Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations.

Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell­derived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

Genetic risk factors and COVID-19 severity in Brazil: results from BRACOVID study.

The coronavirus disease 2019 (COVID-19) pandemic has changed the paradigms for disease surveillance and rapid deployment of scientific-based evidence for understanding disease biology, susceptibility and treatment. We have organized a large-scale genome-wide association study (GWAS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals in Sao Paulo, Brazil, one of the most affected areas of the pandemic in the country, itself one of the most affected in the world. Here, we present the results of the initial analysis in the first 5233 participants of the BRACOVID study. We have conducted a GWAS for COVID-19 hospitalization enrolling 3533 cases (hospitalized COVID-19 participants) and 1700 controls (non-hospitalized COVID-19 participants). Models were adjusted by age, sex and the 4 first principal components. A meta-analysis was also conducted merging BRACOVID hospitalization data with the Human Genetic Initiative (HGI) Consortia results. BRACOVID results validated most loci previously identified in the HGI meta-analysis. In addition, no significant heterogeneity according to ancestral group within the Brazilian population was observed for the two most important COVID-19 severity associated loci: 3p21.31 and Chr21 near IFNAR2. Using only data provided by BRACOVID, a new genome-wide significant locus was identified on Chr1 near the genes DSTYK and RBBP5. The associated haplotype has also been previously associated with a number of blood cell related traits and might play a role in modulating the immune response in COVID-19 cases.

Gender differences in the relationship between sleep and age in a Brazilian cohort: the Baependi Heart Study.

Gender and age are well-established determinants of health and sleep health that influence overall health, which also often varies by gender and age. Sleep architecture is an important component of sleep health. The goal of this analysis was to examine whether associations between age and sleep stages differ by gender in the absence of moderate-severe obstructive sleep apnea (OSA) in a rural setting in Brazil. This study conducted polysomnography recordings in the Baependi Heart Study, a cohort of Brazilian adults. Our sample included 584 women and 309 men whose apnea-hypopnea index was ≤15 events/h. We used splines to distinguish non-linear associations between age, total sleep time, wake after sleep onset (WASO), N2, N3, and rapid-eye-movement sleep. The mean (standard deviation; range) age was 47 (14; 18-89) years. All sleep outcomes were associated with age. Compared to men, women had more N3 sleep and less WASO after adjusting for age. Model-based comparisons between genders at specific ages showed statistically higher mean WASO for men at ages 60 (+13.6 min) and 70 years (+19.5 min) and less N3 for men at ages 50 (-13.2 min), 60 (-19.0 min), and 70 years (-19.5 min) but no differences at 20, 30, 40 or 80 years. The other sleep measures did not differ by gender at any age. Thus, even in the absence of moderate-severe OSA, sleep architecture was associated with age across adulthood, and there were gender differences in WASO and N3 at older ages in this rural community.

Evaluation of wakefulness electroencephalogram in OSA patients.

OBJECTIVE: Obstructive sleep apnea (OSA) has been associated with an elevated cardiovascular risk, increased daytime sleepiness, cognitive decline, and slower electroencephalographic activity (EEG). This study assesses EEG patterns during wakefulness in OSA patients compared to those without sleep-disordered breathing. MATERIALS AND METHODS: This retrospective study analyzed 30 OSA patients with an Apnea/Hypopnea Index (AHI) of 15 or higher, as well as 29 individuals without sleep-disordered breathing (AHI of 5 or lower) who underwent hospital polysomnography and met all inclusion criteria. Sociodemographic and EEG data were obtained from the sleep laboratory database. Blinded EEG analysis was conducted by two observers, assessing activity in the frontal, central, and occipital regions. RESULTS: No significant differences were observed in EEG activity between OSA and non-OSA patients. However, a weak correlation was found between decreased C3 EEG frequency and higher AHI (p = 0.033), as well as increased total sleep time and higher O2 EEG frequency (p = 0.038). Lower amplitudes in C3 (p = 0.043) and O1 (p = 0.031) were correlated with reduced average oxygen saturation. CONCLUSION: Our findings suggest that OSA-related hypoxemia may impact neuronal activity, highlighting the need to address this sleep-disordered breathing in order to potentially prevent the cognitive decline observed in OSA patients.

Discordant clinical features of identical hypertrophic cardiomyopathy twins.

