Tuning commensurability in twisted van der Waals bilayers.

Moiré superlattices based on van der Waals bilayers1-4 created at small twist angles lead to a long wavelength pattern with approximate translational symmetry. At large twist angles (θt), moiré patterns are, in general, incommensurate except for a few discrete angles. Here we show that large-angle twisted bilayers offer distinctly different platforms. More specifically, by using twisted tungsten diselenide bilayers, we create the incommensurate dodecagon quasicrystals at θt = 30° and the commensurate moiré crystals at θt = 21.8° and 38.2°. Valley-resolved scanning tunnelling spectroscopy shows disparate behaviours between moiré crystals (with translational symmetry) and quasicrystals (with broken translational symmetry). In particular, the K valley shows rich electronic structures exemplified by the formation of mini-gaps near the valence band maximum. These discoveries demonstrate that bilayers with large twist angles offer a design platform to explore moiré physics beyond those formed with small twist angles.

Heterogeneous integration of single-crystalline complex-oxide membranes.

Complex-oxide materials exhibit a vast range of functional properties desirable for next-generation electronic, spintronic, magnetoelectric, neuromorphic, and energy conversion storage devices1-4. Their physical functionalities can be coupled by stacking layers of such materials to create heterostructures and can be further boosted by applying strain5-7. The predominant method for heterogeneous integration and application of strain has been through heteroepitaxy, which drastically limits the possible material combinations and the ability to integrate complex oxides with mature semiconductor technologies. Moreover, key physical properties of complex-oxide thin films, such as piezoelectricity and magnetostriction, are severely reduced by the substrate clamping effect. Here we demonstrate a universal mechanical exfoliation method of producing freestanding single-crystalline membranes made from a wide range of complex-oxide materials including perovskite, spinel and garnet crystal structures with varying crystallographic orientations. In addition, we create artificial heterostructures and hybridize their physical properties by directly stacking such freestanding membranes with different crystal structures and orientations, which is not possible using conventional methods. Our results establish a platform for stacking and coupling three-dimensional structures, akin to two-dimensional material-based heterostructures, for enhancing device functionalities8,9.

In situ production and secretion of proteins endow therapeutic benefit against psoriasiform dermatitis and melanoma.

Genetic medicines have the potential to treat various diseases; however, certain ailments including inflammatory diseases and cancer would benefit from control over extracellular localization of therapeutic proteins. A critical gap therefore remains the need to develop and incorporate methodologies that allow for posttranslational control over expression dynamics, localization, and stability of nucleic acid-generated protein therapeutics. To address this, we explored how the body's endogenous machinery controls protein localization through signal peptides (SPs), including how these motifs could be incorporated modularly into therapeutics. SPs serve as a virtual zip code for mRNA transcripts that direct the cell where to send completed proteins within the cell and the body. Utilizing this signaling biology, we incorporated secretory SP sequences upstream of mRNA transcripts coding for reporter, natural, and therapeutic proteins to induce secretion of the proteins into systemic circulation. SP sequences generated secretion of various engineered proteins into the bloodstream following intravenous, intramuscular, and subcutaneous SP mRNA delivery by lipid, polymer, and ionizable phospholipid delivery carriers. SP-engineered etanercept/TNF-α inhibitor proteins demonstrated therapeutic efficacy in an imiquimod-induced psoriasis model by reducing hyperkeratosis and inflammation. An SP-engineered anti-PD-L1 construct mediated mRNA encoded proteins with longer serum half-lives that reduced tumor burden and extended survival in MC38 and B16F10 cancer models. The modular nature of SP platform should enable intracellular and extracellular localization control of various functional proteins for diverse therapeutic applications.

Global proteomic analyses of human cytotrophoblast differentiation/invasion.

