Trophectoderm cells of human mosaic embryos display increased apoptotic levels and impaired differentiation capacity: a molecular clue regarding their reproductive fate?

STUDY QUESTION: Are there cell lineage-related differences in the apoptotic rates and differentiation capacity of human blastocysts diagnosed as euploid, mosaic, and aneuploid after preimplantation genetic testing for aneuploidy (PGT-A) based on concurrent copy number and genotyping analysis? SUMMARY ANSWER: Trophectoderm (TE) cells of mosaic and aneuploid blastocysts exhibit significantly higher levels of apoptosis and significantly reduced differentiation capacity compared to those of euploid blastocysts. WHAT IS KNOWN ALREADY: Embryos diagnosed as mosaic after PGT-A can develop into healthy infants, yet understanding the reasons behind their reproductive potential requires further research. One hypothesis suggests that mosaicism can be normalized through selective apoptosis and reduced proliferation of aneuploid cells, but direct evidence of these mechanisms in human embryos is lacking. Additionally, data interpretation from studies involving mosaic embryos has been hampered by retrospective analysis methods and the high incidence of false-positive mosaic diagnoses stemming from the use of poorly specific PGT-A platforms. STUDY DESIGN, SIZE, DURATION: Prospective cohort study performing colocalization of cell-lineage and apoptotic markers by immunofluorescence (IF). We included a total of 64 human blastocysts donated to research on Day 5 or 6 post-fertilization (dpf) by 43 couples who underwent in vitro fertilization treatment with PGT-A at IVI-RMA Valencia between September 2019 and October 2022. A total of 27 mosaic blastocysts were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study consisted of two phases: Phase I (caspase-3, n = 53 blastocysts): n = 13 euploid, n = 22 mosaic, n = 18 aneuploid. Phase II (terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), n = 11 blastocysts): n = 2 euploid, n = 5 mosaic, n = 4 aneuploid. Following donation for research, vitrified blastocysts were warmed, cultured until re-expansion, fixed, processed for IF, and imaged using confocal microscopy. For each blastocyst, the following cell counts were conducted: total cells (DAPI+), TE cells (GATA3+), inner cell mass (ICM) cells (GATA3-/NANOG+), and apoptotic cells (caspase-3+ or TUNEL+). The incidence of apoptosis was calculated for each blastocyst by dividing the number of caspase-3+ cells (Phase I) or TUNEL+ cells (Phase II) by the number of TE or ICM cells. Statistical analysis was performed according to data type and distribution (P < 0.05 was considered statistically significant). MAIN RESULTS AND THE ROLE OF CHANCE: Phase I: Mosaic blastocysts displayed a similar number of total cells (49.6 ± 15 cells at 5 dpf; 58.8 ± 16.9 cells at 6 dpf), TE cells (38.8 ± 13.7 cells at 5 dpf; 49.2 ± 16.2 cells at 6 dpf), and ICM cells (10.9 ± 4.2 cells at 5 dpf; 9.7 ± 7.1 cells at 6 dpf) compared to euploid and aneuploid blastocysts (P > 0.05). The proportion of TE cells retaining NANOG expression increased gradually from euploid blastocysts (9.7% = 63/651 cells at 5 dpf; 0% = 0/157 cells at 6 dpf) to mosaic blastocysts (13.1% = 104/794 cells at 5 dpf; 3.4% = 12/353 cells at 6 dpf) and aneuploid blastocysts (27.9% = 149/534 cells at 5 dpf; 4.6% = 19/417 cells at 6 dpf) (P < 0.05). At the TE level, caspase-3+ cells were frequently observed (39% = 901/2310 cells). The proportion of caspase-3+ TE cells was significantly higher in mosaic blastocysts (44.1% ± 19.6 at 5 dpf; 43% ± 16.8 at 6 dpf) and aneuploid blastocysts (45.9% ± 16.1 at 5 dpf; 49% ± 15.1 at 6 dpf) compared to euploid blastocysts (26.6% ± 16.6 at 5 dpf; 17.5% ± 14.8 at 6 dpf) (P < 0.05). In contrast, at the ICM level, caspase-3+ cells were rarely observed (1.9% = 11/596 cells), and only detected in mosaic blastocysts (2.6% = 6/232 cells) and aneuploid blastocysts (2.5% = 5/197 cells) (P > 0.05). Phase II: Consistently, TUNEL+ cells were only observed in TE cells (32.4% = 124/383 cells). An increasing trend was identified toward a higher proportion of TUNEL+ cells in the TE of mosaic blastocysts (37.2% ± 21.9) and aneuploid blastocysts (39% ± 41.7), compared to euploid blastocysts (23% ± 32.5), although these differences did not reach statistical significance (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: The observed effects on apoptosis and differentiation may not be exclusive to aneuploid cells. Additionally, variations in aneuploidies and unexplored factors related to blastocyst development and karyotype concordance may introduce potential biases and uncertainties in the results. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate a cell lineage-specific effect of aneuploidy on the apoptotic levels and differentiation capacity of human blastocysts. This contributes to unravelling the biological characteristics of mosaic blastocysts and supports the concept of clonal depletion of aneuploid cells in explaining their reproductive potential. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by grants from Centro para el Desarrollo Tecnológico Industrial (CDTI) (20190022) and Generalitat Valenciana (APOTIP/2019/009). None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The effect of vitrification on blastocyst mitochondrial DNA dynamics and gene expression profiles.