Hypertrophic cardiomyopathy (HCM) is a disease of heart muscle, which affects ∼1 in 500 individuals and is characterized by increased left ventricular wall thickness. While HCM is caused by pathogenic variants in any one of eight sarcomere protein genes, clinical expression varies considerably, even among patients with the same pathogenic variant. To determine whether background genetic variation or environmental factors drive these differences, we studied disease progression in 11 pairs of monozygotic HCM twins. The twin pairs were followed for 5 to 14 y, and left ventricular wall thickness, left atrial diameter, and left ventricular ejection fraction were collected from echocardiograms at various time points. All nine twin pairs with sarcomere protein gene variants and two with unknown disease etiologies had discordant morphologic features of the heart, demonstrating the influence of nonhereditable factors on clinical expression of HCM. Whole genome sequencing analysis of the six monozygotic twins with discordant HCM phenotypes did not reveal notable somatic genetic variants that might explain their clinical differences. Discordant cardiac morphology of identical twins highlights a significant role for epigenetics and environment in HCM disease progression.

Pediatric dentistry systematic reviews using the GRADE approach: methodological study.

BACKGROUND: To assess the reporting of the certainty of the evidence using the GRADE approach in systematic reviews of interventions in pediatric dentistry. METHODS: The inclusion criteria were systematic reviews of randomized clinical trials (RCTs) and non-randomized studies of interventions (NRSIs) in pediatric dentistry that reported the certainty of the evidence through the GRADE approach. Paired independent reviewers screened the studies, extracted data, and appraised the methodological quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) tool. The certainty of the evidence was extracted for each outcome. A descriptive analysis was conducted. RESULTS: Around 28% of pediatric dentistry reviews of interventions used the GRADE approach (n = 24). Twenty reviews reported 112 evidence outcomes from RCTs and 13 from NRSIs using GRADE evidence profile tables. The methodological quality was high (16.7%), moderate (12.5%), low (37.5%), and critically low (33.3%), fulfilling the majority of the AMSTAR 2 criteria. The certainty of the evidence for outcomes generated from RCTs and NRSIs was very low (40.2% and 84.6%), low (33.1% and 7.7%), moderate (17.8% and 7.7%), and high (9.8% and 0.0%). The main reasons to downgrade the certainty were due to (for RCTs and NRSIs, respectively): risk of bias (68.8% and 84.6%), imprecision (67.8% and 100.0%), inconsistency (18.8% and 23.1%), indirectness (17.8% and 0.0%), and publication bias (7.1% and 0.0%). CONCLUSION: The proportion of systematic reviews assessing the certainty of the evidence using the GRADE approach was considered small, considering the total initial number of published pediatric dentistry reviews of intervention. The certainty of the evidence was mainly very low and low, and the main problems for downgrading the certainty of evidence were due to risk of bias and imprecision. REGISTRATION: PROSPERO database #CRD42022365443.

Roadmap for Establishing Large-Scale Genomic Medicine Initiatives in Low- and Middle-Income Countries.

In the post-genomic era, genomic medicine interventions as a key component of personalized medicine and tailored-made health care are greatly anticipated following recent scientific and technological advances. Indeed, large-scale sequencing efforts that explore human genomic variation have been initiated in several, mostly developed, countries across the globe, such as the United States, the United Kingdom, and a few others. Here, we highlight the successful implementation of large-scale national genomic initiatives, namely the Genome of Greece (GoGreece) and the DNA do Brasil (DNABr), aiming to emphasize the importance of implementing such initiatives in developing countries. Based on this experience, we also provide a roadmap for replicating these projects in other low-resource settings, thereby bringing genomic medicine in these countries closer to clinical fruition.

Towards clinical-dose grating interferometry breast CT with fused intensity-based iterative reconstruction.

X-ray grating interferometry CT (GI-CT) is an emerging imaging modality which provides three complementary contrasts that could increase the diagnostic content of clinical breast CT: absorption, phase, and dark-field. Yet, reconstructing the three image channels under clinically compatible conditions is challenging because of severe ill-conditioning of the tomographic reconstruction problem. In this work we propose to solve this problem with a novel reconstruction algorithm that assumes a fixed relation between the absorption and the phase-contrast channel to reconstruct a single image by automatically fusing the absorption and phase channels. The results on both simulations and real data show that, enabled by the proposed algorithm, GI-CT outperforms conventional CT at a clinical dose.

Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency.

[Figure: see text].

Percentiles of predicted 10-year cardiovascular disease risk by sex and age in Brazil and their association with estimated risk of long-term atherosclerotic events.

