Long-read genome sequencing and variant reanalysis increase diagnostic yield in neurodevelopmental disorders.

Variant detection from long-read genome sequencing (lrGS) has proven to be considerably more accurate and comprehensive than variant detection from short-read genome sequencing (srGS). However, the rate at which lrGS can increase molecular diagnostic yield for rare disease is not yet precisely characterized. We performed lrGS using Pacific Biosciences "HiFi" technology on 96 short-read-negative probands with rare disease that were suspected to be genetic. We generated hg38-aligned variants and de novo phased genome assemblies, and subsequently annotated, filtered, and curated variants using clinical standards. New disease-relevant or potentially relevant genetic findings were identified in 16/96 (16.7%) probands, eight of which (8/96, 8.33%) harbored pathogenic or likely pathogenic variants. Newly identified variants were visible in both srGS and lrGS in nine probands (~9.4%) and resulted from changes to interpretation mostly from recent gene-disease association discoveries. Seven cases included variants that were only interpretable in lrGS, including copy-number variants, an inversion, a mobile element insertion, two low-complexity repeat expansions, and a 1 bp deletion. While evidence for each of these variants is, in retrospect, visible in srGS, they were either: not called within srGS data, were represented by calls with incorrect sizes or structures, or failed quality-control and filtration. Thus, while reanalysis of older data clearly increases diagnostic yield, we find that lrGS allows for substantial additional yield (7/96, 7.3%) beyond srGS. We anticipate that as lrGS analysis improves, and as lrGS datasets grow allowing for better variant frequency annotation, the additional lrGS-only rare disease yield will grow over time.

Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.

BACKGROUND: In rheumatoid arthritis (RA), the activation of T and B cell clones specific for self-antigens leads to the chronic inflammation of the synovium. Here, we perform an in-depth quantitative analysis of the seven chains that comprise the adaptive immune receptor repertoire (AIRR) in RA. RESULTS: In comparison to controls, we show that RA patients have multiple and strong differences in the B cell receptor repertoire including reduced diversity as well as altered isotype, chain, and segment frequencies. We demonstrate that therapeutic tumor necrosis factor inhibition partially restores this alteration but find a profound difference in the underlying biochemical reactivities between responders and non-responders. Combining the AIRR with HLA typing, we identify the specific T cell receptor repertoire associated with disease risk variants. Integrating these features, we further develop a molecular classifier that shows the utility of the AIRR as a diagnostic tool. CONCLUSIONS: Simultaneous sequencing of the seven chains of the human AIRR reveals novel features associated with the disease and clinically relevant phenotypes, including response to therapy. These findings show the unique potential of AIRR to address precision medicine in immune-related diseases.

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.

Allele biased transcription factor binding across human brain regions gives mechanistic insight into eQTLs.

Transcription Factors (TFs) influence gene expression by facilitating or disrupting the formation of transcription initiation machinery at particular genomic loci. Because genomic localization of TFs is in part driven by TF recognition of DNA sequence, variation in TF binding sites can disrupt TF-DNA associations and affect gene regulation. To identify variants that impact TF binding in human brain tissues, we quantified allele bias for 93 TFs analyzed with ChIP-seq experiments of multiple structural brain regions from two donors. Using graph genomes constructed from phased genomic sequence data, we compared ChIP-seq signal between alleles at heterozygous variants within each tissue sample from each donor. Comparison of results from different brain regions within donors and the same regions between donors provided measures of allele bias reproducibility. We identified thousands of DNA variants that show reproducible bias in ChIP-seq for at least one TF. We found that alleles that are rarer in the general population were more likely than common alleles to exhibit large biases, and more frequently led to reduced TF binding. Combining ChIP-seq with RNA-seq, we identified TF-allele interaction biases with RNA bias in a phased allele linked to 6,709 eQTL variants identified in GTEx data, 3,309 of which were found in neural contexts. Our results provide insights into the effects of both common and rare variation on gene regulation in the brain. These findings can facilitate mechanistic understanding of cis-regulatory variation associated with biological traits, including disease.

Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting organotropic metastasis.

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. Whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their neural crest, sympatho-adrenal origin remains unclear. Here, we identified the transcriptional signature distinguishing LR-NBs from HR-NBs, which consists mainly of genes that belong to the core sympatho-adrenal developmental program and are associated with favorable patient prognosis and with diminished disease progression. Gain- and loss-of-function experiments revealed that the top candidate gene of this signature, Neurexophilin-1 (NXPH1), has a dual impact on NB cell behavior in vivo: whereas NXPH1 and its receptor α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit organotropic colonization and metastasis. As suggested by RNA-seq analyses, these effects might result from the ability of NXPH1/α-NRXN signalling to restrain the conversion of NB cells from an adrenergic state to a mesenchymal one. Our findings thus uncover a transcriptional module of the sympatho-adrenal program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.