PURPOSE: Does vitrification/warming affect the mitochondrial DNA (mtDNA) content and the gene expression profile of blastocysts? METHODS: Prospective cohort study in which 89 blastocysts were obtained from 50 patients between July 2017 and August 2018. mtDNA was measured in a total of 71 aneuploid blastocysts by means of real-time polymerase chain reaction (RT-PCR). Transcriptomic analysis was performed by RNA sequencing (RNA-seq) in an additional 8 aneuploid blastocysts cultured for 0 h after warming, and 10 aneuploid blastocysts cultured for 4-5 h after warming. RESULTS: A significant decrease in mtDNA content just during the first hour after the warming process in blastocysts was found (P < 0.05). However, mtDNA content experimented a significantly increased along the later culture hours achieving the original mtDNA levels before vitrification after 4-5 h of culture (P < 0.05). Gene expression analysis and functional enrichment analysis revealed that such recovery was accompanied by upregulation of pathways associated with embryo developmental capacity and uterine embryo development. Interestingly, the significant increase in mtDNA content observed in blastocysts just after warming also coincided with the differential expression of several cellular stress response-related pathways, such as apoptosis, DNA damage, humoral immune responses, and cancer. CONCLUSION: To our knowledge, this is the first study demonstrating in humans, a modulation in blastocysts mtDNA content in response to vitrification and warming. These results will be useful in understanding which pathways and mechanisms may be activated in human blastocysts following vitrification and warming before a transfer.

Pharmacy stewardship to reduce recurrent hypoglycemia.

BACKGROUND: Inpatient hypoglycemia is associated with increased morbidity and mortality. After a hypoglycemic event, the likelihood of additional episodes increases. The Joint Commission recommends evaluating all episodes of hypoglycemia for root-cause analysis. Studies have shown that pharmacists' involvement with glycemic control protocols can prevent hypoglycemia. OBJECTIVES: This study aimed to assess whether the implementation of pharmacists' real-time assessment of hypoglycemic events using an electronic alert messaging system contributes to the reduction of the number of recurrent hypoglycemia during hospitalization. PRACTICE DESCRIPTION: A community hospital that provides a wide range of health care services. The pharmacy department provides fully decentralized clinical services and team-based specialist services. PRACTICE INNOVATION: The pharmacist-led hypoglycemia stewardship initiative included a comprehensive review of hypoglycemic alerts received via an automated message. The alerts generated in the electronic health record (EHR) every time a patient's blood glucose resulted in less than 70 mg/dL if there was a documented administration of a hypoglycemic agent 48 hours before the hypoglycemia event. Once the alert was received by the pharmacists via an EHR in-basket, a real-time review was conducted to identify the potential causes of the event and opportunities for therapy modification. EVALUATION METHODS: A single-center retrospective observational study including a pre- and post-implementation phase from January 1 to June 3, 2020, and January 1 to June 30, 2021, respectively. Continuous data were analyzed using paired and equal variance t test. Noncontinuous data were analyzed using Fisher exact and chi-square test. Descriptive statistics were used to describe distribution and frequency of data. RESULTS: There was a 5.1% absolute reduction in recurrent hypoglycemic events (P < 0.001) and a 0.6% reduction of severe hypoglycemic days (P = 0.269) in the postimplementation group. The average time to pharmacist intervention was 4 (± 3.5) hours with a 92% acceptance rate. CONCLUSION: This study demonstrated the utility of pharmacist-led hypoglycemia reviews in the reduction of recurrent hypoglycemic events in the inpatient setting.