During human pregnancy, cytotrophoblasts (CTBs) from the placenta differentiate into specialized subpopulations that play crucial roles in proper fetal growth and development. A subset of these CTBs differentiate along an invasive pathway, penetrating the decidua and anchoring the placenta to the uterus. A crucial hurdle in pregnancy is the ability of these cells to migrate, invade and remodel spiral arteries, ensuring adequate blood flow to nourish the developing fetus. Although advances continue in describing the molecular features regulating the differentiation of these cells, assessment of their global proteomic changes at mid-gestation remain undefined. Here, using sequential window acquisition of all theoretical fragment-ion spectra (SWATH), which is a data-independent acquisition strategy, we characterized the protein repertoire of second trimester human CTBs during their differentiation towards an invasive phenotype. This mass spectrometry-based approach allowed identification of 3026 proteins across four culture time points corresponding to sequential stages of differentiation, confirming the expression dynamics of established molecules and offering new information into other pathways involved. The availability of a SWATH CTB global spectral library serves as a beneficial resource for hypothesis generation and as a foundation for further understanding CTB differentiation dynamics.

Watching (De)Intercalation of 2D Metals in Epitaxial Graphene: Insight into the Role of Defects.

Intercalation forms heterostructures, and over 25 elements and compounds are intercalated into graphene, but the mechanism for this process is not well understood. Here, the de-intercalation of 2D Ag and Ga metals sandwiched between bilayer graphene and SiC are followed using photoemission electron microscopy (PEEM) and atomistic-scale reactive molecular dynamics simulations. By PEEM, de-intercalation "windows" (or defects) are observed in both systems, but the processes follow distinctly different dynamics. Reversible de- and re-intercalation of Ag is observed through a circular defect where the intercalation velocity front is 0.5 nm s-1 ± 0.2 nm s.-1 In contrast, the de-intercalation of Ga is irreversible with faster kinetics that are influenced by the non-circular shape of the defect. Molecular dynamics simulations support these pronounced differences and complexities between the two Ag and Ga systems. In the de-intercalating Ga model, Ga atoms first pile up between graphene layers until ultimately moving to the graphene surface. The simulations, supported by density functional theory, indicate that the Ga atoms exhibit larger binding strength to graphene, which agrees with the faster and irreversible diffusion kinetics observed. Thus, both the thermophysical properties of the metal intercalant and its interaction with defective graphene play a key role in intercalation.

Proximity-induced superconductivity in epitaxial topological insulator/graphene/gallium heterostructures.

The introduction of superconductivity to the Dirac surface states of a topological insulator leads to a topological superconductor, which may support topological quantum computing through Majorana zero modes1,2. The development of a scalable material platform is key to the realization of topological quantum computing3,4. Here we report on the growth and properties of high-quality (Bi,Sb)2Te3/graphene/gallium heterostructures. Our synthetic approach enables atomically sharp layers at both hetero-interfaces, which in turn promotes proximity-induced superconductivity that originates in the gallium film. A lithography-free, van der Waals tunnel junction is developed to perform transport tunnelling spectroscopy. We find a robust, proximity-induced superconducting gap formed in the Dirac surface states in 5-10 quintuple-layer (Bi,Sb)2Te3/graphene/gallium heterostructures. The presence of a single Abrikosov vortex, where the Majorana zero modes are expected to reside, manifests in discrete conductance changes. The present material platform opens up opportunities for understanding and harnessing the application potential of topological superconductivity.

GRASP reconstruction amplified with view-sharing and KWIC filtering reduces underestimation of peak velocity in highly-accelerated real-time phase-contrast MRI: A preliminary evaluation in pediatric patients with congenital heart disease.

