Neuronal MAPT expression is mediated by long-range interactions with cis-regulatory elements.

Tauopathies are a group of neurodegenerative diseases defined by abnormal aggregates of tau, a microtubule-associated protein encoded by MAPT. MAPT expression is near absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression could be controlled by transcription factors and cis-regulatory elements specific to differentiated cell types. Given the relevance of MAPT expression to neurodegeneration pathogenesis, identification of such elements is relevant to understanding disease risk and pathogenesis. Here, we performed chromatin conformation assays (HiC & Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27ac and CTCF in NPCs and differentiated neurons to nominate candidate cis-regulatory elements (cCREs). We assayed these cCREs using luciferase assays and CRISPR interference (CRISPRi) experiments to measure their effects on MAPT expression. Finally, we integrated cCRE annotations into an analysis of genetic variation in neurodegeneration-affected individuals and control subjects. We identified both proximal and distal regulatory elements for MAPT and confirmed the regulatory function for several regions, including three regions centromeric to MAPT beyond the H1/H2 haplotype inversion breakpoint. We also found that rare and predicted damaging genetic variation in nominated CREs was nominally depleted in dementia-affected individuals relative to control subjects, consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduced MAPT expression, may be protective against neurodegenerative disease. Overall, this study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Availability and characteristics of pulmonary rehabilitation programs in family health centers and hospitals from Chile: Descriptive, retrospective and multicentric study.

OBJECTIVE: To determine availability and characteristics of pulmonary rehabilitation programs performed in 2019 in family health centers and hospitals from Chile. METHODOLOGY: A descriptive and retrospective study was designed, considering PR programs operated in 2019. A non-probability and convenience sample was obtained. Availability and characteristics of centers and PR were measured using a questionnaire translated, modified, validated, and sent by email. RESULTS: Out of 80 responses (22.8%), 60% of centers offered PR program, where the lack of time was the greatest barrier. The programs were mainly outpatient, non-personalized, with 10(IQR 4-11) participants, 12 (IQR 12-16) weeks of length, with 2.4 ± 0.6 session/week, and 1 (IQR 1-2) hours/session. Chronic Obstructive Pulmonary Disease (COPD) was the most frequent diagnostic. The programs were mainly comprised of strength training exercises of lower extremity, upper extremity, walking and education. Team was constituted of physiotherapist and physician, with completed training, and directed by a physiotherapist. Modified Borg, MRC dyspnea scale, six-minute walking test and oximetry were used in the assessments. Between 40-80% of patients completed PR, and the major barrier was patient relocated. CONCLUSION: Increasing PR availability, homogenization of exercises and education, prioritization of assessments supported by scientific evidence, and inclusion of follow-up could be useful to improve the access, quality and results of the treatment, considering new models of PR that allow greater access and acceptability.

Psychometric Properties of the Arabic Version of the EPInfant Scale among Typically Developing Children Aged 6-16 Years.

AIMS: The EPInfant scale is a self-assessment for children that measures perceived exertion (PE) during physical exercise. This study aimed to translate the scale into Arabic (EPInfant-Ar) and test its psychometric properties. METHODS: The revised version was tested for face and content validity. Oxygen saturation, heart rate (HR), and ratings of perceived exertion were measured during a 3-minute step test with a sample of 93 children. PE and HR were examined using the Pearson correlation coefficient (r) to assess the concurrent validity. Internal consistency and test-retest reliability were calculated using Cronbach's alpha (α), intraclass correlation coefficient (ICC2,1), and r coefficient. A minimum detectable change with 95% confidence interval (MDC95) and percentage of change (MDC%) was also measured. RESULTS: Content validity showed an excellent level of expert agreement. There was a moderate correlation between PE rated by the scale and HR (r = 0.47, p < .001). The internal consistency and test-retest reliability were acceptable (α = 0.89; ICC2,1= 0.81; 95%Cl: 0.71-0.87, r = 0.81) with low measurement error (MDC95 = 2.66 and MDC% = 61.10%). CONCLUSIONS: The EPInfant-Ar scale was considered valid and reliable for assessing PE after physical exercises in typically developing children aged 6-16 years.

Effects of physical exercise on baroreflex sensitivity and renal sympathetic nerve activity in chronic nicotine-treated rats.