Effects of home confinement on physical activity, nutrition, and sleep quality during the COVID-19 outbreak in amateur and elite athletes.

Introduction: Despite the progress in the management of the pandemic caused by COVID-19, it is necessary to continue exploring and explaining how this situation affected the athlete population around the world to improve their circumstances and reduce the negative impact of changes in their lifestyle conditions that were necessitated due to the pandemic. The aim of this study was to analyze the moderating influence of physical activity (PA) and dietary habits on the impact of the COVID-19 pandemic experience on sleep quality in elite and amateur athletes. Materials and methods: A total of 1,420 elite (40.1%) and amateur (59.9%) athletes (41% women; 59% men) from 14 different countries participated in a cross-sectional design study. Data were collected using a battery of questionnaires that identified sociodemographic data, sleep quality index, PA levels, dietary habits, and the athletes' perception of their experience during the COVID-19 pandemic. Means and standard deviations were calculated for each variable. The analysis of variances and the correlation between variables were carried out with non-parametric statistics. A simple moderation effect was calculated to analyze the interaction between PA or dietary habits on the perception of the COVID-19 experience effect on sleep quality in elite and amateur athletes. Results: The PA level of elite athletes was higher than amateur athletes during COVID-19 (p < 0.001). However, the PA level of both categories of athletes was lower during COVID-19 than pre-COVID-19 (p < 0.01). In addition, amateurs had a higher diet quality than elite athletes during the pandemic (p = 0.014). The perception of the COVID-19 experience as controllable was significantly higher (p = 0.020) among elite athletes. In addition, two moderating effects had significant interactions. For amateur athletes, the PA level moderated the effect of controllable COVID-19 experience on sleep quality [F (3,777) = 3.05; p = 0.028], while for elite athletes, the same effect was moderated by dietary habits [F (3,506) = 4.47, p = 0.004]. Conclusion: Elite athletes had different lifestyle behaviors compared to amateurs during the COVID-19 lockdown. Furthermore, the relevance of maintaining high levels of PA for amateurs and good quality dietary habits by elite athletes was noted by the moderating effect that both variables had on the influence of the controllable experience during the COVID-19 pandemic on sleep quality.

One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients.

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.

Physical activity level measured by accelerometry and physical fitness of schoolchildren / Nível de atividade física mensurada por acelerometria e aptidão física de escolares

Abstract Objective: To describe and compare physical fitness variables according to compliance with the recommendations of physical activity, measured by accelerometry. Methods: The sample gathered 120 students, 57 boys and 63 girls aged 9 to 11 years. The variables analyzed were: weight, stature, BMI, skinfolds, waist circumference, agility, flexibility, speed and strength of upper and lower limbs, and abdominal strength. Physical activity was measured objectively using an accelerometer. The students were divided into two groups: "complies with recommendations" (≥60min/day) and "does not comply with recommendations" (<60min/day). To verify the normality of the data, the Kolmogorov-Smirnov test was used. The mean values of students who do or do not comply with the physical activity recommendation were compared using Student's t and U-Mann Whitney tests. The level of significance was set at p<0.05. Results: The students who followed the recommendation showed significantly lower values compared to those who did not for adiposity (sum of 7 skinfolds); body weight; body mass index (BMI) and abdominal strength. No significant differences were found in the variables of speed and agility, and the upper limbs' strength was greater in subjects who did not comply with recommendations. Conclusions: Students who complied with physical activity recommendations had better body composition and more abdominal strength than those who did not.

