Transforming growth factor beta signaling: The master sculptor of fingers.

Transforming growth factor beta (TGFß) constitutes a large and evolutionarily conserved superfamily of secreted factors that play essential roles in embryonic development, cancer, tissue regeneration, and human degenerative pathology. Studies of this signaling cascade in the regulation of cellular and tissue changes in the three-dimensional context of a developing embryo have notably advanced in the understanding of the action mechanism of these growth factors. In this review, we address the role of TGFß signaling in the developing limb, focusing on its essential function in the morphogenesis of the autopod. As we discuss in this work, modern mouse genetic experiments together with more classical embryological approaches in chick embryos, provided very valuable information concerning the role of TGFß and Activin family members in the morphogenesis of the digits of tetrapods, including the formation of phalanxes, digital tendons, and interphalangeal joints. We emphasize the importance of the Activin and TGFß proteins as digit inducing factors and their critical interaction with the BMP signaling to sculpt the hand and foot morphology.

Regulation of Developmental Cell Death in the Animal Kingdom: A Critical Analysis of Epigenetic versus Genetic Factors.

The present paper proposes a new level of regulation of programmed cell death (PCD) in developing systems based on epigenetics. We argue against the traditional view of PCD as an altruistic "cell suicide" activated by specific gene-encoded signals with the function of favoring the development of their neighboring progenitors to properly form embryonic organs. In contrast, we propose that signals and local tissue interactions responsible for growth and differentiation of the embryonic tissues generate domains where cells retain an epigenetic profile sensitive to DNA damage that results in its subsequent elimination in a fashion reminiscent of what happens with scaffolding at the end of the construction of a building. Canonical death genes, including Bcl-2 family members, caspases, and lysosomal proteases, would reflect the downstream molecular machinery that executes the dying process rather than being master cell death regulatory signals.

Cell death in the developing vertebrate limb: A locally regulated mechanism contributing to musculoskeletal tissue morphogenesis and differentiation.

Our aim is to critically review current knowledge of the function and regulation of cell death in the developing limb. We provide a detailed, but short, overview of the areas of cell death observed in the developing limb, establishing their function in morphogenesis and structural development of limb tissues. We will examine the functions of this process in the formation and growth of the limb primordia, formation of cartilaginous skeleton, formation of synovial joints, and establishment of muscle bellies, tendons, and entheses. We will analyze the plasticity of the cell death program by focusing on the developmental potential of progenitors prior to death. Considering the prolonged plasticity of progenitors to escape from the death process, we will discuss a new biological perspective that explains cell death: this process, rather than secondary to a specific genetic program, is a consequence of the tissue building strategy employed by the embryo based on the formation of scaffolds that disintegrate once their associated neighboring structures differentiate.

Cell senescence, apoptosis and DNA damage cooperate in the remodeling processes accounting for heart morphogenesis.

During embryonic development, organ morphogenesis requires major tissue rearrangements that are tightly regulated at the genetic level. A large number of studies performed in recent decades assigned a central role to programmed cell death for such morphogenetic tissue rearrangements that often sculpt the shape of embryonic organs. However, accumulating evidence indicates that far from being the only factor responsible for sculpting organ morphology, programmed cell death is accompanied by other tissue remodeling events that ensure the outcome of morphogenesis. In this regard, cell senescence has been recently associated with morphogenetic degenerative embryonic processes as an early tissue remodeling event in development of the limbs, kidney and inner ear. Here, we have explored cell senescence by monitoring ß-galactosidase activity during embryonic heart development where programmed cell death is believed to exert an important morphogenetic function. We report the occurrence of extensive cell senescence foci during heart morphogenesis. These foci overlap spatially and temporally with the areas of programmed cell death that are associated with remodeling of the outflow tract to build the roots of the great arteries and with the septation of cardiac cavities. qPCR analysis allowed us to identify a gene expression profile characteristic of the so-called senescence secretory associated phenotype in the remodeling outflow tract of the embryonic heart. In addition, we confirmed local upregulation of numerous tumor suppressor genes including p21, p53, p63, p73 and Btg2. Interestingly, the areas of cell senescence were also accompanied by intense lysosomal activation and non-apoptotic DNA damage revealed by γH2AX immunolabeling. Considering the importance of sustained DNA damage as a triggering factor for cell senescence and apoptosis, we propose the coordinated contribution of DNA damage, senescence and apoptotic cell death to assure tissue remodeling in the developing vertebrate heart.

