New approach for early and specific Alzheimer disease diagnosis from different plasma biomarkers.

BACKGROUND: Alzheimer Disease (AD) is a complex pathology, in which several biochemical pathways could be involved. Therefore, the development of clinical studies combining different nature biomarkers in an AD diagnosis approach is required. Specifically, the present study evaluated blood biomarkers from different molecular pathways (epigenomics, lipid metabolism, lipid peroxidation), to obtain an early and specific AD diagnosis approach. METHODS: The participants were classified into early AD (n = 53), and non-AD (healthy controls, other dementias) (n = 83). Blood samples were collected and biochemical determinations (microRNAs, lipids, lipid peroxidation compounds) were carried out by quantitative PCR and liquid chromatography coupled to mass spectrometry, respectively. Then, a logistic regression model with a Bayesian variable selection procedure was developed. RESULTS: The Bayesian variable selection procedure for microRNAs did not show any relevant variable. Therefore, microRNA biomarkers were excluded. So, the developed model considered only lipids and lipid peroxidation compounds. The corresponding selected variables were age, 18:0 LPC, PGE2, isoprostanes and, isofurans. The validated model (by leave-one-out cross-validation) provided satisfactory diagnosis indexes (AUC 0.83, Sensitivity 87 %, Specificity 79 %). CONCLUSION: The developed model included biomarkers from different pathways (lipid metabolism, oxidative stress), achieving a promising approach to early, specific and, minimally invasive AD diagnosis. Nevertheless, further work to validate clinically these preliminary results with an external cohort is required. Also, the integration of different compounds coming from several biochemical pathways could constitute a relevant research field for the development of AD therapeutic targets.

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2).

The methyl-CpG binding protein 2 gene (MECP2) encodes an epigenetic transcriptional regulator implicated in neuronal plasticity. Loss-of-function mutations in this gene are the primary cause of Rett syndrome and, to a lesser degree, of other neurodevelopmental disorders. Recently, we demonstrated that both Mecp2 haploinsuficiency and mild early life stress decrease anxiety-like behaviours and neuronal activation in brain areas controlling these responses in adolescent female mice. Here, we extend this work to males by using Mecp2-null and wild type adolescent mice subjected to maternal separation and their non-stressed controls. We assessed their behavioural responses in a battery of anxiety-provoking tests. Upon exposure to an elevated plus maze in aversive conditions, we evaluated changes in c-FOS expression in stress- and anxiety-related brain regions. In addition, we assessed the impact of maternal separation in neuronal maturation using doublecortin and reelin as surrogate markers. Mutant males showed reduced motor abilities, increased activation of the olfactory bulbs, probably due to breathing abnormalities, and decreased activation of the paraventricular thalamic nucleus, when compared to wild type mice. In addition, maternal separation increased the number of immature doublecortin-like neurons found in Mecp2-null animals. Moreover, this work shows for the first time that reelin is decreased in the mutant animals at the olfactory tubercle, piriform cortex and hippocampal dentate gyrus, an effect also associated to maternal separation. Taken together, our results suggest that maternal separation exacerbates some phenotypical alterations associated with lack of MeCP2 in adolescent males.

Does peer review improve the statistical content of manuscripts? A study on 27 467 submissions to four journals.

Improving the methodological rigour and the quality of data analysis in manuscripts submitted to journals is key to ensure the validity of scientific claims. However, there is scant knowledge of how manuscripts change throughout the review process in academic journals. Here, we examined 27 467 manuscripts submitted to four journals from the Royal Society (2006-2017) and analysed the effect of peer review on the amount of statistical content of manuscripts, i.e. one of the most important aspects to assess the methodological rigour of manuscripts. We found that manuscripts with both initial low or high levels of statistical content increased their statistical content during peer review. The availability of guidelines on statistics in the review forms of journals was associated with an initial similarity of statistical content of manuscripts but did not have any relevant implications on manuscript change during peer review. We found that when reports were more concentrated on statistical content, there was a higher probability that these manuscripts were eventually rejected by editors.

On the Design and Validation of Assessing Tools for Measuring the Impact of Programs Promoting STEM Vocations.

