Members of the GATA family of transcription factors are critical regulators of heart development and mutations in 2 of them,
GATA4 and
GATA6 are associated with outflow tract and septal defects in ...human. The heart expresses 3 GATA factors, GATA4, 5 and 6 in a partially overlapping pattern. Here, we report that compound
Gata4/
Gata5 and
Gata5/
Gata6 mutants die embryonically or perinatally due to severe congenital heart defects. Almost all
Gata4
+/−
Gata5
+/−
mutant embryos have double outlet right ventricles (DORV), large ventricular septal defects (VSD) as well as hypertrophied mitral and tricuspid valves. Only 25% of double compound
Gata4/
Gata5 heterozygotes survive to adulthood and these mice have aortic stenosis. Compound loss of a
Gata5 and a
Gata6 allele also leads to DORVs associated with subaortic VSDs. Expression of several transcription factors important for endocardial and myocardial cell differentiation, such as Tbx20, Mef2c, Hey1 and Hand2, was reduced in compound heterozygote embryos. These findings suggest the existence of important genetic interactions between Gata5 and the 2 other cardiac GATA factors in endocardial cushion formation and outflow tract morphogenesis. The data identify
GATA5 as a potential genetic modifier of congenital heart disease and provide insight for elucidating the genetic basis of an important class of human birth defects.
►We analyzed the genetic interactions between GATA5 and GATA4/6 in heart development. ►Double hets die embryonically and perinatally from severe congenital heart defects. ►Endocardial and myocardial differentiation markers are downregulated in double hets. ►This will help elucidate the molecular basis of an important class of CHDs. ►This identifies GATA5 as a potential genetic modifier of congenital heart defects.
Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected ...molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
First-principles calculations show that ZnSnN sub(2) has a very small formation enthalpy, and the donor defects such as Sn sub(Zn) antisites and O sub(N) impurities have high concentration, making ...the material degenerately n-type, which explains the observed high electron concentration. ZnSnN sub(2) can be regarded as a new material that combines a metal-like conductivity with an optical bandgap around 2 eV.
•Common defects and anomalies in powder bed fusion metal additive manufacturing.•Formation mechanism and practical mitigation strategies are discussed.•Defects/anomalies are classified as ...powder-related, processing-related, and post-processing related issues.•Properties such as mechanical behavior and corrosion resistance of defective parts are discussed.•Current challenges, gaps, and future trends are discussed.
Metal additive manufacturing is a disruptive technology that is revolutionizing the manufacturing industry. Despite its unrivaled capability for directly fabricating metal parts with complex geometries, the wide realization of the technology is currently limited by microstructural defects and anomalies, which could significantly degrade the structural integrity and service performance of the product. Accurate detection, characterization, and prediction of these defects and anomalies have an important and immediate impact in manufacturing fully-dense and defect-free builds. This review seeks to elucidate common defects/anomalies and their formation mechanisms in powder bed fusion additive manufacturing processes. They could arise from raw materials, processing conditions, and post-processing. While defects/anomalies in laser welding have been studied extensively, their formation and evolution remain unclear. Additionally, the existence of powder in powder bed fusion techniques may generate new types of defects, e.g., porosity transferring from powder to builds. Practical strategies to mitigate defects are also addressed through fundamental understanding of their formation. Such explorations enable the validation and calibration of models and ease the process qualification without costly trial-and-error experimentation.
To quantify the burden of selected congenital anomalies in low and middle-income countries (LMICs) that could be reduced should surgical programmes cover the entire population with access to quality ...care.
Burden of disease and epidemiological modelling.
LMICs from all global regions.
All prevalent cases of selected congenital anomalies at birth in 2010.
Disability-adjusted life years (DALYs).
Surgical programmes for three congenital conditions were analysed: clefts (lip and palate); congenital heart anomalies; and neural tube defects. Data from the Global Burden of Disease 2010 Study were used to estimate the combination of fatal burden that could be addressed by surgical care and the additional long-term non-fatal burden associated with increased survival.