Chronic nicotine exposure may increase cardiovascular risk by impairing the cardiac autonomic function. Besides, physical exercise (PE) has shown to improve cardiovascular health. Thus, we aimed to investigate the effects of PE on baroreflex sensitivity (BRS), heart rate variability (HRV), and sympathetic nerve activity (SNA) in chronically nicotine-exposed rats. Male Wistar rats were assigned to four independent groups: Control (treated with saline solution), Control+Ex (treated with saline and submitted to treadmill training), Nicotine (treated with Nicotine), and Nicotine+Ex (treated with nicotine and submitted to treadmill training). Nicotine (1 mg·kg-1) was administered daily for 28 consecutive days. PE consisted of running exercise (60%-70% of maximal aerobic capacity) for 45 min, 5 days per week, for 4 weeks. At the end of the protocol, cardiac BRS, HRV, renal SNA (rSNA), and renal BRS were assessed. Nicotine treatment decreased absolute values of HRV indexes, increased low frequency/high frequency ratio of HRV, reduced the bradycardic and sympatho-inhibitory baroreceptor reflex responses, and reduced the rSNA. PE effectively restored time-domain HRV indexes, the bradycardic and sympatho-inhibitory reflex responses, and the rSNA in chronic nicotine-treated rats. PE was effective in preventing the deterioration of time-domain parameters of HRV, arterial baroreceptor dysfunction, and the rSNA after nicotine treatment.

Conceptual validation of an innovative remote pulmonary rehabilitation solution for Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the world. Pulmonary rehabilitation (PR) reduces COPD hospitalisations, although its use is low. Telerehabilitation is effective; however, in Chile the development of remote PR technology is incipient. Therefore, the aim of the study was to validate conceptual aspects of an innovative remote PR solution for COPD. METHODS: This mixed study used a nonprobabilistic sample of PR professionals and people with COPD (PwCOPD) from Santiago. The perception of a conceptual solution for PR through a semi-structured interview was determined. Professionals were also asked about willingness to use technology using a questionnaire designed and validated in 75 professionals in this study. The study was approved by the Ethics Committee and data were collected after informed consent. RESULTS: Twenty-two participants were recruited, of which 14 were professionals and eight were PwCOPD. Among professionals and patients, the willingness to use the solution is positive because it would reduce visits and improve self-management, although it should include a remote/in-person combination, training, and user-friendly interface. Most of the professionals were willing to use technology for pulmonary rehabilitation. CONCLUSIONS: The development of telehealth technologies should consider the expectations of patients and professionals and may incorporate elements of persuasive technologies in the design. The results could contribute to the development of digital solutions for remote PR in PwCOPD.

Physical activity assessments in children with congenital heart disease: A systematic review.

AIM: To describe the physical activity (PA) of children with congenital heart disease (CHD) according to different assessment methods and compare their results with the World Health Organization (WHO) recommendations. METHODS: A systematic review was conducted using five databases. We included cross-sectional, longitudinal, observational studies and clinical trials in a paediatric population with CHD. In publications with indirect measurement, the score in each dimension was considered. Similarly, moderate-to-vigorous PA (MVPA) was considered as the main outcome in articles with direct measurement. RESULTS: A total of 1103 articles were found, and 16 primary articles were considered. Eight articles evaluated PA with indirect methods, six with direct methods and two used both methods, representing 1649 subjects evaluated. It was found that 46% of children with CHD do not exceed WHO recommendations for MVPA, with no differences depending on the severity of CHD. CONCLUSION: There are a variety of ways to measure PA in children with CHD. In the articles that objectively evaluated PA, the most measured outcome was the MVPA, which shows that the MVPA time was shorter in about half of the children with CHD than what is recommended by WHO.

[Pediatric polygraphy: A 6-year experience]. / Poligrafía pediátrica: Experiencia de 6 años.

INTRODUCTION: The early diagnosis of Sleep Disordered Breathing (SDB) may allow proper intervention. Currently, polygraphy (PG) is a reliable and accessible alternative. OBJECTIVE: To describe and analyze the PG of children > 1 year old with suspicion of SDB. PATIENTS AND METHOD: PG of children > 1 year old and adolescents from Concepcion, Chile, with suspected SDB were included, from December 2011 to Au gust 2017. Demographic, clinical and polygraphic variables were collected. It was used descriptive sta tistics, expressing results in median and range. The association between apnea-hypopnea index (AHI) and oxygen saturation was determined by Spearman's Rho, considering significance of p < 0.05. Re sults: 190 studies were analyzed. Age 7.9 years old (1.0-20.6), 61% males. DIAGNOSIS: neuromuscular disease (NMD) (24.2%), chronic lung damage (21.1%), upper airway obstruction (UAO) (19.5%), neurological damage (11%), Down syndrome (8.9%), upper airway malformations (7.4%), central hypoventilation (3.7%), obesity (2.6%), and others (1.6%). 55.3% were altered PG, with 53.3% of mild Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS), 30.5% moderate, and 16.2% severe. There were no significant differences in AHI between groups of pathologies (p = 0.032), highlighting a higher AHI in obese patients 9 (0.41-51), and those with NMD 23.9 (0.4-36.6). It was found asso ciation between AHI and oxygen saturation parameters: mean saturation (rho = -0.425; p = 0.001), minimum (rho = -0.654; p = 0.001), and oxygen saturation below 90% (rho = 0.323; p = 0.001) in the whole sample. DISCUSSION: There was a high percentage of OSAHS in at-risk pediatric patients, especially in those with NMD and obesity. PG is an accessible and implementable tool in a public hospital, a situation that can potentially be extrapolated to other healthcare centers.