Interdigital tissue remodelling in the embryonic limb involves dynamic regulation of the miRNA profiles.

Next-generation sequencing in combination with quantitative polymerase chain reaction analysis revealed a dynamic miRNA signature in the interdigital mesoderm of the chick embryonic hinlimb in the course of interdigit remodelling. During this period, 612 previously known chicken miRNAs (gga-miRNAs) and 401 non-identified sequences were expressed in the interdigital mesoderm. Thirty-six microRNAs, represented by more than 750 reads per million, displayed differential expression between stages HH29 (6 id) and HH32 (7.5 id), which correspond to the onset and the peak of interdigital cell death. Twenty miRNAs were upregulated by at least 1.5-fold, and sixteen were downregulated by at least 0.5-fold. Upregulated miRNAs included miRNAs with recognized proapoptotic functions in other systems (miR-181 family, miR-451 and miR-148a), miRNAs associated with inflammation and cell senescence (miR-21 and miR-146) and miRNAs able to induce changes in the extracellular matrix (miR-30c). In contrast, miRNAs with known antiapoptotic effects in other systems, such as miR-222 and miR-205, became downregulated. In addition, miR-92, an important positive regulator of cell proliferation, was also downregulated. Together, these findings indicate a role for miRNAs in the control of tissue regression and cell death in a characteristic morphogenetic embryonic process based on massive apoptosis.

Ecological regime shift drives declining growth rates of sea turtles throughout the West Atlantic.

Somatic growth is an integrated, individual-based response to environmental conditions, especially in ectotherms. Growth dynamics of large, mobile animals are particularly useful as bio-indicators of environmental change at regional scales. We assembled growth rate data from throughout the West Atlantic for green turtles, Chelonia mydas, which are long-lived, highly migratory, primarily herbivorous mega-consumers that may migrate over hundreds to thousands of kilometers. Our dataset, the largest ever compiled for sea turtles, has 9690 growth increments from 30 sites from Bermuda to Uruguay from 1973 to 2015. Using generalized additive mixed models, we evaluated covariates that could affect growth rates; body size, diet, and year have significant effects on growth. Growth increases in early years until 1999, then declines by 26% to 2015. The temporal (year) effect is of particular interest because two carnivorous species of sea turtles-hawksbills, Eretmochelys imbricata, and loggerheads, Caretta caretta-exhibited similar significant declines in growth rates starting in 1997 in the West Atlantic, based on previous studies. These synchronous declines in productivity among three sea turtle species across a trophic spectrum provide strong evidence that an ecological regime shift (ERS) in the Atlantic is driving growth dynamics. The ERS resulted from a synergy of the 1997/1998 El Niño Southern Oscillation (ENSO)-the strongest on record-combined with an unprecedented warming rate over the last two to three decades. Further support is provided by the strong correlations between annualized mean growth rates of green turtles and both sea surface temperatures (SST) in the West Atlantic for years of declining growth rates (r = -.94) and the Multivariate ENSO Index (MEI) for all years (r = .74). Granger-causality analysis also supports the latter finding. We discuss multiple stressors that could reinforce and prolong the effect of the ERS. This study demonstrates the importance of region-wide collaborations.

The tumor suppressor BTG1 is expressed in the developing digits and regulates skeletogenic differentiation of limb mesodermal progenitors in high density cultures.