RESUMO Objetivo: Descrever e comparar as variáveis da aptidão física de acordo com o cumprimento da recomendação de atividade física, medida por acelerometria. Métodos: A amostra foi composta de 120 escolares, sendo 57 meninos e 63 meninas, de 9 a 11 anos de idade. As variáveis analisadas foram: peso, estatura, índice de massa corpórea (IMC), dobras cutâneas, circunferências, agilidade, flexibilidade, velocidade e força de membros superiores, inferiores e abdominal. A atividade física foi mensurada de forma objetiva por meio de acelerômetro. Os escolares foram divididos em dois grupos: "cumpre a recomendação" (≥60min/dia) e "não cumpre a recomendação" (<60min/dia). Para verificar a normalidade dos dados, foi utilizado o teste de Kolmogorov-Smirnov. A comparação dos valores médios dos escolares que cumprem ou não a recomendação de atividade física foi feita pelos testes t de Student e U de Mann-Whitney. O nível de significância adotado foi de p<0,05. Resultados: Os escolares que cumpriram a recomendação, comparados com os que não cumpriram, apresentaram valores significativamente menores para adiposidade (somatória das sete dobras cutâneas), peso corporal, IMC e força abdominal. Não foram encontradas diferenças significativas nas variáveis de velocidade e agilidade; quanto à força de membros superiores (MMSS), constatou-se que ela foi maior em quem não cumpriu a recomendação. Conclusões: Crianças que cumpriram a recomendação de atividade física apresentaram melhor composição corporal e força abdominal que as crianças que não cumpriram.

Physical activity level measured by accelerometry and physical fitness of schoolchildren.

OBJECTIVE: To describe and compare physical fitness variables according to compliance with the recommendations of physical activity, measured by accelerometry. METHODS: The sample gathered 120 students, 57 boys and 63 girls aged 9 to 11 years. The variables analyzed were: weight, stature, BMI, skinfolds, waist circumference, agility, flexibility, speed and strength of upper and lower limbs, and abdominal strength. Physical activity was measured objectively using an accelerometer. The students were divided into two groups: "complies with recommendations" (≥60min/day) and "does not comply with recommendations" (<60min/day). To verify the normality of the data, the Kolmogorov-Smirnov test was used. The mean values of students who do or do not comply with the physical activity recommendation were compared using Student's t and U-Mann Whitney tests. The level of significance was set at p<0.05. RESULTS: The students who followed the recommendation showed significantly lower values compared to those who did not for adiposity (sum of 7 skinfolds); body weight; body mass index (BMI) and abdominal strength. No significant differences were found in the variables of speed and agility, and the upper limbs' strength was greater in subjects who did not comply with recommendations. CONCLUSIONS: Students who complied with physical activity recommendations had better body composition and more abdominal strength than those who did not.

Fatores do estilo de vida estão associados à adiposidade em escolares de Ilhabela? Um estudo transversal / Are lifestyle factors associated with adiposity in schoolchildren from Ilhabela? A cross-sectional study

Excesso de peso e obesidade têm aumentado no Brasil e no mundo causando grande impacto na saúde pública. O objetivo foi medir a associação do nível de atividade física, o comportamento sedentário e o tempo de sono com a composição corporal de escolares. Uma amostra por conveniência foi composta por 97 escolares participantes do Projeto Misto-Longitudinal de Crescimento, Desenvolvimento de Ilhabela, aparentemente saudáveis, 50 meninos e 47 meninas entre 9 e 11 anos (x 9,8 ± 0,7), com avaliação completa no período analisado (2015 e 2019) em estágio pré-púbere de maturação sexual. Variáveis analisadas: peso (kg); índice de massa corporal (kg/m2); adiposidade pela média de três dobras cutâneas: tríceps, subescapular e suprailíaca (mm); relação cintura quadril (cm). Nível de atividade física, comportamento sedentário e tempo de sono mensurados por acelerômetro (ActiGraph GT3X, analisado com Freedson 1998) dados em counts por minuto. Dados descritos em média (x) e desvio padrão. Normalidade dos dados obtida com o teste de Kolmogorov-Smirnov e para as associações utilizou-se o coeficiente de correlação de Spearman Rho (SPSS-20.0). Nível de significância adotado P < 0,05. Houve associações significativas entre comportamento sedentário, atividades físicas leve, moderada/vigorosa e as variáveis da composição corporal. Nas meninas, as associações entre o comportamento sedentário e as variáveis da composição corporal foram de maior número e intensidade nas correlações encontradas. Verificamos que meninos realizaram atividade física leve apresentando menores valores na composição corporal. As meninas realizaram pouca atividade física de moderada a vigorosa necessitando aumento desta variável para diminuir adiposidade. O tempo de sono não apresentou associação significativa.

