechin-3-gallate, gigantol, eupatolide, baicalin and baicalein and nitidine chloride inhibit EMT acting on other signaling pathways (SIRT1, p38 MAPK, NFAT1, SMAD, IL-6, STAT3, AQP5, notch 1, PI3K/Akt, Wnt/-catenin, NF-B, FAK/AKT, Hh). Despite the huge amount of preclinical data regarding EMT modulation by the natural compounds of plant, clinical translation is poor. Additionally, this review highlights some relevant examples of clinical trials using natural plant compounds to modulate EMT and its deleterious effects. Overall, this opens up new therapeutic alternatives in cancer, inflammatory and fibrosing diseases through the control of EMT process.

BACKGROUND: People with dementia die prematurely. Identifying differences in mortality rates between different types of dementia might aid in the development of preventive interventions for the most vulnerable populations. The aim of this study was to compare the difference in mortality rates between individuals without dementia and individuals with various types of dementia. METHODS: For this systematic review and meta-analysis, we did a systematic search of MEDLINE, PubMed, Embase, and Cochrane Library from inception to July 11, 2020, for cross-sectional or cohort studies that assessed mortality and survival-related outcomes among people with different types of dementia compared with people without dementia. Single-arm studies without comparison groups and autopsy studies or family studies that used a selected sample were excluded. The Newcastle-Ottawa Scale was used by two authors (D-JL and C-SC) independently to measure the methodological quality of included studies, and two authors (F-CY and P-TT) independently extracted data. We assessed differences in all-cause mortality rate and survival time from dementia diagnosis between individuals without dementia, individuals with Alzheimer's disease, and individuals with non-Alzheimer's disease dementias. The secondary outcomes were age at death and survival time from disease onset. Random-effects meta-analyses were done. Effect sizes included hazard ratios (HRs) and mean differences (MDs) with 95% CIs. Potential moderators, including age-associated moderators, were identified through meta-regression and subgroup analyses. This study is registered with PROSPERO, CRD42020198786. FINDINGS: >75%) was observed for most of the study outcomes. INTERPRETATION: Alzheimer's disease is the most common type of dementia and one of the major causes of mortality worldwide. However, the findings from the current study suggest that non-Alzheimer's disease dementias were associated with higher morality rates and shorter life expectancy than Alzheimer's disease. Developing tailored treatment and rehabilitation programmes for different types of dementia is important for mental health providers, patients, and their families. FUNDING: None.