In the developing limb, differentiation of skeletal progenitors towards distinct connective tissues of the digits is correlated with the establishment of well-defined domains of Btg1 gene expression. Zones of high expression of Btg1 include the earliest digit blastemas, the condensing mesoderm at the tip of the growing digits, the peritendinous mesenchyme, and the chondrocytes around the developing interphalangeal joints. Gain- and loss-of function experiments in micromass cultures of skeletal progenitors reveal a negative influence of Btg1 in cartilage differentiation accompanied by up-regulation of Ccn1, Scleraxis and PTHrP. Previous studies have assigned a role to these factors in the aggregation of progenitors in the digit tips (Ccn1), in the differentiation of tendon blastemas (Scleraxis) and repressing hypertrophic cartilage differentiation (PTHrP). Overexpression of Btg1 up-regulates the expression of retinoic acid and thyroid hormone receptors, but, different from other systems, the influence of BTG1 in connective tissue differentiation appears to be independent of retinoic acid and thyroid hormone signaling.

Reelin/DAB-1 signaling in the embryonic limb regulates the chondrogenic differentiation of digit mesodermal progenitors.

Reelin is a bioactive component of some extracellular matrices. Most studies on this signaling glycoprotein have been performed in the developing nervous system, where Reelin binds to the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) of target cells. This induces phosphorylation of the intracellular adaptor protein Disabled-1 (Dab-1), which subsequently activates downstream effectors to regulate important aspects of neuroblast biology. Here, we show that the components of the Reelin signaling pathway exhibit a dynamic expression pattern during the development of the digits in chick and mouse embryonic limbs. Reelin and Dab-1 are highly expressed in the differentiating digit cartilages and tendinous blastemas. Immunolabeling of phospho-Dab-1 indicates that the pattern of gene expression correlates with zones of active signaling. Intense signaling is also present in the early stages of cartilage differentiation in micromass cultures of digit mesodermal progenitors. In this in vitro assay, disruption of the Reelin signaling pathway by gene silencing causes cystoskeletal and cell shape modifications accompanied by reduced chondrogenesis and down-regulation of specific cartilage molecular markers. Of note, Scleraxis and Six2, which are master genes of tendinous blastemas, become up-regulated in these experiments. We further show that the receptors ApoER2 and VLDLR are differentially expressed in cartilage and tendons and that these receptors show temporal expression differences in the micromass cultures. Sox9 and other chondrogenic markers were downregulated in micromass cultures after ApoER2 gene silencing, while gene silencing of VLDLR up-regulates Scleraxis. In summary, our findings provide evidence of a role for Reelin signaling in skeletogenesis that promotes chondrogenesis through ApoER2 and inhibits tenogenic differentiation through VLDLR.

The first hominin of Europe.

The earliest hominin occupation of Europe is one of the most debated topics in palaeoanthropology. However, the purportedly oldest of the Early Pleistocene sites in Eurasia lack precise age control and contain stone tools rather than human fossil remains. Here we report the discovery of a human mandible associated with an assemblage of Mode 1 lithic tools and faunal remains bearing traces of hominin processing, in stratigraphic level TE9 at the site of the Sima del Elefante, Atapuerca, Spain. Level TE9 has been dated to the Early Pleistocene (approximately 1.2-1.1 Myr), based on a combination of palaeomagnetism, cosmogenic nuclides and biostratigraphy. The Sima del Elefante site thus emerges as the oldest, most accurately dated record of human occupation in Europe, to our knowledge. The study of the human mandible suggests that the first settlement of Western Europe could be related to an early demographic expansion out of Africa. The new evidence, with previous findings in other Atapuerca sites (level TD6 from Gran Dolina), also suggests that a speciation event occurred in this extreme area of the Eurasian continent during the Early Pleistocene, initiating the hominin lineage represented by the TE9 and TD6 hominins.

Comparative transcriptional analysis of three human ligaments with distinct biomechanical properties.