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.

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

Background: Tauopathies are a group of neurodegenerative diseases driven by abnormal aggregates of tau, a microtubule associated protein encoded by the MAPT gene. MAPT expression is absent in neural progenitor cells (NPCs) and increases during differentiation. This temporally dynamic expression pattern suggests that MAPT expression is 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 genetic risk factors. Methods: We performed HiC, chromatin conformation capture (Capture-C), single-nucleus multiomics (RNA-seq+ATAC-seq), bulk ATAC-seq, and ChIP-seq for H3K27Ac and CTCF in NPCs and neurons differentiated from human iPSC cultures. We nominated candidate cis-regulatory elements (cCREs) for MAPT in human NPCs, differentiated neurons, and pure cultures of inhibitory and excitatory neurons. We then 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 AD cases and controls. Results: Using orthogonal genomics approaches, we nominated 94 cCREs for MAPT, including the identification of cCREs specifically active in differentiated neurons. Eleven regions enhanced reporter gene transcription in luciferase assays. Using CRISPRi, 5 of the 94 regions tested were identified as necessary for MAPT expression as measured by RT-qPCR and RNA-seq. Rare and predicted damaging genetic variation in both nominated and confirmed CREs was depleted in AD cases relative to controls (OR = 0.40, p = 0.004), consistent with the hypothesis that variants that disrupt MAPT enhancer activity, and thereby reduce MAPT expression, may be protective against neurodegenerative disease. Conclusions: 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 well-described H1/H2 haplotype inversion breakpoint. This study provides compelling evidence for pursuing detailed knowledge of CREs for genes of interest to permit better understanding of disease risk.

Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer's disease-specific cis-regulatory elements.

Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer's disease (AD) and unaffected controls have been well documented, but few studies have rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated from cortical tissues from 7 AD and 8 unaffected donors to identify candidate cis-regulatory elements (CREs) involved in AD-associated transcriptional changes. We detected 319,861 significant correlations, or links, between gene expression and cell type-specific transposase accessible regions enriched for active CREs. Among these, 40,831 were unique to AD tissues. Validation experiments confirmed the activity of many regions, including several candidate regulators of APP expression. We identified ZEB1 and MAFB as candidate transcription factors playing important roles in AD-specific gene regulation in neurons and microglia, respectively. Microglia links were globally enriched for heritability of AD risk and previously identified active regulatory regions.

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.

Inclusion in the university: Who assumes responsibility? A qualitative study.

Society challenges higher education institutions and their members to generate inclusive communities to enable the full development of all members. This study aims to analyze who is responsible for generating inclusion according to community members from a traditional Chilean University. We carried out qualitative research based on the Grounded Theory. We collected data through focus group and semi-structured Interviews, involving 14 undergraduate students, two post-graduate students, 17 faculty members, five non-teaching staff members, and nine executives officers. All of thembelonging to the three campuses of the University. We analyzed data using ATLAS.ti 7.5.7, using the constant comparison method and reaching an axial codification level. From the data analysis, 25 subcategories emerged, grouped into six categories. Later we organized them under the codification paradigm. Results highlighted the perception of the interaction and influence of the social, institutional, and personal fields in the inclusion phenomenon. Also, that inclusive practices must be a responsibility shared among different educational community members.

The cardiorespiratory response and physiological determinants of the 6-min handbike cycle test in healthy children: A cross-sectional study.

INTRODUCTION: The submaximal tests are used to measure aerobic capacity and correlate with activities of daily living in chronic patients. The 6-min handbike cycle test (6mhct) was created for nonambulatory subjects, but there are no reference values to quantify and classify the cardiorespiratory fitness of children in this condition. OBJECTIVE(S): Generate 6mhct reference values and determine predictive variables in a population of Chilean children between 8 and 13 years old. MATERIALS AND METHODS: Cross-sectional study. Sampling for convenience, stratified by age. Evaluation of anthropometric variables, handgrip strength, heart rate (HR), effort perception, and blood pressure were performed, then the 6mhct was applied. Descriptive statistics, Student's t test and Mann-Whitney U test, correlation coefficient, and regression equation were used to estimate the total revolutions by age, being significant p < 0.05. RESULTS: Were evaluated 120 children homogeneously distributed by age. The total revolutions performed by boys and girls were 861.4 ± 102.9 and 771.8 ± 90.2, respectively (p < 0.001). There was a significant correlation between total revolutions and age (r = .52), weight (r = .29), height (r = .46), average  UULL (length of the upper limb) length (r = .44), average handgrip strength (r = .53), peak HR (r = .67), recovery HR (r = .44), and HR reserve (r = .72). The regression equation was established. CONCLUSIONS: These results can be used as preliminary reference values for the 6mhct in Chilean children from 8 to 13 years old. Handgrip strength, age, peak HR, and HR reserve influenced the performance of the 6mhct.