This paper presents the design and validation process of a set of instruments to evaluate the impact of an informal learning initiative to promote Science, Technology, Engineering, and Mathematics (STEM) vocations in students, their families (parents), and teachers. The proposed set of instruments, beyond assessing the satisfaction of the public involved, allow collecting data to evaluate the impact in terms of changes in the consideration of the role of women in STEM areas and STEM vocations. The procedure followed to develop the set of instruments consisted of two phases. In the first phase, a preliminary version (v1) of the questionnaires was designed based on the objectives of the Girls4STEM initiative, an inclusive project promoting STEM vocations between 6 and 18 years old boys and girls. Five specific questionnaires were designed, one for the families (post activity), two for the students (pre and post activity) and two for the teachers (pre and post avitivity). A refined version (v2) of each questionnaire was obtained with evidence of content validity after undergoing an expert judgment process. The second phase was the refinement of the (v2) instruments, to ascertain the evidence of reliability and validity so that a final version (v3) was derived. In the paper, a high-quality set of good practices focused on promoting diversity and gender equality in the STEM sector are presented from a Higher Education Institution perspective, the University of Valencia. The main contribution of this work is the achievement of a set of instruments, rigorously designed for the evaluation of the implementation and effectiveness of a STEM promoting program, with sufficient validity evidence. Moreover, the proposed instruments can be a reference for the evaluation of other projects aimed at diversifying the STEM sector.

Subsurface swimming and stationary diving are metabolically cheap in adult Pacific walruses (Odobenus rosmarus divergens).

Walruses rely on sea-ice to efficiently forage and rest between diving bouts while maintaining proximity to prime foraging habitat. Recent declines in summer sea ice have resulted in walruses hauling out on land where they have to travel farther to access productive benthic habitat while potentially increasing energetic costs. Despite the need to better understand the impact of sea ice loss on energy expenditure, knowledge about metabolic demands of specific behaviours in walruses is scarce. In the present study, 3 adult female Pacific walruses (Odobenus rosmarus divergens) housed in professional care participated in flow-through respirometry trials to measure metabolic rates while floating inactive at the water surface during a minimum of 5 min, during a 180 s stationary dive, and while swimming ∼90 m horizontally underwater. Metabolic rates during stationary dives (3.82±0.56 l O2 min-1) were lower than those measured at the water surface (4.64±1.04 l O2 min-1), which did not differ from rates measured during subsurface swimming (4.91±0.77 l O2 min-1). Thus, neither stationary diving nor subsurface swimming resulted in metabolic rates above those exhibited by walruses at the water surface. These results suggest that walruses minimize their energetic investment during underwater behaviours as reported for other marine mammals. Although environmental factors experienced by free-ranging walruses (e.g. winds or currents) likely affect metabolic rates, our results provide important information for understanding how behavioural changes affect energetic costs and can be used to improve bioenergetics models aimed at predicting the metabolic consequences of climate change on walruses.

A Trans-Omics Comparison Reveals Common Gene Expression Strategies in Four Model Organisms and Exposes Similarities and Differences between Them.

The ultimate goal of gene expression regulation is on the protein level. However, because the amounts of mRNAs and proteins are controlled by their synthesis and degradation rates, the cellular amount of a given protein can be attained by following different strategies. By studying omics data for six expression variables (mRNA and protein amounts, plus their synthesis and decay rates), we previously demonstrated the existence of common expression strategies (CESs) for functionally related genes in the yeast Saccharomyces cerevisiae. Here we extend that study to two other eukaryotes: the yeast Schizosaccharomyces pombe and cultured human HeLa cells. We also use genomic data from the model prokaryote Escherichia coli as an external reference. We show that six-variable profiles (6VPs) can be constructed for every gene and that these 6VPs are similar for genes with similar functions in all the studied organisms. The differences in 6VPs between organisms can be used to establish their phylogenetic relationships. The analysis of the correlations among the six variables supports the hypothesis that most gene expression control occurs in actively growing organisms at the transcription rate level, and that translation plays a minor role. We propose that living organisms use CESs for the genes acting on the same physiological pathways, especially for those belonging to stable macromolecular complexes, but CESs have been modeled by evolution to adapt to the specific life circumstances of each organism.

Short and Long-Term Trainability in Older Adults: Training and Detraining Following Two Years of Multicomponent Cognitive-Physical Exercise Training.