Prevalência e fatores associados à sarcopenia em homens e mulheres ativos acima de 50 anos de idade. Um estudo transversal / Prevalence and factors associated with sarcopenia in active men and women over 50 years of age. A cross-sectional study

Introdução: As alterações na composição corporal em idosos, principalmente na redução da massa muscular, provocam o declínio físico e prejuízo da qualidade de vida, aumentando o risco de quedas, institucionalizações e morte. Identificar os fatores associados à sarcopenia possibilita a realização de estratégias para prevenção e reversão deste fenômeno durante o processo de envelhecimento. Objetivo: O estudo teve como objetivo verificar a prevalência e fatores associados à sarcopenia em homens e mulheres não sedentários acima de 50 anos de idade. Tipo de estudo e local: Estudo transversal com homens e mulheres de São Caetano do Sul. Métodos: Foram avaliados 787 mulheres e 123 homens do Projeto Longitudinal de Envelhecimento e Aptidão Física de São Caetano do Sul que frequentam duas vezes na semana um programa de atividade física orientado do município. Para determinar a sarcopenia, utilizou-se o critério de redução da massa muscular (circunferência muscular do braço) e redução da força (preensão manual) ou a redução do desempenho (velocidade de andar). As variáveis independentes foram sexo, idade, índice de massa corporal (IMC), socioeconômicas, comportamentais, de saúde e nível de atividade física. Resultados: A prevalência de sarcopenia foi de 13,5%, na qual 18,4% da amostra apresentou redução da massa muscular, 34,2% diminuição da velocidade de andar e 50,9% redução da força muscular. A prevalência de sarcopenia foi maior em quem não cumpria a recomendação de atividade física (65,8%), assim como quem ultrapassava o recomendado de tempo sentado durante a semana (63,2%). Conclusão: Os fatores associados à sarcopenia são IMC, circunferência de cintura e panturrilha. PALAVRAS-CHAVE: Envelhecimento, sarcopenia, sistema musculoesquelético, força muscular, desempenho físico funcional

Valgismo associado à aptidão física, nível de atividade física e tempo sedentário em escolares. Um estudo transversal / Valgus associated with fitness physical, physical activity level and sedentary time in schoolchildren. A cross-sectional study

Introdução: Os desvios axiais dos membros inferiores estão associados ao aumento da adiposidade, desconforto na prática da atividade física, dificultando um estilo de vida fisicamente ativo. Objetivo: Associar os graus de geno valgo com a intensidade da atividade física e o tempo sedentário, assim como determinar a relação com a aptidão física em escolares de Ilhabela. Tipo de estudo e local: Estudo transversal em escolares de Ilhabela, SP. Métodos: Estudo transversal, com amostra por conveniência, de 96 escolares entre 9 e 11 anos, residentes em Ilhabela, São Paulo. O geno valgo foi avaliado por goniômetro, classificando a distância intermaleolar (DIM, cm) em leve, moderada e grave. O nível de atividade física foi avaliado por acelerômetro (ActiGraph GT3X-BT, Freedson P.S), sendo classificado em atividade física: leve, moderada, moderada a vigorosa, vigorosa e tempo sedentário. Análise estatística: Foi utilizado o Teste t de Student, análise de variância (ANOVA oneway) seguido da correlação de Pearson, por meio do software SPSS versão 20.0, adotando nível de significância de P < 0,05. Resultados: No grau leve DIM, as associações moderadas e significativas das intensidades do nivel de atividade física foram mais fortes no sexo feminino. Com o aumento do grau na classificação moderado e grave (DIM) as associações são de moderada a forte e significativas somente no sexo masculino. Conclusão: Concluímos que o aumento dos graus de geno valgo foi associado a um maior tempo sedentário e à intensidade da atividade física leve; e há um menor envolvimento com atividades de intensidades moderada e moderada/vigorosa.

Location and Species Matters: Variable Influence of the Environment on the Gene Flow of Imperiled, Native and Invasive Cottontails.