PURPOSE: To develop a highly-accelerated, real-time phase contrast (rtPC) MRI pulse sequence with 40 fps frame rate (25 ms effective temporal resolution). METHODS: Highly-accelerated golden-angle radial sparse parallel (GRASP) with over regularization may result in temporal blurring, which in turn causes underestimation of peak velocity. Thus, we amplified GRASP performance by synergistically combining view-sharing (VS) and k-space weighted image contrast (KWIC) filtering. In 17 pediatric patients with congenital heart disease (CHD), the conventional GRASP and the proposed GRASP amplified by VS and KWIC (or GRASP + VS + KWIC) reconstruction for rtPC MRI were compared with respect to clinical standard PC MRI in measuring hemodynamic parameters (peak velocity, forward volume, backward volume, regurgitant fraction) at four locations (aortic valve, pulmonary valve, left and right pulmonary arteries). RESULTS: The proposed reconstruction method (GRASP + VS + KWIC) achieved better effective spatial resolution (i.e., image sharpness) compared with conventional GRASP, ultimately reducing the underestimation of peak velocity from 17.4% to 6.4%. The hemodynamic metrics (peak velocity, volumes) were not significantly (p > 0.99) different between GRASP + VS + KWIC and clinical PC, whereas peak velocity was significantly (p < 0.007) lower for conventional GRASP. RtPC with GRASP + VS + KWIC also showed the ability to assess beat-to-beat variation and detect the highest peak among peaks. CONCLUSION: The synergistic combination of GRASP, VS, and KWIC achieves 25 ms effective temporal resolution (40 fps frame rate), while minimizing the underestimation of peak velocity compared with conventional GRASP.

High rates of placental inflammation among samples collected by the Multi-Omics for Mothers and Infants consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality. OBJECTIVE: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Cardiac magnetic resonance imaging in detection of progressive graft dysfunction in pediatric heart transplantation.

BACKGROUND: Chronic graft failure (CGF) in pediatric heart transplant (PHT) is multifactorial and may present with findings of fibrosis and microvessel disease (MVD) on endomyocardial biopsy (EMB). There is no optimal CGF surveillance method. We evaluated associations between cardiac magnetic resonance imaging (CMR) and historical/EMB correlates of CGF to assess CMR's utility as a surveillance method. METHODS: Retrospective analysis of PHT undergoing comprehensive CMR between September 2015 and January 2022 was performed. EMB within 6 months was graded for fibrosis (scale 0-5) and MVD (number of capillaries with stenotic wall thickening per field of view). Correlation analysis and logistic regression were performed. RESULTS: Forty-seven PHT with median age at CMR of 15.7 years (11.6, 19.3) and time from transplant of 6.4 years (4.1, 11.0) were studied. Cardiac allograft vasculopathy (CAV) was present in 11/44 (22.0%) and historical rejection in 14/41 (34.2%). CAV was associated with higher global T2 (49.0 vs. 47.0 ms; p = 0.038) and peak T2 (57.0 vs. 53.0 ms; p = 0.013) on CMR. Historical rejection was associated with higher global T2 (49.0 vs. 47.0 ms; p = 0.007) and peak T2 (57.0 vs. 53.0 ms; p = 0.03) as well as global extracellular volume (31.0 vs. 26.3%; p = 0.03). Higher fibrosis score on EMB correlated with smaller indexed left ventricular mass (rho = -0.34; p = 0.019) and greater degree of MVD with lower indexed left ventricular end-diastolic volume (rho = -0.35; p = 0.017). CONCLUSION: Adverse ventricular remodeling and abnormal myocardial characteristics on CMR are present in PHT with CAV, historical rejection, as well as greater fibrosis and MVD on EMB. CMR has the potential use for screening of CGF.

Tricuspid Atresia with Absent Pulmonary Valve with Nearly Discontinuous Branch Pulmonary Arteries.

Absent pulmonary valve with tricuspid atresia or tricuspid stenosis (APV-TA/TS) is an extremely rare congenital heart defect associated with significant morbidity and mortality. Compared to Tetralogy of Fallot with Absent Pulmonary Valve Syndrome, branch pulmonary arteries are not typically significantly dilated. We present the case of a newborn male prenatally diagnosed APV-TA with intact ventricular septum (IVS) and nearly discontinuous branch pulmonary arteries, the surgical strategy employed, and the salient hemodynamic factors considered in the medical decision-making.

Ultrascaled Contacts to Monolayer MoS2 Field Effect Transistors.