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.

Impact of pulmonary rehabilitation pre- and post-lung transplantation in a child with cystic fibrosis: a case report / Impacto da reabilitação pulmonar pré e pós-transplante de pulmão em paciente pediátrico com fibrose cística: relato de caso / Impacto de la rehabilitación pulmonar en el pretrasplante y en el postrasplante pulmonar en paciente pediátrico con fibrosis quística: un reporte de caso

ABSTRACT Cystic Fibrosis (CF) is a genetic disease that reduces quality of life. Lung transplantation (LTx) is a strategy for end-stage lung disease treatment in CF. Pulmonary rehabilitation (PR) in LTx is effective, however, only one study has determined its effectiveness in children, and most studies have not included CF exclusively. Thus, reports showing components for PR protocols and outcomes not considered in previous studies of PR in LTx due to CF in children are still needed. To report this case, written informed assent and consent of patient and parent were obtained. Ethical Requirement was formally waived by the institution. A 12-year-old patient with CF was referred to PR due to LTx. A general and respiratory training was conducted daily for six months (pre) and two years (post) the transplantation, with the parents' full support. General training included treadmill and cycle ergometer use and upper limbs exercises. Respiratory protocol included inspiratory training and respiratory physical therapy. We observed improvements in pulmonary function, exercise capacity, inspiratory muscle strength, and quality of life, including school functioning, with progress maintenance after 2.5 years of continuous intervention. This case presents a PR protocol pre- and post-LTx with good long-term results. These components for treatment protocols and outcomes may be useful to consider in clinical interventions or future investigations.

RESUMO Fibrose cística (FC) é uma doença genética que reduz a qualidade de vida. O transplante pulmonar (LTx) é uma estratégia para o tratamento de doenças pulmonares em fase terminal na FC. A reabilitação pulmonar (PR) no LTx é eficaz, porém apenas um estudo determinou sua eficácia em crianças, e outros estudos não incluíram a FC exclusivamente. Portanto, relatórios que mostram componentes para protocolos e resultados de RP, não considerados em estudos anteriores de RP em LTx devido à FC em crianças, ainda são necessários. Assim, descreve-se o caso de um paciente de 12 anos com FC encaminhado para RP devido à LTx. Foi obtido o consentimento informado e por escrito do paciente e dos pais. O requisito ético foi formalmente renunciado pela instituição. Um treinamento geral e respiratório foi realizado por seis meses antes e dois anos após a LTx, diariamente, com total apoio dos pais. O treinamento geral incluiu esteira, cicloergômetro e exercícios para os membros superiores. O protocolo respiratório incorporou treinamento inspiratório e fisioterapia respiratória. Foram observadas melhorias na função pulmonar, capacidade de exercício, força muscular inspiratória e qualidade de vida, incluindo o funcionamento escolar, com manutenção dos avanços após 2,5 anos de intervenção contínua. O caso apresenta um protocolo de RP pré e pós-LTx com bons resultados a longo prazo. Os componentes para protocolos de tratamento e resultados encontrados podem ser úteis para intervenções clínicas ou investigações futuras.

RESUMEN La fibrosis quística (FQ) es una enfermedad genética que reduce la calidad de vida de los afectados. El trasplante de pulmón (LTx) es una estrategia para el tratamiento de enfermedades pulmonares en fase terminal en FQ. La rehabilitación pulmonar (RP) en el LTx es eficaz, aunque solo un estudio evaluó su eficacia en niños, y otros estudios no han tratado exclusivamente de FQ. Por lo tanto, se necesitan informes que contengan elementos de los protocolos y de los resultados de RP y que no habían sido considerados en los estudios anteriores sobre RP en LTx por FQ pediátrica. Así se describe el caso del paciente de 12 años de edad con FQ que fue remitido a RP debido a LTx. Para ello, se obtuvieron el consentimiento informado y el consentimiento por escrito del paciente y sus padres. La institución renunció formalmente a los requisitos éticos. Se realizó entrenamiento general y respiratorio durante seis meses antes de LTx y dos años después de LTx, diariamente, con apoyo de los padres. El entrenamiento general incluyó cinta de correr, cicloergómetro y ejercicios para extremidades superiores. El protocolo respiratorio incluía entrenamiento inspiratorio y fisioterapia respiratoria. Se observaron mejorías en la función pulmonar, capacidad de ejercicio, fuerza muscular inspiratoria y calidad de vida del participante, incluida en la limitación de actividades, con mantenimiento de los logros tras 2,5 años de la intervención continua. El caso del estudio presentó un protocolo de RP pre- y post-LTx con buenos resultados a largo plazo. Estos elementos de los protocolos de tratamiento y los resultados encontrados pueden ser útiles en las intervenciones clínicas o en futuras investigaciones.