The environment plays an important role in the movement of individuals and their associated genes among populations, which facilitates gene flow. Gene flow can help maintain the genetic diversity both within and between populations and counter the negative impact of genetic drift, which can decrease the fitness of individuals. Sympatric species can have different habitat preferences, and thus can exhibit different patterns of genetic variability and population structure. The specialist-generalist variation hypothesis (SGVH) predicts that specialists will have lower genetic diversity, lower effective population sizes (Ne), and less gene flow among populations. In this study, we used spatially explicit, individual-based comparative approaches to test SGVH predictions in two sympatric cottontail species and identify environmental variables that influence their gene flow. New England cottontail (Sylvilagus transitionalis) is the only native cottontail in the Northeast US, an early successional habitat specialist, and a species of conservation concern. Eastern cottontail (S. floridanus) is an invasive species in the Northeast US and a habitat generalist. We characterized each species' genomic variation by developing double-digest Restriction-site Associated DNA sequence single nucleotide polymorphism markers, quantified their habitat with Geographic Information System environmental variables, and conducted our analyses at multiple scales. Surprisingly, both species had similar levels of genetic diversity and eastern cottontail's Ne was only higher than New England cottontail in one of three subregions. At a regional level, the population clusters of New England cottontail were more distinct than eastern cottontail, but the subregional levels showed more geographic areas of restricted gene flow for eastern cottontail than New England cottontail. In general, the environmental variables had the predicted effect on each species' gene flow. However, the most important environmental variable varied by subregion and species, which shows that location and species matter. Our results provide partial support for the SGVH and the identification of environmental variables that facilitate or impede gene flow can be used to help inform management decisions to conserve New England cottontail.

Kynurenines increase MRS metabolites in basal ganglia and decrease resting-state connectivity in frontostriatal reward circuitry in depression.

Inflammation is associated with the development of anhedonia in major depression (MD), but the pathway by which inflammatory molecules gain access to the brain and lead to anhedonia is not clear. Molecules of the kynurenine pathway (KP), which is activated by inflammation, readily influx into the brain and generate end products that alter brain chemistry, disrupt circuit functioning, and result in the expression of inflammatory behaviors such as anhedonia. We examined the impact of plasma and CSF KP metabolites on brain chemistry and neural function using multimodal neuroimaging in 49 depressed subjects. We measured markers of glial dysfunction and distress including glutamate (Glu) and myo-inositol in the left basal ganglia using magnetic resonance spectroscopy (MRS); metrics of local activity coherence (regional homogeneity, ReHo) and functional connectivity from resting-state functional MRI measures; and anhedonia from the Inventory for Depressive Symptoms-Self Report Version (IDS-SR). Plasma kynurenine/tryptophan (KYN/TRP) ratio and cerebrospinal fluid (CSF) 3-hydroxykynurenine (3HK) were associated with increases in left basal ganglia myo-inositol. Plasma kynurenic acid (KYNA) and KYNA/QA were associated with decreases and quinolinic acid (QA) with increases in left basal ganglia Glu. Plasma and CSF KP were associated with decreases in ReHo in the basal ganglia and dorsomedial prefrontal regions (DMPFC) and impaired functional connectivity between these two regions. DMPFC-basal ganglia mediated the effect of plasma and CSF KP on anhedonia. These findings highlight the pathological impact of KP system dysregulation in mediating inflammatory behaviors such as anhedonia.

Changes in sleep EEG with aging in humans and rodents.

Sleep is one of the most ubiquitous but also complex animal behaviors. It is regulated at the global, systems level scale by circadian and homeostatic processes. Across the 24-h day, distribution of sleep/wake activity differs between species, with global sleep states characterized by defined patterns of brain electric activity and electromyography. Sleep patterns have been most intensely investigated in mammalian species. The present review begins with a brief overview on current understandings on the regulation of sleep, and its interaction with aging. An overview on age-related variations in the sleep states and associated electrophysiology and oscillatory events in humans as well as in the most common laboratory rodents follows. We present findings observed in different studies and meta-analyses, indicating links to putative physiological changes in the aged brain. Concepts requiring a more integrative view on the role of circadian and homeostatic sleep regulatory mechanisms to explain aging in sleep are emerging.

The morphokinetic signature of mosaic embryos: evidence in support of their own genetic identity.