One major aim of regenerative medicine targeting the musculoskeletal system is to provide complementary and/or alternative therapeutic approaches to current surgical therapies, often involving the removal and prosthetic substitution of damaged tissues such as ligaments. For these approaches to be successful, detailed information regarding the cellular and molecular composition of different musculoskeletal tissues is required. Ligaments have often been considered homogeneous tissues with common biomechanical properties. However, advances in tissue engineering research have highlighted the functional relevance of the organisational and compositional differences between ligament types, especially in those with higher risks of injury. The aim of this study was to provide information concerning the relative expression levels of a subset of key genes (including extracellular matrix components, transcription factors and growth factors) that confer functional identity to ligaments. We compared the transcriptomes of three representative human ligaments subjected to different biomechanical demands: the anterior cruciate ligament (ACL); the ligamentum teres of the hip (LT); and the iliofemoral ligament (IL). We revealed significant differences in the expression of type I collagen, elastin, fibromodulin, biglycan, transforming growth factor ß1, transforming growth interacting factor 1, hypoxia-inducible factor 1-alpha and transforming growth factor ß-induced gene between the IL and the other two ligaments. Thus, considerable molecular heterogeneity can exist between anatomically distinct ligaments with differing biomechanical demands. However, the LT and ACL were found to show remarkable molecular homology, suggesting common functional properties. This finding provides experimental support for the proposed role of the LT as a hip joint stabiliser in humans.

Anionic Phospholipids Shift the Conformational Equilibrium of the Selectivity Filter in the KcsA Channel to the Conductive Conformation: Predicted Consequences on Inactivation.

Here, we report an allosteric effect of an anionic phospholipid on a model K+ channel, KcsA. The anionic lipid in mixed detergent-lipid micelles specifically induces a change in the conformational equilibrium of the channel selectivity filter (SF) only when the channel inner gate is in the open state. Such change consists of increasing the affinity of the channel for K+, stabilizing a conductive-like form by maintaining a high ion occupancy in the SF. The process is highly specific in several aspects: First, lipid modifies the binding of K+, but not that of Na+, which remains unperturbed, ruling out a merely electrostatic phenomenon of cation attraction. Second, no lipid effects are observed when a zwitterionic lipid, instead of an anionic one, is present in the micelles. Lastly, the effects of the anionic lipid are only observed at pH 4.0, when the inner gate of KcsA is open. Moreover, the effect of the anionic lipid on K+ binding to the open channel closely emulates the K+ binding behaviour of the non-inactivating E71A and R64A mutant proteins. This suggests that the observed increase in K+ affinity caused by the bound anionic lipid should result in protecting the channel against inactivation.

Lysosomes, caspase-mediated apoptosis, and cytoplasmic activation of P21, but not cell senescence, participate in a redundant fashion in embryonic morphogenetic cell death.

Micromass cultures of embryonic limb skeletal progenitors replicate the tissue remodelling processes observed during digit morphogenesis. Here, we have employed micromass cultures in an in vitro assay to study the nature of cell degeneration events associated with skeletogenesis. In the assay, "naive" progenitors obtained from the autopod aggregate to form chondrogenic nodules and those occupying the internodular spaces exhibit intense apoptosis and progressive accumulation of larger cells, showing intense SA-ß-Gal histochemical labelling that strictly overlaps with the distribution of neutral red vital staining. qPCR analysis detected intense upregulation of the p21 gene, but P21 immunolabelling showed cytoplasmic rather than the nuclear distribution expected in senescent cells. Semithin sections and transmission electron microscopy confirmed the presence of canonical apoptotic cells, degenerated cell fragments in the process of phagocytic internalization by the neighbouring cells, and large vacuolated cells containing phagosomes. The immunohistochemical distribution of active caspase 3, cathepsin D, and ß-galactosidase together with the reduction in cell death by chemical inhibition of caspases (Q-VAD) and lysosomal cathepsin D (Pepstatin A) supported a redundant implication of both pathways in the dying process. Chemical inhibition of P21 (UC2288) revealed a complementary role of this factor in the dying process. In contrast, treatment with the senolytic drug Navitoclax increased cell death without changing the number of cells positive for SA-ß-Gal. We propose that this model of tissue remodelling involves the cooperative activation of multiple degradation routes and, most importantly, that positivity for SA-ß-Gal reflects the occurrence of phagocytosis, supporting the rejection of cell senescence as a defining component of developmental tissue remodelling.

Modeling the Differentiation of Embryonic Limb Chondroprogenitors by Cell Death and Cell Senescence in High Density Micromass Cultures and Their Regulation by FGF Signaling.