Two-dimensional (2D) semiconductors possess promise for the development of field-effect transistors (FETs) at the ultimate scaling limit due to their strong gate electrostatics. However, proper FET scaling requires reduction of both channel length (LCH) and contact length (LC), the latter of which has remained a challenge due to increased current crowding at the nanoscale. Here, we investigate Au contacts to monolayer MoS2 FETs with LCH down to 100 nm and LC down to 20 nm to evaluate the impact of contact scaling on FET performance. Au contacts are found to display a ∼2.5× reduction in the ON-current, from 519 to 206 µA/µm, when LC is scaled from 300 to 20 nm. It is our belief that this study is warranted to ensure an accurate representation of contact effects at and beyond the technology nodes currently occupied by silicon.

Cytotrophoblast extracellular vesicles enhance decidual cell secretion of immune modulators via TNFα.

The placenta releases large quantities of extracellular vesicles (EVs) that likely facilitate communication between the embryo/fetus and the mother. We isolated EVs from second trimester human cytotrophoblasts (CTBs) by differential ultracentrifugation and characterized them using transmission electron microscopy, immunoblotting and mass spectrometry. The 100,000  g pellet was enriched for vesicles with a cup-like morphology typical of exosomes. They expressed markers specific to this vesicle type, CD9 and HRS, and the trophoblast proteins placental alkaline phosphatase and HLA-G. Global profiling by mass spectrometry showed that placental EVs were enriched for proteins that function in transport and viral processes. A cytokine array revealed that the CTB 100,000  g pellet contained a significant amount of tumor necrosis factor α (TNFα). CTB EVs increased decidual stromal cell (dESF) transcription and secretion of NF-κB targets, including IL8, as measured by qRT-PCR and cytokine array. A soluble form of the TNFα receptor inhibited the ability of CTB 100,000  g EVs to increase dESF secretion of IL8. Overall, the data suggest that CTB EVs enhance decidual cell release of inflammatory cytokines, which we theorize is an important component of successful pregnancy.

Crossover from Ising- to Rashba-type superconductivity in epitaxial Bi2Se3/monolayer NbSe2 heterostructures.

A topological insulator (TI) interfaced with an s-wave superconductor has been predicted to host topological superconductivity. Although the growth of epitaxial TI films on s-wave superconductors has been achieved by molecular-beam epitaxy, it remains an outstanding challenge for synthesizing atomically thin TI/superconductor heterostructures, which are critical for engineering the topological superconducting phase. Here we used molecular-beam epitaxy to grow Bi2Se3 films with a controlled thickness on monolayer NbSe2 and performed in situ angle-resolved photoemission spectroscopy and ex situ magnetotransport measurements on these heterostructures. We found that the emergence of Rashba-type bulk quantum-well bands and spin-non-degenerate surface states coincides with a marked suppression of the in-plane upper critical magnetic field of the superconductivity in Bi2Se3/monolayer NbSe2 heterostructures. This is a signature of a crossover from Ising- to Rashba-type superconducting pairings, induced by altering the Bi2Se3 film thickness. Our work opens a route for exploring a robust topological superconducting phase in TI/Ising superconductor heterostructures.

Aquaporin 9 induction in human iPSC-derived hepatocytes facilitates modeling of ornithine transcarbamylase deficiency.