Assessment of EPInfant scale for exercise intensity perceptual self-regulation in healthy children. / Evaluación de la escala EPInfant para la auto-regulación perceptual de la intensidad del ejercicio en niños sanos.

INTRODUCTION: The EPInfant scale has been validated for the perceptual estimation of physical exer tion in Chilean children, but its usefulness for self-regulation of exercise intensity is unknown. The objective of the study was to evaluate the criterion validity of the EPInfant scale to regulate and re produce exercise intensity in a sample of healthy children. SUBJECTS AND METHOD: 15 children between the ages of eight and 12 were selected for an incremental exercise test (IET) and three perceptually regulated exercise tests (PRET) on a treadmill. The tests were performed with a 48-hour interval between them. In the PRET, the exercise load was adjusted perceptually for five minutes, randomly considering levels 3, 6, and 9 of the EPInfant scale. The average heart rate (HR) during PRET was considered as the perceptually reproduced intensity. Variance analysis, simple linear regression, and reliability analysis were used to determine the reproducibility of HR during PRET. RESULTS: There was a significant difference in HR between perceptual levels during PRET (p < 0.001). Additionally, a correlation was observed between HR during the IET and the PRET (r = 0.83, r2 = 0.69). The intra class correlation coefficient was 0.76, 0.83. and 0.93 at perceptual levels 3, 6, and 9; and the mean dis cordance between HR during the IET and the PRET was -2.4 beats/min. CONCLUSION: In the studied sample, the EPInfant scale was valid to allow the perceptual regulation and reproduction of exercise intensity in a treadmill.

[Normal values of 6-minute walk test in healthy children and adolescents: A systematic review and meta-analysis]. / Valores normales del test de marcha de 6 minutos en niños y adolescentes sanos: Una revisión sistemática y metaanálisis.

INTRODUCTION: The 6-minute walk test (SMWT) is a submaximal exercise test widely used in the clinical setting, which allows the assessment of physical capacity in healthy and chronic children. For a proper interpretation of SMWT it is necessary to compare the value obtained by the patient with a normal value appropriate for the studied population. The aim of this study was to analyze the normal values of SMWT, in order to establish grouped normal values and to evaluate their association with anthropometric and racial variables in healthy children and adolescents. METHODS: Systematic review performed in 6 electronic databases. We included studies aimed at determining normal values of SMWT in healthy children and adolescents. Normal values of the SMWT were weighted according to the sample size and their association with the gender, age and continent of origin of the study was evaluated. Additionally, the correlation coefficients between the distance during SMWT and the pre dictor variables were meta-analyzed using the random effects model. RESULTS: The review included 10 articles that included 5352 individuals (51.9% men). The weighted average of the distance dur ing SMWT was 619.8 m, there being a difference between the age, gender and continent of origin groups. The meta-analysis of random effects revealed a moderate association between the distance and height, weight and age variables. CONCLUSION: SMWT is associated with gender, continent and anthropometric variables. However, the predictive variables determine a low percentage of normal walked distance in children and adolescents.

[Validity of scales for the functional assessment of critically ill patients]. / Validez y confiabilidad de las escalas de evaluación funcional en pacientes críticamente enfermos. Revisión sistemática.

The decrease in mortality in critical patient units led to an increase in intensive care unit acquired weakness (ICUAW), which significantly affects the functional performance and quality of life of patients. There are several scales that measure functionality in critical patients. The aim of this systematic review is to determine the criterion validity and reliability of the scales that evaluate functionality in critically ill adult patients. We considered studies in critically ill adult subjects of both genders that determined the psychometric properties of the scales that evaluate functionality. Six minutes' walk test (6MWT), timed up and go (TUG), the Medical Research Council sum score (MRC-SS), grip strength, discharge destination and need for rehabilitation at discharge were considered as gold standards. Three scales were identified: PFIT-s, Perme MS, and DEMMI. PFIT-s has a positive correlation with 6MWT, MRC-SS and grip strength, and a negative correlation with TUG. It also predicts the need for rehabilitation at discharge and discharge to the home. DEMMI has a positive correlation with MRC-SS. the interobserver reliability was evaluated in three articles, demonstrating an almost perfect association. The intraobserver agreement was considered good in one report. With this information, it is not possible to determine which is the instrument with better measurement properties.