Despite the benefits of multicomponent physical-cognitive training programs (MCCogTPs), lower training intensities in the concurrent approach, and bigger heterogeneity with aging, suggest the need for long-term analyses, with special attention to training and detraining in older adults. The present study aims to examine these training/detraining effects in a two year MCCogTP, looking for specific dynamics in the trainability of their physical and cognitive capacities. The intervention was divided into four periods: T1, T2 (8 months of training each), and D1, D2 (3.5 months of detraining plus 0.5 of testing each). Twenty-five healthy seniors (70.82 ± 5.18 years) comprised the final sample and were assessed for cardiovascular fitness (6-minutes walking test), lower-limbs strength (30-seconds chair-stand test) and agility (8-feet timed up-and-go test). Inhibition (Stroop test) was considered for executive function. Physical and cognitive status improved significantly (p < 0.05) throughout the two years, with larger enhancements for physical function (mainly strength and agility). Strength and cardiovascular fitness were more sensitive to detraining, whilst agility proved to have larger training retentions. Inhibition followed an initial similar trend, but it was the only variable to improve along D2 (d = 0.52), and changes were not significant within periods. Notwithstanding aging, and the exercise cessation in D2, physical and cognitive status remained enhanced two years later compared to baseline, except for lower-limb strength. According to these results, basic physical capacities are very sensitive to training/detraining, deserving continuous attention (especially strength). Both reducing detraining periods and complementary resistance training should be considered. Additionally, physical enhancements following MCcogTPs may help cognition maintenance during detraining.

Bayesian joint modeling for assessing the progression of chronic kidney disease in children.

Joint models are rich and flexible models for analyzing longitudinal data with nonignorable missing data mechanisms. This article proposes a Bayesian random-effects joint model to assess the evolution of a longitudinal process in terms of a linear mixed-effects model that accounts for heterogeneity between the subjects, serial correlation, and measurement error. Dropout is modeled in terms of a survival model with competing risks and left truncation. The model is applied to data coming from ReVaPIR, a project involving children with chronic kidney disease whose evolution is mainly assessed through longitudinal measurements of glomerular filtration rate.

Bayesian joint modeling of bivariate longitudinal and competing risks data: An application to study patient-ventilator asynchronies in critical care patients.

Mechanical ventilation is a common procedure of life support in intensive care. Patient-ventilator asynchronies (PVAs) occur when the timing of the ventilator cycle is not simultaneous with the timing of the patient respiratory cycle. The association between severity markers and the events death or alive discharge has been acknowledged before, however, little is known about the addition of PVAs data to the analyses. We used an index of asynchronies (AI) to measure PVAs and the SOFA (sequential organ failure assessment) score to assess overall severity. To investigate the added value of including the AI, we propose a Bayesian joint model of bivariate longitudinal and competing risks data. The longitudinal process includes a mixed effects model for the SOFA score and a mixed effects beta regression model for the AI. The survival process is defined in terms of a cause-specific hazards model for the competing risks death or alive discharge. Our model indicates that the SOFA score is strongly related to vital status. PVAs are positively associated with alive discharge but there is not enough evidence that PVAs provide a more accurate indication of death prognosis than the SOFA score alone.

Clinical audit of COPD patients requiring hospital admissions in Spain: AUDIPOC study.

BACKGROUNDS: AUDIPOC is a nationwide clinical audit that describes the characteristics, interventions and outcomes of patients admitted to Spanish hospitals because of an exacerbation of chronic obstructive pulmonary disease (ECOPD), assessing the compliance of these parameters with current international guidelines. The present study describes hospital resources, hospital factors related to case recruitment variability, patients' characteristics, and adherence to guidelines. METHODOLOGY/PRINCIPAL FINDINGS: An organisational database was completed by all participant hospitals recording resources and organisation. Over an 8-week period 11,564 consecutive ECOPD admissions to 129 Spanish hospitals covering 70% of the Spanish population were prospectively identified. At hospital discharge, 5,178 patients (45% of eligible) were finally included, and thus constituted the audited population. Audited patients were reassessed 90 days after admission for survival and readmission rates. A wide variability was observed in relation to most variables, hospital adherence to guidelines, and readmissions and death. Median inpatient mortality was 5% (across-hospital range 0-35%). Among discharged patients, 37% required readmission (0-62%) and 6.5% died (0-35%). The overall mortality rate was 11.6% (0-50%). Hospital size and complexity and aspects related to hospital COPD awareness were significantly associated with case recruitment. Clinical management most often complied with diagnosis and treatment recommendations but rarely (<50%) addressed guidance on healthy life-styles. CONCLUSIONS/SIGNIFICANCE: The AUDIPOC study highlights the large across-hospital variability in resources and organization of hospitals, patient characteristics, process of care, and outcomes. The study also identifies resources and organizational characteristics associated with the admission of COPD cases, as well as aspects of daily clinical care amenable to improvement.