BACKGROUND AND AIMS: Patient-derived human-induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes (hiPSC-Heps) have facilitated the study of rare genetic liver diseases. Here, we aimed to establish an in vitro liver disease model of the urea cycle disorder ornithine transcarbamylase deficiency (OTCD) using patient-derived hiPSC-Heps. APPROACH AND RESULTS: Before modeling OTCD, we addressed the question of why hiPSC-Heps generally secrete less urea than adult primary human hepatocytes (PHHs). Because hiPSC-Heps are not completely differentiated and maintain some characteristics of fetal PHHs, we compared gene-expression levels in human fetal and adult liver tissue to identify genes responsible for reduced urea secretion in hiPSC-Heps. We found lack of aquaporin 9 (AQP9) expression in fetal liver tissue as well as in hiPSC-Heps, and showed that forced expression of AQP9 in hiPSC-Heps restores urea secretion and normalizes the response to ammonia challenge by increasing ureagenesis. Furthermore, we proved functional ureagenesis by challenging AQP9-expressing hiPSC-Heps with ammonium chloride labeled with the stable isotope [15 N] (15 NH4 Cl) and by assessing enrichment of [15 N]-labeled urea. Finally, using hiPSC-Heps derived from patients with OTCD, we generated a liver disease model that recapitulates the hepatic manifestation of the human disease. Restoring OTC expression-together with AQP9-was effective in fully correcting OTC activity and normalizing ureagenesis as assessed by 15 NH4 Cl stable-isotope challenge. CONCLUSION: Our results identify a critical role for AQP9 in functional urea metabolism and establish the feasibility of in vitro modeling of OTCD with hiPSC-Heps. By facilitating studies of OTCD genotype/phenotype correlation and drug screens, our model has potential for improving the therapy of OTCD.

Right Ventricular Remodeling Assessed by MRI in Duchenne Muscular Dystrophy.

BACKGROUND: In Duchenne muscular dystrophy (DMD), the right ventricle (RV) tends to be relatively well preserved, but characterization remains difficult due to its complex architecture. Tissue phase mapping (TPM) is a phase contrast cine MRI technique that allows for multidirectional assessment of myocardial velocities. PURPOSE: To use TPM to elucidate relationships between myocardial structure, function, and clinical variables in DMD. STUDY TYPE: Retrospective. SUBJECTS: A total of 20 patients with muscular dystrophy (median age: 16 years); 18 age-matched normal controls (median age: 15 years). FIELD STRENGTH/SEQUENCE: Three-directional velocity encoded cine gradient echo sequence (TPM) at 1.5 T, balanced steady-state free procession (bSSFP), T1 mapping with extracellular volume (ECV), and late gadolinium enhancement (LGE). ASSESSMENT: TPM in basal, mid, and apical short-axis planes was performed as part of a standard MRI study with collection of clinical data. Radial, circumferential, and longitudinal velocities (Vr, Vφ, and Vz, respectively) and corresponding time to peak (TTP) velocities were quantified from TPM and used to calculate RV twist as well as intraventricular and interventricular dyssynchrony. The correlations between TPM velocities, myocardial structure/function, and clinical variables were assessed. STATISTICAL TEST: Unpaired t-test, Wilcoxon rank-sum test, Bland-Altman analyses were used for comparisons between DMD patients and controls and between DMD subgroups. Pearson's test was used for correlations (r). Significance level: P < 0.05. RESULTS: Compared to controls, DMD patients had preserved RV ejection fraction (RVEF 53% ± 8%) but significantly increased interventricular dyssynchrony (Vφ: 0.49 ± 0.21 vs. 0.72 ± 0.17). Within the DMD cohort, RV dyssynchrony significantly increased with lower LV ejection fraction (intraventricular Vr and Vz: r = -0.49; interventricular Vz: r = 0.48). In addition, RV intraventricular dyssynchrony significantly increased with older age (Vz: r = 0.67). DATA CONCLUSION: RV remodeling in DMD occurs in the context of preserved RVEF. Within DMD, this abnormal RV deformation is associated with older age and decreased LVEF. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Late-gadolinium enhancement is common in older pediatric heart transplant recipients and is associated with lower ejection fraction.