[Diagnosis of respiratory sleep disorders in newborns with suspected apneas: comparison between nocturnal saturometry and polygraphy]. / Diagnóstico de los trastornos respiratorios del sueño en recién nacidos con sospecha de apneas: comparación entre la saturometría nocturna y la poligrafía.

INTRODUCTION: Night Continuous Saturometry (CSO2) is used in Neonatal Units to detect events of hypoxemia in Newborns (NB) with apnea episodes. Polygraphy (PG) has a larger number of measuring channels. Our goal was to evaluate the diagnostic performance of CSO2 compared to Polygra phy in NB with suspected sleep apneas. PATIENTS AND METHOD: Results of CSO2 and PG performed simultaneously in RN with suspected apneas were retrospectively analyzed over a three-year period. A 2-channel Masimo Radical-7® pulse oximeter and an Apnea Link Plus® polygraph with 5 simulta neous recording channels were used. Altered PG was defined as: desaturation index under 80% per hour > 1 and/or number of desaturations under 80% > 20 seconds greater than one in the whole va lidated registry and/or hypoapnea apnea index > 1 event per hour. In parallel, altered SpO2C was de fined when one or both of the 80% saturation criteria were altered. Sensitivity, specificity, predictive values and Likelihood Ratio (LLR) for CSO2 were calculated. Results were expressed in absolute value, with 95% confidence interval. RESULTS: Simultaneous 40 CSO2 and PG were performed; 80% (32/40) of them were preterm infants, 60% (24/40) males. 38% (15/40) of the CSO2 and 15% (6/40) of the PGs were altered (p < 0.05). CSO2 has a 100% Sensitivity, 74% Specificity, 40% VPP, 100% VPN, LLR + 3.78 and LLR-0. CONCLUSION: In the studied NB, CSO2 has a high diagnostic value, however, it may present false positives; It is suggested to use as a screening method and to perform diagnostic confirmation with another sleep test, such as PG.

[Polygraphy in hospitalized children under 3 months]. / Poligrafía en menores de 3 meses hospitalizados.

Apnea and apparently lethal events have great etiological diversity thus complementary tests may help diagnosis. The aim of this study was to describe the results of polygraph studies of children under 3 months hospitalized with suspected apnea. PATIENTS AND METHODS: Retrospective case series. Children under 3 months with suspected apnea were considered and in whom a polygraphy (PG) was performed during hospitalization. General data, the apnea/hypopnea index (AHI), index of central. apnea, obstructive apnea index, average and minimum saturation were recorded. Desaturation index (ID) below 80% higher 1 per hour, one or more events of desaturation below 80% for more than 20 seconds or an AHI greater than or equal 1 were considered as criteria of sleep disorder breathing (SLB). Descriptive analysis was performed and the associations between AHI and saturation parameters were determined. RESULTS: 51 patients, 32 males, entered the study. 15,6% had altered PG. In 5 of them coexisted more than one diagnostic criterion. Iin 15,6% of the patients was observed an IAH greater 1, in 7.8% a desaturation index below 80% and in 11,8% a desaturation index under 80% for 20 seconds greater than 1. The AHI was associated with the parameters of saturation. CONCLUSION: Most of the patients had normal PG and among patients with a suggestive SLB a pattern of respiratory immaturity prevailed, which is characteristic of this age.

The identification of additional zebrafish DICP genes reveals haplotype variation and linkage to MHC class I genes.

Bony fish encode multiple multi-gene families of membrane receptors that are comprised of immunoglobulin (Ig) domains and are predicted to function in innate immunity. One of these families, the diverse immunoglobulin (Ig) domain-containing protein (DICP) genes, maps to three chromosomal loci in zebrafish. Most DICPs possess one or two Ig ectodomains and include membrane-bound and secreted forms. Membrane-bound DICPs include putative inhibitory and activating receptors. Recombinant DICP Ig domains bind lipids with varying specificity, a characteristic shared with mammalian CD300 and TREM family members. Numerous DICP transcripts amplified from different lines of zebrafish did not match the zebrafish reference genome sequence suggesting polymorphic and haplotypic variation. The expression of DICPs in three different lines of zebrafish has been characterized employing PCR-based strategies. Certain DICPs exhibit restricted expression in adult tissues whereas others are expressed ubiquitously. Transcripts of a subset of DICPs can be detected during embryonic development suggesting roles in embryonic immunity or other developmental processes. Transcripts representing 11 previously uncharacterized DICP sequences were identified. The assignment of two of these sequences to an unplaced genomic scaffold resulted in the identification of an alternative DICP haplotype that is linked to a MHC class I Z lineage haplotype on zebrafish chromosome 3. The linkage of DICP and MHC class I genes also is observable in the genomes of the related grass carp (Ctenopharyngodon idellus) and common carp (Cyprinus carpio) suggesting that this is a shared character with the last common Cyprinidae ancestor.