Considering the importance of programmed cell death in the formation of the skeleton during embryonic development, the aim of the present study was to analyze whether regulated cell degeneration also accompanies the differentiation of embryonic limb skeletal progenitors in high-density tridimensional cultures (micromass cultures). Our results show that the formation of primary cartilage nodules in the micromass culture assay involves a patterned process of cell death and cell senescence, complementary to the pattern of chondrogenesis. As occurs in vivo, the degenerative events were preceded by DNA damage detectable by γH2AX immunolabeling and proceeded via apoptosis and cell senescence. Combined treatments of the cultures with growth factors active during limb skeletogenesis, including FGF, BMP, and WNT revealed that FGF signaling modulates the response of progenitors to signaling pathways implicated in cell death. Transcriptional changes induced by FGF treatments suggested that this function is mediated by the positive regulation of the genetic machinery responsible for apoptosis and cell senescence together with hypomethylation of the Sox9 gene promoter. We propose that FGF signaling exerts a primordial function in the embryonic limb conferring chondroprogenitors with their biological properties.

A plant-like battery: a biodegradable power source ecodesigned for precision agriculture.

The natural environment has always been a source of inspiration for the research community. Nature has evolved over thousands of years to create the most complex living systems, with the ability to leverage inner and outside energetic interactions in the most efficient way. This work presents a flow battery profoundly inspired by nature, which mimics the fluid transport in plants to generate electric power. The battery was ecodesigned to meet a life cycle for precision agriculture (PA) applications; from raw material selection to disposability considerations, the battery is conceived to minimize its environmental impact while meeting PA power requirements. The paper-based fluidic system relies on evaporation as the main pumping force to pull the reactants through a pair of porous carbon electrodes where the electrochemical reaction takes place. This naturally occurring transpiration effect enables to significantly expand the operational lifespan of the battery, overcoming the time-limitation of current capillary-based power sources. Most relevant parameters affecting the battery performance, such as evaporation flow and redox species degradation, are thoroughly studied to carry out device optimization. Flow rates and power outputs comparable to those of capillary-based power sources are achieved. The prototype practicality has been demonstrated by powering a wireless plant-caring device. Standardized biodegradability and phytotoxicity assessments show that the battery is harmless to the environment at the end of its operational lifetime. Placing sustainability as the main driver leads to the generation of a disruptive battery concept that aims to address societal needs within the planetary environmental boundaries.

Rapid artificial intelligence solutions in a pandemic-The COVID-19-20 Lung CT Lesion Segmentation Challenge.

Artificial intelligence (AI) methods for the automatic detection and quantification of COVID-19 lesions in chest computed tomography (CT) might play an important role in the monitoring and management of the disease. We organized an international challenge and competition for the development and comparison of AI algorithms for this task, which we supported with public data and state-of-the-art benchmark methods. Board Certified Radiologists annotated 295 public images from two sources (A and B) for algorithms training (n=199, source A), validation (n=50, source A) and testing (n=23, source A; n=23, source B). There were 1,096 registered teams of which 225 and 98 completed the validation and testing phases, respectively. The challenge showed that AI models could be rapidly designed by diverse teams with the potential to measure disease or facilitate timely and patient-specific interventions. This paper provides an overview and the major outcomes of the COVID-19 Lung CT Lesion Segmentation Challenge - 2020.

Carcass transport decisions in Homo antecessor subsistence strategies.

Pleistocene foragers used several prey acquisition and processing strategies. These strategies and their associated decisions are elucidated by taphonomic studies that cover animal transport, modifications by different agents and archaeological remains. Interpretative models of archaeological sites are by necessity based on natural and experimental observations. Ethno-archaeological data shows that several factors influenced decisions about carcass transport from the kill site to the home site. These factors often have little archaeological visibility. Díez et al. (1999) has previously interpreted the general characteristics of the macro-mammal remains from Gran Dolina Level TD6-2 (Sierra de Atapuerca, Burgos, Spain) as the result of anthropic accumulation, in which the anatomical profiles appeared to be the result of selective transport based on the animals' weight. Recent taphonomic analysis has shown that carcasses with different weights may be subject to similar transport strategies, suggesting that other factors influenced these choices. The hominins that occupied TD6-2 (the TD6-2 hominin group), at least sometimes, transported large carcasses to the cave in their entirety, implying participation by groups of individuals in hunting parties. These individuals delayed their consumption of large amounts of food, instead moving it to Gran Dolina, where it was shared with other group members. These decisions are evidence of social cooperation and food sharing amongst early European hominins.

Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors.

INTRODUCTION: Berberine (BBR) is an isoquinoline plant alkaloid with demonstrated anti-inflammatory, anti-tumor and immunosuppressive pharmacological properties that functions via multiple signaling pathways and epigenetic modulators. Numerous studies have proposed BBR as a promising therapeutic agent for joint cartilage degeneration, and other connective tissue diseases. PURPOSE AND METHODS: This work aimed to evaluate the effects of BBR on the growth and differentiation of embryonic skeletal progenitors using the limb mesoderm micromass culture assay. RESULTS: Our findings show that at difference of its apoptotic influence on a variety of tumor tissues, cell death was not induced in skeletal progenitors by the addition of 12 or 25 µM BBR concentration to the culture medium. Morphological and transcriptional analysis revealed dual and opposite effects of BBR treatments on chondrogenesis depending on the stage of differentiation of the cultured progenitors. At early stage of culture, BBR was a potent chondrogenic inhibitor, while chondrogenesis was intensified in treatments at advanced stages of culture. The chondrogenic promoting effect was accompanied by a moderate upregulation of gene markers of prehypertrophic cartilage, including ColXa1, alkaline phosphatase Alpl, Runx2, and Indian Hedgehog Ihh. We further observed a positive transcriptional influence of BBR in the expression of DNA methyltransferase genes, Dnmt1, Dnmt3a and Dnmt3b, suggesting a potential involvement of epigenetic factors in its effects. CONCLUSION: Our study uncovers a new pharmacological influence of BBR in cartilage differentiation that must be taken into account in designing clinical protocols for its employment in the treatment of cartilage degenerative diseases.

SCA-1/Ly6A Mesodermal Skeletal Progenitor Subpopulations Reveal Differential Commitment of Early Limb Bud Cells.

At early developmental stages, limb bud mesodermal undifferentiated cells are morphologically indistinguishable. Although the identification of several mesodermal skeletal progenitor cell populations has been recognized, in advanced stages of limb development here we identified and characterized the differentiation hierarchy of two new early limb bud subpopulations of skeletal progenitors defined by the differential expression of the SCA-1 marker. Based on tissue localization of the mesenchymal stromal cell-associated markers (MSC-am) CD29, Sca-1, CD44, CD105, CD90, and CD73, we identified, by multiparametric analysis, the presence of cell subpopulations in the limb bud capable of responding to inductive signals differentially, namely, sSca+ and sSca- cells. In concordance with its gene expression profile, cell cultures of the sSca+ subpopulation showed higher osteogenic but lower chondrogenic capacity than those of sSca-. Interestingly, under high-density conditions, fibroblast-like cells in the sSca+ subpopulation were abundant. Gain-of-function employing micromass cultures and the recombinant limb assay showed that SCA-1 expression promoted tenogenic differentiation, whereas chondrogenesis is delayed. This model represents a system to determine cell differentiation and morphogenesis of different cell subpopulations in similar conditions like in vivo. Our results suggest that the limb bud is composed of a heterogeneous population of progenitors that respond differently to local differentiation inductive signals in the early stages of development, where SCA-1 expression may play a permissive role during cell fate.

Development and evaluation of a machine learning-based point-of-care screening tool for genetic syndromes in children: a multinational retrospective study.