OBJECTIVE: Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk. METHODS: A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group. RESULTS: Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25th risk percentile, those at the ≥75th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6. CONCLUSIONS: We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals.

Loss of mTORC2 Activity in Neutrophils Impairs Fusion of Granules and Affects Cellular Metabolism Favoring Increased Bacterial Burden in Sepsis.

Sepsis is a complex infectious syndrome in which neutrophil participation is crucial for patient survival. Neutrophils quickly sense and eliminate the pathogen by using different effector mechanisms controlled by metabolic processes. The mammalian target of rapamycin (mTOR) pathway is an important route for metabolic regulation, and its role in neutrophil metabolism has not been fully understood yet, especially the importance of mTOR complex 2 (mTORC2) in the neutrophil effector functions. In this study, we observed that the loss of Rictor (mTORC2 scaffold protein) in primary mouse-derived neutrophils affects their chemotaxis by fMLF and their microbial killing capacity, but not the phagocytic capacity. We found that the microbicidal capacity was impaired in Rictor-deleted neutrophils because of an improper fusion of granules, reducing the hypochlorous acid production. The loss of Rictor also led to metabolic alterations in isolated neutrophils, increasing aerobic glycolysis. Finally, myeloid-Rictor-deleted mice (LysMRic Δ/Δ) also showed an impairment of the microbicidal capacity, increasing the bacterial burden in the Escherichia coli sepsis model. Overall, our results highlight the importance of proper mTORC2 activation for neutrophil effector functions and metabolism during sepsis.

Body posture as a factor determining sleep quality in patients using non-invasive ventilation.

OBJECTIVE: Sleep quality is influenced by multiple factors. Slow-wave sleep and REM sleep play a key role in homeostasis and are useful indicators of sleep quality. Studies indicate that obstructive sleep apnea (OSA) in the supine position correlates with anatomical changes that exacerbate respiratory events and influence the effectiveness of ventilation therapy. This study aimed to evaluate the correlation of body posture with polysomnographic data and adherence of patients using continuous positive airway pressure (CPAP). MATERIAL AND METHODS: This was a retrospective study of patients with OSA who had polysomnography in Rainha Santa Isabel Hospital's sleep laboratory in Torres Novas, Portugal, and met all the inclusion and exclusion criteria. Sociodemographic, polysomnographic, and ventilation therapy variables were collected from that sleep laboratory database between 2015 and 2019. RESULTS: In 30 patients with OSA, residual apnea-hypopnea index (AHIr) and arousal index were lower in the non-supine position compared to the supine position (p value 0.005 and 0.009 respectively). As measures of sleep quality, total sleep time in SWS and REM sleep were greater in the non-supine position compared to the supine position (p value of 0.002 and 0.010 respectively). CONCLUSION: The findings suggest that a supine position significantly impairs sleep quality mainly by increasing the number of respiratory events and associated sleep fragmentation. The findings also suggest that the difference in AHIr between supine and non-supine positions may contribute to non-adherence with CPAP in patients with OSA.

Change detection versus change localization for faces, houses, and words.

Holistic processing aids in the discrimination of visually similar objects, but it may also come with a cost. Indeed holistic processing may improve the ability to detect changes to a face while impairing the ability to locate where the changes occur. We investigated the capacity to detect the occurrence of a change versus the capacity to detect the localization of a change for faces, houses, and words. Change detection was better than change localization for faces. Change localization outperformed change detection for houses. For words, there was no difference between detection and localization. We know from previous studies that words are processed holistically. However, being an object of visual expertise processed holistically, visual words are also a linguistic entity. Previously, the word composite effect was found for phonologically consistent words but not for phonologically inconsistent words. Being an object of visual expertise for which linguistic information is important, letter position information, is also crucial. Thus, the importance of localization of letters and features may augment the capacity to localize a change in words making the detection of a change and the detection of localization of a change equivalent.

The mechanisms supporting holistic perception of words and faces are not independent.

The question of whether word and face recognition rely on overlapping or dissociable neural and cognitive mechanisms received considerable attention in the literature. In the present work, we presented words (aligned or misaligned) superimposed on faces (aligned or misaligned) and tested the interference from the unattended stimulus category on holistic processing of the attended category. In Experiment 1, we found that holistic face processing is reduced when a face was overlaid with an unattended, aligned word (processed holistically). In Experiment 2, we found a similar reduction of holistic processing for words when a word was superimposed on an unattended, aligned face (processed holistically). This reciprocal interference effect indicates a trade-off in holistic processing of the two stimuli, consistent with the idea that word and face recognition may rely on non-independent, overlapping mechanisms.