[Vitamin D deficiency in children admitted to the paediatric intensive care unit]. / Déficit de vitamina D en niños ingresados en cuidados intensivos pediátricos.

INTRODUCTION: Vitamin D is essential for bone health, as well as for cardiovascular and immune function. In critically ill adults vitamin D deficiency (VDD) is common, and is associated with sepsis and higher critical illness severity. OBJECTIVES: To establish the prevalence of VDD and its association with clinically relevant outcomes in children admitted to a Paediatric Intensive Care Unit (PICU) in Concepcion, Chile. PATIENTS AND METHOD: Prospective observational cohort study in 90 consecutive children admitted to the PICU in a university general hospital. Blood was collected on admission to PICU and analysed for 25-OH-D levels. Severity of illness and vasopressor use were assessed using PRISM, PELOD, and vasoactive-inotropic score (VIS) score. VDD was defined as a serum 25-OH-D level<20ng/ml. Relative risks (RR) were calculated to determine the association between VDD and relevant clinical outcomes. RESULTS: Mean (SD) serum vitamin D (25-OH-D) level in the cohort was 22.8 (1.0)ng/ml. The prevalence of VDD was 43.3%. VDD was associated with vasopressors use (RR1.6; 95%CI: 1.2-2.3; P<.01), mechanical ventilation (RR2.2; 95%CI: 1.2-3.9, P<.01), septic shock (RR1.9; 95%CI: 1.3-2.9, P<.001), and fluid bolus>40ml/kg in the first 24h of admission (RR 1.5; 95%CI: 1.1-2.1, P<.05). CONCLUSIONS: In this study, VDD at PICU admission was prevalent in critically ill children and was associated with adverse clinical outcomes. Further studies are needed to assess the potential benefit of optimizing vitamin D status in the PICU.

Differential expression and ligand binding indicate alternative functions for zebrafish polymeric immunoglobulin receptor (pIgR) and a family of pIgR-like (PIGRL) proteins.

The polymeric immunoglobulin (Ig) receptor (pIgR) is an integral transmembrane glycoprotein that plays an important role in the mammalian immune response by transporting soluble polymeric Igs across mucosal epithelial cells. Single pIgR genes, which are expressed in lymphoid organs including mucosal tissues, have been identified in several teleost species. A single pigr gene has been identified on zebrafish chromosome 2 along with a large multigene family consisting of 29 pigr-like (PIGRL) genes. Full-length transcripts from ten different PIGRL genes that encode secreted and putative inhibitory membrane-bound receptors have been characterized. Although PIGRL and pigr transcripts are detected in immune tissues, only PIGRL transcripts can be detected in lymphoid and myeloid cells. In contrast to pIgR which binds Igs, certain PIGRL proteins bind phospholipids. PIGRL transcript levels are increased after infection with Streptococcus iniae, suggesting a role for PIGRL genes during bacterial challenge. Transcript levels of PIGRL genes are decreased after infection with Snakehead rhabdovirus, suggesting that viral infection may suppress PIGRL function.

Multiomic profiling of transcription factor binding and function in human brain.

Transcription factors (TFs) orchestrate gene expression programs crucial for brain function, but we lack detailed information about TF binding in human brain tissue. We generated a multiomic resource (ChIP-seq, ATAC-seq, RNA-seq, DNA methylation) on bulk tissues and sorted nuclei from several postmortem brain regions, including binding maps for more than 100 TFs. We demonstrate improved measurements of TF activity, including motif recognition and gene expression modeling, upon identification and removal of high TF occupancy regions. Further, predictive TF binding models demonstrate a bias for these high-occupancy sites. Neuronal TFs SATB2 and TBR1 bind unique regions depleted for such sites and promote neuronal gene expression. Binding sites for TFs, including TBR1 and PKNOX1, are enriched for risk variants associated with neuropsychiatric disorders, predominantly in neurons. This work, titled BrainTF, is a powerful resource for future studies seeking to understand the roles of specific TFs in regulating gene expression in the human brain.