BACKGROUND: Chronic graft failure and cumulative rejection history in pediatric heart transplant recipients (PHTR) are associated with myocardial fibrosis on endomyocardial biopsy (EMB). Cardiovascular magnetic resonance imaging (CMR) is a validated, non-invasive method to detect myocardial fibrosis via the presence of late gadolinium enhancement (LGE). In adult heart transplant recipients, LGE is associated with increased risk of future adverse clinical events including hospitalization and death. We describe the prevalence, pattern, and extent of LGE on CMR in a cohort of PHTR and its associations with recipient and graft characteristics. METHODS: This was a retrospective study of consecutive PHTR who underwent CMR over a 6-year period at a single center. Two independent reviewers assessed the presence and distribution of left ventricular (LV) LGE using the American Heart Association (AHA) 17-segment model. LGE quantification was performed on studies with visible fibrosis (LGE+). Patient demographics, clinical history, and CMR-derived volumetry and ejection fractions were obtained. RESULTS: Eighty-one CMR studies were performed on 59 unique PHTR. Mean age at CMR was 14.8 ± 6.2 years; mean time since transplant was 7.3 ± 5.0 years. The CMR indication was routine surveillance (without a clinical concern based on laboratory parameters, echocardiography, or cardiac catheterization) in 63% (51/81) of studies. LGE was present in 36% (29/81) of PHTR. In these LGE + studies, patterns included inferoseptal in 76% of LGE + studies (22/29), lateral wall in 41% (12/29), and diffuse, involving > 4 AHA segments, in 21% (6/29). The mean LV LGE burden as a percentage of myocardial mass was 18.0 ± 9.0%. When reviewing only the initial CMR per PHTR (n = 59), LGE + patients were older (16.7 ± 2.9 vs. 12.8 ± 4.6 years, p = 0.001), with greater time since transplant (8.3 ± 5.4 vs. 5.7 ± 3.9 years, p = 0.041). These patients demonstrated higher LV end-systolic volume index (LVESVI) (34.7 ± 11.7 vs. 28.7 ± 6.1 ml/m2, p = 0.011) and decreased LV ejection fraction (LVEF) (56.2 ± 8.1 vs. 60.6 ± 5.3%, p = 0.015). There were no significant differences in history of moderate/severe rejection (p = 0.196) or cardiac allograft vasculopathy (CAV) (p = 0.709). CONCLUSIONS: LV LGE was present in approximately one third of PHTR, more commonly in older patients with longer time since transplantation. Grafts with LGE have lower LVEF. CMR-derived LGE may aid in surveillance of chronic graft failure in PHTR.

The impact of maternal asthma on the fetal lung: Outcomes, mechanisms and interventions.

Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers.

Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Impact of pulmonary artery flow distribution on Fontan hemodynamics and flow energetics.

BACKGROUND: With improved life expectancy following Fontan palliation, there is an increasing population of patients with a total cavopulmonary connection. However, there is a poor understanding of which patients will experience Fontan failure and when. 4D flow MRI has identified several metrics of clinical interest, but longitudinal studies investigating hemodynamics in Fontan patients are lacking. OBJECTIVE: We aimed to investigate the relationship between flow distribution to the pulmonary arteries and regional hemodynamic metrics in a unique cohort with follow-up 4D flow MRI. MATERIALS AND METHODS: Patients with > 6 months of 4D flow MRI follow-up were included. Flow distribution from the caval veins to pulmonary arteries was measured in addition to regional measures of peak velocity, viscous energy loss (ELmean and ELtot), and kinetic energy. RESULTS: Ten patients with total cavopulmonary connection (17.7 ± 8.8 years at baseline, follow-up: 4.4 ± 2.6 years) were included. Five subjects had unequal flow distribution from the IVC to the pulmonary arteries at baseline. Over time, these subjects tended to have larger increases in peak velocity (39.2% vs 6.6%), ELmean (11.6% vs -38.3%), ELtot (9.5% vs -36.2%), and kinetic energy (96.1% vs 36.3%) in the IVC. However, these differences were statistically insignificant. We found that changes in ELmean and ELtot were significantly associated with changes in peak velocity in the caval veins (R2 > 0.5, P < 0.001). CONCLUSION: Unequal flow distribution from the IVC may drive increasing peak velocities and viscous energy losses, which have been associated with worse clinical outcomes. Changes in peak velocity may serve as a surrogate measure for changes in viscous energy loss.