OBJECTIVE: To provide full morphokinetic characterization of embryos ranked with different degrees of chromosomal mosaicism. DESIGN: Retrospective cohort study. SETTING: University-affiliated private in vitro fertilization clinic. PATIENT(S): We analyzed 1,511 embryos from 424 intracytoplasmic sperm injection cycles by culturing embryos in a time-lapse imaging system and performing next-generation sequencing. We assessed 106 mosaic embryos. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Comparison of chromosomal, morphological, and morphokinetic characteristics of blastocysts classified as euploid, aneuploid, low-degree mosaic (30% to <50% aneuploid cells in trophectoderm biopsy), and high-degree mosaic (50% to <70% aneuploid cells in trophectoderm biopsy). Statistical analysis was performed using χ2, Kruskal-Wallis, or analysis of variance tests according to data type and distribution. A two-way random effects model was used to calculate interoperator correlation of annotations, and a logistic mixed effects model was performed to evaluate the effect of confounders on morphokinetic timing. RESULT(S): The mosaicism rate was ∼7% regardless of parental age. Mosaicism and uniform aneuploidies were not evenly distributed across chromosomes. The percentage of high-quality blastocysts significantly decreased from euploid (66.9%) to mosaic (52.8%) and aneuploid (47.7%). Aneuploid blastocysts significantly delayed development compared with euploid blastocysts in start of compaction (median, 84.72 hours postmicroinjection [hpm], interquartile range [IQR], 13.2; vs. median, 82.10 hpm, IQR, 11.5), start of blastulation (median, 101 hpm; IQR, 11.7; vs. median, 98.29 hpm, IQR, 10.5), and timing of blastocyst (median, 108.04 hpm, IQR, 11.50; vs. median, 104.71 hpm, IQR, 11.35). However, embryo morphokinetics were not correlated to the degree of mosaicism or to a mosaicism configuration that was apt for embryo transfer. CONCLUSION(S): Morphokinetic timing of mosaic embryos overlaps with that of euploid and aneuploid embryos, which may reflect their unique genetic and developmental identity. Although this suggests mosaic embryos are not simply a misdiagnosis by-product, further studies are needed to reveal the true identity of this particular type of embryo.

Tendência secular de 30 anos da frequência cardíaca em meninos escolares de Ilhabela, São Paulo / Secular trend of 30 years of heart rate in boys schoolchildren from Ilhabela, São Paulo

Introdução: A frequência cardíaca de repouso (FCR) pode ser considerada como indicador de saúde, uma vez que a baixa FCR está associada a uma maior expectativa de vida. Objetivo: Descrever a tendência secular da FCR em escolares do Município de Ilhabela. Métodos: Foram selecionados para esta amostra um total de 196 meninos que envolviam três décadas, com dados de 1978 (n = 41), 1988 (n = 42), 1998 (n = 61) e 2008 (n = 52), com idades entre 12 a 14 anos. A FCR foi mensurada sempre antes de realizar o teste no cicloergômetro. Foi utilizada a análise de variância simples (ANOVA oneway) para comparar as médias da FCR de cada ano e um teste post-hoc Scheffé, com nível de significância de P < 0,01. Resultados: A média da FCR foi de 81,3 bpm no ano de 1978; 85,2 bpm no ano de 1988; 89,4 bpm no ano de 1998 e 91,7 bpm no ano de 2008. Esse aumento se mostrou significativo na comparação de 1998 e 2008 em relação a 1978 e 1988. Conclusão: Os resultados mostram que houve tendência secular positiva para o aumento da FCR, sugerindo declínio das condições cardiorrespiratórias dos escolares daquela região.

Efficacy of a two-session repetitive negative thinking-focused acceptance and commitment therapy (ACT) protocol for depression and generalized anxiety disorder: A randomized waitlist control trial.

This parallel randomized controlled trial aimed to evaluate the effect of acceptance and commitment therapy (ACT) focused on disrupting repetitive negative thinking (RNT) versus a waitlist control (WLC) in the treatment of depression and generalized anxiety disorder (GAD). Forty-eight participants with a main diagnosis of depression and/or GAD were allocated by means of simple randomization to a 2-session RNT-focused ACT intervention or to the WLC. The primary outcomes were emotional symptoms as measured by the Depression, Anxiety, and Stress Scales-21. Process outcomes included ACT- and RNT-related measures: general RNT, experiential avoidance, cognitive fusion, values, and generalized pliance. At the 1-month follow-up, linear mixed effects models showed that the intervention was efficacious in reducing emotional symptoms (d = 2.42, 95% confidence interval [1.64, 3.19]), with 94.12% of participants in the RNT-focused ACT condition showing clinically significant change in the Depression, Anxiety, and Stress Scales-21 total scores versus 9.09% in the WLC condition (70% vs. 8% in intention-to-treat analysis). The intervention effects were maintained at the 3-month follow-up. No adverse events were found. A very brief RNT-focused ACT intervention was highly effective in the treatment of depression and GAD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Mitochondrial DNA content decreases during in vitro human embryo development: insights into mitochondrial DNA variation in preimplantation embryos donated for research.