BACKGROUND: Delays in the diagnosis of genetic syndromes are common, particularly in low and middle-income countries with limited access to genetic screening services. We, therefore, aimed to develop and evaluate a machine learning-based screening technology using facial photographs to evaluate a child's risk of presenting with a genetic syndrome for use at the point of care. METHODS: In this retrospective study, we developed a facial deep phenotyping technology based on deep neural networks and facial statistical shape models to screen children for genetic syndromes. We trained the machine learning models on facial photographs from children (aged <21 years) with a clinical or molecular diagnosis of a genetic syndrome and controls without a genetic syndrome matched for age, sex, and race or ethnicity. Images were obtained from three publicly available databases (the Atlas of Human Malformations in Diverse Populations of the National Human Genome Research Institute, Face2Gene, and the dataset available from Ferry and colleagues) and the archives of the Children's National Hospital (Washington, DC, USA), in addition to photographs taken on a standard smartphone at the Children's National Hospital. We designed a deep learning architecture structured into three neural networks, which performed image standardisation (Network A), facial morphology detection (Network B), and genetic syndrome risk estimation, accounting for phenotypic variations due to age, sex, and race or ethnicity (Network C). Data were divided randomly into 40 groups for cross validation, and the performance of the model was evaluated in terms of accuracy, sensitivity, and specificity in both the total population and stratified by race or ethnicity, age, and sex. FINDINGS: Our dataset included 2800 facial photographs of children (1318 [47%] female and 1482 [53%] male; 1576 [56%] White, 432 [15%] African, 430 [15%] Hispanic, and 362 [13%] Asian). 1400 children with 128 genetic conditions were included (the most prevalent being Williams-Beuren syndrome [19%], Cornelia de Lange syndrome [17%], Down syndrome [16%], 22q11.2 deletion [13%], and Noonan syndrome [12%] syndrome) in addition to 1400 photographs of matched controls. In the total population, our deep learning-based model had an accuracy of 88% (95% CI 87-89) for the detection of a genetic syndrome, with 90% sensitivity (95% CI 88-92) and 86% specificity (95% CI 84-88). Accuracy was greater in White (90%, 89-91) and Hispanic populations (91%, 88-94) than in African (84%, 81-87) and Asian populations (82%, 78-86). Accuracy was also similar in male (89%, 87-91) and female children (87%, 85-89), and similar in children younger than 2 years (86%, 84-88) and children aged 2 years or older (eg, 89% [87-91] for those aged 2 years to <5 years). INTERPRETATION: This genetic screening technology could support early risk stratification at the point of care in global populations, which has the potential accelerate diagnosis and reduce mortality and morbidity through preventive care. FUNDING: Children's National Hospital and Government of Abu Dhabi.

Chest X-ray lung imaging features in pediatric COVID-19 and comparison with viral lower respiratory infections in young children.

RATIONALE: Chest radiography (CXR) is a noninvasive imaging approach commonly used to evaluate lower respiratory tract infections (LRTIs) in children. However, the specific imaging patterns of pediatric coronavirus disease 2019 (COVID-19) on CXR, their relationship to clinical outcomes, and the possible differences from LRTIs caused by other viruses in children remain to be defined. METHODS: This is a cross-sectional study of patients seen at a pediatric hospital with polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 95). Patients were subdivided in infants (0-2 years, n = 27), children (3-10 years, n = 27), and adolescents (11-19 years, n = 41). A sample of young children (0-2 years, n = 68) with other viral lower respiratory infections (LRTI) was included to compare their CXR features with the subset of infants (0-2 years) with COVID-19. RESULTS: Forty-five percent of pediatric patients with COVID-19 were hospitalized and 20% required admission to intensive care unit (ICU). The most common abnormalities identified were ground-glass opacifications (GGO)/consolidations (35%) and increased peribronchial markings/cuffing (33%). GGO/consolidations were more common in older individuals and perihilar markings were more common in younger subjects. Subjects requiring hospitalization or ICU admission had significantly more GGO/consolidations in CXR (p < .05). Typical CXR features of pediatric viral LRTI (e.g., hyperinflation) were more common in non-COVID-19 viral LRTI cases than in COVID-19 cases (p < .05). CONCLUSIONS: CXR may be a complemental exam in the evaluation of moderate or severe pediatric COVID-19 cases. The severity of GGO/consolidations seen in CXR is predictive of clinically relevant outcomes. Hyperinflation could potentially aid clinical assessment in distinguishing COVID-19 from other types of viral LRTI in young children.