Tuberculosis transmission continues to be a major public health challenge. In this cluster-randomized, controlled trial conducted in Vietnam, active community-wide screening for tuberculosis over 4 ...years is shown to decrease the prevalence of tuberculosis.
Since February 2020, over 2.5 million Texans have been diagnosed with COVID-19, and 20% are young adults at risk for SARS-CoV-2 exposure at work, academic, and social settings. This study ...investigated demographic and clinical risk factors for severe disease and readmission among young adults 18-29 years old, who were diagnosed at a hospital encounter in Houston, Texas, USA. A retrospective registry-based chart review was conducted investigating demographic and clinical risk factors for severe COVID-19 among patients aged 18-29 with positive SARS-CoV-2 tests within a large metropolitan healthcare system in Houston, Texas, USA. In the cohort of 1,853 young adult patients diagnosed with COVID-19 infection at a hospital encounter, including 226 pregnant women, 1,438 (78%) scored 0 on the Charlson Comorbidity Index, and 833 (45%) were obese (greater than or equal to30 kg/m.sup.2). Within 30 days of their diagnostic encounter, 316 (17%) patients were diagnosed with pneumonia, 148 (8%) received other severe disease diagnoses, and 268 (14%) returned to the hospital after being discharged home. In multivariable logistic regression analyses, increasing age (adjusted odds ratio aOR 1.1, 95% confidence interval CI 1.1-1.2, p<0.001), male gender (aOR 1.8, 95% CI 1.2-2.7, p = 0.002), Hispanic ethnicity (aOR 1.9, 95% CI 1.2-3.1, p = 0.01), obesity (3.1, 95% CI 1.9-5.1, p<0.001), asthma history (aOR 2.3, 95% CI 1.3-4.0, p = 0.003), congestive heart failure (aOR 6.0, 95% CI 1.5-25.1, p = 0.01), cerebrovascular disease (aOR 4.9, 95% CI 1.7-14.7, p = 0.004), and diabetes (aOR 3.4, 95% CI 1.9-6.2, p<0.001) were predictive of severe disease diagnoses within 30 days. Non-Hispanic Black race (aOR 1.6, 95% CI 1.0-2.4, p = 0.04), obesity (aOR 1.7, 95% CI 1.0-2.9, p = 0.046), asthma history (aOR 1.7, 95% CI 1.0-2.7, p = 0.03), myocardial infarction history (aOR 6.2, 95% CI 1.7-23.3, p = 0.01), and household exposure (aOR 1.5, 95% CI 1.1-2.2, p = 0.02) were predictive of 30-day readmission. This investigation demonstrated the significant risk of severe disease and readmission among young adult populations, especially marginalized communities and people with comorbidities, including obesity, asthma, cardiovascular disease, and diabetes. Health authorities must emphasize COVID-19 awareness and prevention in young adults and continue investigating risk factors for severe disease, readmission and long-term sequalae.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration
. This adaptability is lost in cultured adult endothelial cells, which do not vascularize ...tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)
in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens
. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The density and architecture of capillary beds that form within a tissue depend on many factors, including local metabolic demand and blood flow. Here, using microfluidic control of local fluid ...mechanics, we show the existence of a previously unappreciated flow-induced shear stress threshold that triggers angiogenic sprouting. Both intraluminal shear stress over the endothelium and transmural flow through the endothelium above 10 dyn/cm ² triggered endothelial cells to sprout and invade into the underlying matrix, and this threshold is not impacted by the maturation of cell–cell junctions or pressure gradient across the monolayer. Antagonizing VE-cadherin widened cell–cell junctions and reduced the applied shear stress for a given transmural flow rate, but did not affect the shear threshold for sprouting. Furthermore, both transmural and luminal flow induced expression of matrix metalloproteinase 1, and this up-regulation was required for the flow-induced sprouting. Once sprouting was initiated, continuous flow was needed to both sustain sprouting and prevent retraction. To explore the potential ramifications of a shear threshold on the spatial patterning of new sprouts, we used finite-element modeling to predict fluid shear in a variety of geometric settings and then experimentally demonstrated that transmural flow guided preferential sprouting toward paths of draining interstitial fluid flow as might occur to connect capillary beds to venules or lymphatics. In addition, we show that luminal shear increases in local narrowings of vessels to trigger sprouting, perhaps ultimately to normalize shear stress across the vasculature. Together, these studies highlight the role of shear stress in controlling angiogenic sprouting and offer a potential homeostatic mechanism for regulating vascular density.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying ...diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood-brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (
,
, and
) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
In the absence of perfusable vascular networks, three-dimensional (3D) engineered tissues densely populated with cells quickly develop a necrotic core. Yet the lack of a general approach to rapidly ...construct such networks remains a major challenge for 3D tissue culture. Here, we printed rigid 3D filament networks of carbohydrate glass, and used them as a cytocompatible sacrificial template in engineered tissues containing living cells to generate cylindrical networks that could be lined with endothelial cells and perfused with blood under high-pressure pulsatile flow. Because this simple vascular casting approach allows independent control of network geometry, endothelialization and extravascular tissue, it is compatible with a wide variety of cell types, synthetic and natural extracellular matrices, and crosslinking strategies. We also demonstrated that the perfused vascular channels sustained the metabolic function of primary rat hepatocytes in engineered tissue constructs that otherwise exhibited suppressed function in their core.