Gender, race/skin colour and incidence of hypertension in ELSA-Brasil: an intersectional approach.

OBJECTIVE: Race and gender inequities in the incidence of hypertension (HTN) are well documented; however, few empirical investigations looked into these associations, considering the synergies and heterogeneous experiences of intersectional gender and race/skin colour groups. This study investigated the association of intersectional identities defined by gender and race/skin colour with HTN incidence, and verified whether they are affected by educational level in adulthood. DESIGN: We used the Longitudinal Study of Adult Health (ELSA-Brasil) data to estimate the incidence of HTN between visits 1 (2008-2010) and 2 (2012-2014), in 8528 participants without hypertension at visit 1. HTN was defined as systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or use of antihypertensive drugs. Generalized linear models with Poisson distribution and log link function were used to assess the associations. RESULTS: The incidence of HTN was 43.4/1000 person-years, ranging from 30.5/1000 in White women to 59.4/1000 in Black men. After adjusting by age and family history of HTN, the incidence rate ratio (IRR) was higher in Black men (2.25; 95%CI: 1.65-3.08), Brown (Pardo) men (1.89; 95%CI: 1.59-2.25), Black women (1.85; 95%CI: 1.50-2.30), Brown (Parda) women (1.47; 95%CI: 1.31-1.67) and White men (1.76; 95%CI: 1.49-2.08), compared to White women. These associations were maintained even after considering socioeconomic, behavioural and health mediators in the model. No interaction was found between education level and intersectional identities in the IRRs observed. CONCLUSION: By using an intersectional approach, we showed the complex relations between race/skin colour and gender inequities in the incidence of HTN, pointing not only that Black men have the highest risk of developing HTN, but also that the risk of HTN is greater in Black women than in White men, when compared to White women.

Genomic insight into the origins and dispersal of the Brazilian coastal natives.

In the 15th century, ∼900,000 Native Americans, mostly Tupí speakers, lived on the Brazilian coast. By the end of the 18th century, the coastal native populations were declared extinct. The Tupí arrived on the east coast after leaving the Amazonian basin ∼2,000 y before present; however, there is no consensus on how this migration occurred: toward the northern Amazon and then directly to the Atlantic coast, or heading south into the continent and then migrating to the coast. Here we leveraged genomic data from one of the last remaining putative representatives of the Tupí coastal branch, a small, admixed, self-reported Tupiniquim community, as well as data of a Guaraní Mbyá native population from Southern Brazil and of three other native populations from the Amazonian region. We demonstrated that the Tupiniquim Native American ancestry is not related to any extant Brazilian Native American population already studied, and thus they could be considered the only living representatives of the extinct Tupí branch that used to settle the Atlantic Coast of Brazil. Furthermore, these data show evidence of a direct migration from Amazon to the Northeast Coast in pre-Columbian time, giving rise to the Tupí Coastal populations, and a single distinct migration southward that originated the Guaraní people from Brazil and Paraguay. This study elucidates the population dynamics and diversification of the Brazilian natives at a genomic level, which was made possible by recovering data from the Brazilian coastal population through the genomes of mestizo individuals.

Association between carotid intima-media thickness and cognitive decline differs by race.

INTRODUCTION: Common carotid intima-media thickness (cIMT) is a marker of subclinical atherosclerosis and is associated with cognitive decline. Although carotid atherosclerosis is more frequent in White than in Black participants, little is known whether race modifies the association between cIMT and cognitive decline. METHODS: In this longitudinal analysis of the ELSA-Brasil, we assessed cIMT using ultrasound and cognitive performance using different domain tests. We used linear mixed models, interaction analysis, and race stratified analyses. RESULTS: Baseline high IMT values were associated with memory (p < 0.001), verbal fluency (p < 0.001), TMT-B (p < 0.001)), and global cognitive decline (p < 0.001). Race was an effect modifier in the association between IMT and global cognitive decline (0.043), with stronger association in White (p < 0.001) than in Black (p = 0.009) participants. DISCUSSION: Baseline IMT was associated with global and domain-specific cognitive decline and race modified this relationship, with stronger associations in White participants. HIGHLIGHTS: Carotid intima-media thickness (cIMT) was associated with cognitive decline. cIMT and cognitive decline association was stronger in White than in Black participants. We used inverse probability weighting to address attrition bias.

Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and Excitation-Contraction Coupling.

Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.