Of the estimated 21.6 million DALYs caused by these three conditions in LMICs, 12.4 million DALYs (57%) are potentially addressable by surgical care among the population born with such conditions. Neural tube defects have the largest potential with 76% of burden amenable by surgery, followed by clefts (59%) and congenital heart anomalies (49%). Sub-Saharan Africa and South Asia have the greatest proportion of surgically addressable burden for clefts (68%), North Africa and Middle East for congenital heart anomalies (73%), and South Asia for neural tube defects (81%).
There is an important and neglected role surgical programmes can play in reducing the burden of congenital anomalies in LMICs.
Abstract
Introduction: Anatomical localization of brain infarcts based on clinical symptoms and signs is a key step in stroke diagnosis, but evidence linking specific clinical features with infarct ...locations is limited. We aimed to identify symptoms and signs of ischemic events that statistically favor precise posterior circulation locations.
Patients and Methods: We analyzed data from the New England Medical Center Posterior Circulation Registry for 407 adults with previous posterior circulation ischemia (confirmed by brain/vascular imaging). Using multivariate logistic regression and the binary sorting table method, we determined the negative and positive predictive values of 24 signs and symptoms for infarct localization within the proximal, middle, or distal posterior circulation territories.
Results: Visual field defect (hemianopia) was a positive or negative sign for all 3 brain stem regions. The presence of visual field defect positively correlated only with the distal region (P < .001), and its absence indicated infarction in the proximal (P = .007) or middle (P < .001) territories. Visual field defect showed the greatest localizing sensitivity and specificity with other signs: visual field defect absence with presence of nausea−vomiting for the proximal region, or hemiparesis and other motor signs in the middle region; presence of visual field defect alone or with absence of generalized weakness in the distal region.
Discussion and Conclusion: Presence of visual field defect alone statistically confirms the occurrence of a distal region infarct and excludes proximal or middle territory involvement. Moreover, presence or absence of this sign in the presence of other signs or symptoms localizes the event to proximal or middle regions.
The prevalence of pulmonary hypertension (PH) appears to be high after shunt closure (2) and is associated with increased morbidity and mortality (3). ...only limited data on the risk of PH after ...shunt closure were available, and these data were hampered by the use of database encoded analyses, single-center studies, or small cohort studies in specific cardiac defects. In multivariate conditional logistic regression analysis of the case-control cohort, presence of PH pre-closure (rate ratio 5.7; 95% CI: 2.4 to 13.6; p <0.001) and New York Heart Association functional class >I pre-closure (rate ratio: 2.9; 95% CI: 1.3 to 6.8; p = 0.009) were the strongest predictors for PH development after closure, corrected for age at closure, sex, underlying CHD defect, presence of right bundle branch block, right atrial or ventricular dilation, right ventricular dysfunction, and history of supraventricular tachycardia.
Congenital heart disease is the most frequent birth defect and the leading cause of death for the fetus and in the first year of life. The wide phenotypic diversity of congenital heart defects ...requires expert diagnosis and sophisticated repair surgery. Although these defects have been described since the seventeenth century, it was only in 2005 that a consensus international nomenclature was adopted, followed by an international classification in 2017 to help provide better management of patients. Advances in genetic engineering, imaging, and omics analyses have uncovered mechanisms of heart formation and malformation in animal models, but approximately 80% of congenital heart defects have an unknown genetic origin. Here, we summarize current knowledge of congenital structural heart defects, intertwining clinical and fundamental research perspectives, with the aim to foster interdisciplinary collaborations at the cutting edge of each field. We also discuss remaining challenges in better understanding congenital heart defects and providing benefits to patients.
Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown.
To compare the risk of congenital malformations ...following in utero exposure to buprenorphine vs methadone.
This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022.
A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester.
Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights.
The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean SD maternal age, 28.4 4.6 years) and 3846 with methadone exposure (mean SD maternal age, 28.8 4.7 years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses.
In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, ...implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.
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