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IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this randomized trial involving women without the polycystic ovary syndrome undergoing IVF, there was no significant difference in the rate of ongoing pregnancy or live birth between a strategy of ...freezing all embryos versus fresh transfer.
Angiogenesis is a complex morphogenetic process whereby endothelial cells from existing vessels invade as multicellular sprouts to form new vessels. Here, we have engineered a unique organotypic ...model of angiogenic sprouting and neovessel formation that originates from preformed artificial vessels fully encapsulated within a 3D extracellular matrix. Using this model, we screened the effects of angiogenic factors and identified two distinct cocktails that promoted robust multicellular endothelial sprouting. The angiogenic sprouts in our system exhibited hallmark structural features of in vivo angiogenesis, including directed invasion of leading cells that developed filopodia-like protrusions characteristic of tip cells, following stalk cells exhibiting apical–basal polarity, and lumens and branches connecting back to the parent vessels. Ultimately, sprouts bridged between preformed channels and formed perfusable neovessels. Using this model, we investigated the effects of angiogenic inhibitors on sprouting morphogenesis. Interestingly, the ability of VEGF receptor 2 inhibition to antagonize filopodia formation in tip cells was context-dependent, suggesting a mechanism by which vessels might be able to toggle between VEGF-dependent and VEGF-independent modes of angiogenesis. Like VEGF, sphingosine-1-phosphate also seemed to exert its proangiogenic effects by stimulating directional filopodial extension, whereas matrix metalloproteinase inhibitors prevented sprout extension but had no impact on filopodial formation. Together, these results demonstrate an in vitro 3D biomimetic model that reconstitutes the morphogenetic steps of angiogenic sprouting and highlight the potential utility of the model to elucidate the molecular mechanisms that coordinate the complex series of events involved in neovascularization.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The brain activity of multiple subjects has been shown to synchronize during salient moments of natural stimuli, suggesting that correlation of neural responses indexes a brain state operationally ...termed ‘engagement’. While past electroencephalography (EEG) studies have considered both auditory and visual stimuli, the extent to which these results generalize to music—a temporally structured stimulus for which the brain has evolved specialized circuitry—is less understood. Here we investigated neural correlation during natural music listening by recording EEG responses from N=48 adult listeners as they heard real-world musical works, some of which were temporally disrupted through shuffling of short-term segments (measures), reversal, or randomization of phase spectra. We measured correlation between multiple neural responses (inter-subject correlation) and between neural responses and stimulus envelope fluctuations (stimulus-response correlation) in the time and frequency domains. Stimuli retaining basic musical features, such as rhythm and melody, elicited significantly higher behavioral ratings and neural correlation than did phase-scrambled controls. However, while unedited songs were self-reported as most pleasant, time-domain correlations were highest during measure-shuffled versions. Frequency-domain measures of correlation (coherence) peaked at frequencies related to the musical beat, although the magnitudes of these spectral peaks did not explain the observed temporal correlations. Our findings show that natural music evokes significant inter-subject and stimulus-response correlations, and suggest that the neural correlates of musical ‘engagement’ may be distinct from those of enjoyment.
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•We recorded EEG from 48 adults as they heard intact and scrambled natural music.•Inter-subject and stimulus-response EEG correlation and coherence were computed.•Neural correlation was significant for all stimuli retaining musical features.•Time-domain correlation was highest for music shuffled in short time segments.•Coherence peaks implicated frequencies related to metrical pulse.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Interferon-γ release assays (IGRAs) are the preferred diagnostic test for tuberculosis (TB) infection in at-risk populations in developed countries. However, IGRAs have high false-negative rates in ...patients with TB disease. Population-based studies assessing the factors associated with negative IGRA results in TB patients have not been performed. Using statewide TB surveillance data of culture-confirmed TB patients in Texas, USA, during 2013-2015, we describe the patient characteristics and treatment outcomes associated with false-negative IGRA results. Among 2,854 TB patients, 1,527 (53.5%) had an IGRA result; 97.4% (1,487/1,527) of those had a positive (87.7%) or negative (12.3%) result. Older age, HIV co-infection, non-Hispanic white race/ethnicity, and being tested with T-SPOT.TB were associated with negative IGRA results. TB patients with negative IGRA results had a higher mortality, potentially due to delayed treatment. Healthcare providers should consider these risk factors when making decisions for patients with suspected TB and negative IGRA results and potentially provide treatment.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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