[Validiation of EPInfant scale in children: Estimation and production paradigms, using VO2 as reference criteria]. / Validación de la escala EPInfant en niños: Paradigmas de estimación y producción, considerando VO2 como estándar de referencia.

The EPInfant scale was developed to quantify perceived exertion (PE) during exercise in children and adolescents. OBJECTIVE: to determine the criterion validity of the EPInfant scale in children in the estimation and production paradigm considering oxygen consumption (VO2) as the reference standard. SUBJECTS AND METHOD: Twenty healthy boys, aged 9.8 ± 1.5 years, were selected. They all performed an incremental shuttle walking test (ISWT) followed by a perceptual regulated-exercise test (PRET). VO2 and heart rate (HR) were recorded during both exercise tests. Average VO2 and HR values were considered as a perceptual reproduction test (PRT). EPInfant's validity in estimating the exercise intensity was evaluated by regression analysis between VO2, HR, and PE during ISWT and PRET. RESULTS: All regression analysis models showed a robust positive relationship between PE and benchmarks (r2 > 0.90). The intraclass correlation coefficient for VO2 and HR was 0.89 (0.70 to 0.96) and 0.64 (0.08 to 0.86), respectively. Low mean discordance for VO2 and HR was observed in the Bland-Altman analysis. CONCLUSION: The EPInfant scale presented adequate criterion validity for estimating and regulating running exercise intensity in boys between 8 and 12 years.

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

Efectos de las medidas de restricción sobre la actividad física y conducta sedentaria de niños, niñas y adolescentes durante la pandemia por COVID-19: revisión sistemática / Effects of restriction measures on physical activity and sedentary behavior of children and adolescents during COVID-19 pandemic: a systematic review

Introducción: La pandemia por COVID-19 obligó a los gobiernos a implementar medidas de restricción social para proteger la salud de la población, afectando la calidad de vida de las personas, especialmente en grupos vulnerables como los niños, niñas y adolescentes (NNA). El objetivo de esta revisión sistemática (RS) fue evaluar el efecto de las medidas de restricción sobre la actividad física (AF) y conducta sedentaria (CS) de los NNA. Adicionalmente, se exploraron posibles factores determinantes de estos cambios. Métodos: Se realizó una RS, utilizando tres bases de datos. Se incluyeron estudios observacionales en donde se hubiera analizado la AF y CS de los participantes, utilizando cualquier método de evaluación. Dos investigadores analizaron los estudios, extrajeron los datos y evaluaron la calidad metodológica de los artículos primarios. El metaanálisis se realizó utilizando el modelo de efectos aleatorios, considerando un valor p < 0,05 como estadísticamente significativo. Resultados: Se incluyeron 19 artículos, con una muestra total de 15.095 NNA. La mayoría de los estudios reveló una reducción de la AF y un incremento de la CS en los sujetos, durante los confinamientos por COVID-19. El metaanálisis mostró una caída en la AF total, la AF moderada a vigorosa y un incremento del tiempo de sedentarismo. Diversos factores biodemográficos, familiares y ambientales exacerbaron las variaciones en la AF y la CS de los NNA. Conclusión: Las medidas de restricción aplicadas durante pandemia por COVID-19 redujo la AF e incrementó la CS de los NNA. Factores biodemográficos, familiares y ambientales determinaron estas variaciones.

Introduction: The COVID-19 pandemic forced governments to implement social restriction measures to protect the health of the population, affecting the quality of life of people, especially in vulnerable groups, such as children and adolescents (CA). The objective of this systematic review (SR) was to evaluate the effect of restriction measures on physical activity (PA) and sedentary behavior (SB) of CA. Additionally, possible determining factors of these changes were explored. Methods: An SR was carried out, using three databases. Observational studies were included in which the PA and SB of the participants were analyzed, using any evaluation method. Two investigators analyzed the studies, extracted data, and assessed the methodological quality of the primary articles. The meta-analysis was performed using the random effects model, considering a value of p < 0.05 as statistically significant. Results: 19 articles were included, with a total sample of 15,095 subjects. Most studies revealed a reduction in PA and an increase in SB in subjects during COVID-19 lockdowns. The meta-analysis showed a drop in total PA, moderate to vigorous PA, and an increase in sedentary time. Various biodemographic, family and environmental factors exacerbated the variations in the PA and SB of the CA. Conclusion: The restriction measures applied during the COVID-19 pandemic reduced the PA and increased the SB of the CA. Biodemographic, family and environmental factors determined these variations.

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.