OBJECTIVE: To assess the mitochondrial DNA (mtDNA) load and variation in human oocytes and during preimplantation embryo development using specimens donated for research. DESIGN: Prospective cohort study. SETTING: Not applicable. PATIENTS: A total of 50 in vitro fertilization patients and 11 oocyte donors whose specimens were obtained between July 2017 and July 2018. INTERVENTIONS: None. MAIN OUTCOME MEASURES: All specimens were separately collected. Quantitative polymerase chain reaction was performed with SurePlex DNA Amplification System (Illumina). Primers for the adenosine triphosphate 8 mitochondrial gene and the ß-actin were used. Data were statistically analyzed by analysis of variance with the Scheffé multiple pairwise comparison for categorical variables and by linear regression for numerical variables. RESULTS: Human metaphase II (MII) oocytes had significantly more total mtDNA copy number than day 3 embryos, and day 3 embryos had more total and per-cell mtDNA copy number than aneuploid blastocysts. There was a significant decrease in mtDNA content associated with failed-fertilized oocytes compared to noninseminated metaphase II oocytes. CONCLUSIONS: During preimplantation development, before implantation, human embryos undergo a significant decrease in total mtDNA content and no increase in mtDNA content at the blastocyst stage. Oocytes need to carry a correct threshold of mitochondrial load in the oocyte in order to successfully fertilize. An active degradation of mtDNA before implantation occurs after fertilization takes place. These findings could be used to improve knowledge about the best embryo culture conditions and would serve as a basis for further studies addressing again the use of mtDNA content as an embryo viability marker.

Single-case experimental design evaluation of repetitive negative thinking-focused acceptance and commitment therapy in generalized anxiety disorder with couple-related worry

Young adults suffering from generalized anxiety disorder (GAD) show high levels of worry about different domains, with couple relationships being the most frequent one. Excessive worry in this domain might lead to couple dysfunction, which is associated with lower outcomes of cognitive behavioral therapy. The current study analyzes the effect of an individual, 3-session, acceptance and commitment therapy (ACT) protocol focused on repetitive negative thinking (RNT) in the treatment of GAD with couple relationship as the main worry domain. Three young adults with GAD participated in this study. A delayed multiple-baseline design was implemented. All participants completed a 5 to 7-week baseline without showing improvement trends in couple-related worry (Experiences in Close Relationships -Anxiety; ECR-A) and general pathological worry (Penn State Worry Questionnaire; PSWQ). Afterwards, they received the ACT protocol, and a 3-month follow-up was conducted. All 3 participants showed evidence of intervention effects on the ECR-A and PSWQ. The standardized mean difference effect sizes for single-case experimental design were very large for the ECR-A (g= 5.93) and PSWQ (g= 3.19). No adverse events were found. Brief, RNT-focused ACT protocols for treating GAD with couple relationship as the main worry domain deserve further empirical tests

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Exercício: quanto mais, melhor? / Exercise: The more the merrier?

O entusiasmo com a melhora progressiva da potência aeróbica faz com que as pessoas se animem a se envolver cada vez mais com corridas de longa duração. Mas será que quanto mais, melhor? As evidências têm se acumulado mostrando que realmente a redução do risco de morte por todas as causas e mortalidade cardiovascular ocorre de forma marcante em volumes modestos ou intermediários. No entanto, é surpreendente verificar que a maior parte desses benefícios se reduzem à medida que o envolvimento com esses exercícios passa a ser muito intenso ou extremamente intenso. A somatória das evidências permite concluir que temos uma relação do tipo curva L ou mesmo U entre nível de intensidade do exercício e a mortalidade. Uma interessante hipótese para explicar o alto índice de mortes cardiovasculares entre esses grandes corredores recebeu a denominação de síndrome de Fidípides, em que esses excessos levariam a microisquemias miocárdicas, que evoluíram para áreas de microfibrose disparando o aparecimento de arritmias que poderiam evoluir para fibrilação ventricular.

Todo passo conta! Novas recomendações para atividade física e saúde / Every step counts! New recommendations for physical activity and health

A prescrição de atividade física para a saúde passou por diversas fases, desde uma ênfase inicial muito acentuada à intensidade, que foi progressivamente sendo suavizada em função das novas evidências, que foram confirmando benefícios imensos de atividades moderadas, e mais recentemente com atividades leves, reforçando a recomendação de pelo menos 150 minutos de atividade física por semana de intensidade moderada-vigorosa, sentar menos e a grande novidade de que todo passo conta!