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"Steinberg, Daniel"
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Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime
A historical perspective on atherosclerosis allows us to reflect on the once controversial hypotheses in the field. Plaque formation was once thought to be dependent upon hypercholesterolemia alone, or solely in response to injury. More recently, inflammatory cascades were thought to be at the root of lesion development. A more realistic view may be that atherosclerosis is neither exclusively an inflammatory disease nor solely a lipid disorder: it is both.
Journal Article
Comparison of Diagnostic Value of a Novel Noninvasive Coronary Computed Tomography Angiography Method Versus Standard Coronary Angiography for Assessing Fractional Flow Reserve
Noninvasive fractional flow reserve (FFR) from coronary computed tomography angiography (cCTA) correlates well with invasive FFR and substantially improves the detection of obstructive coronary artery disease. However, with current algorithms, computed tomography (CT)–based FFR is derived off-site in an involved time-consuming manner. We sought to investigate the diagnostic performance of a novel CT-based FFR algorithm, developed for time-efficient in-hospital evaluation of hemodynamically indeterminate coronary lesions. In a blinded fashion, CT-based FFR was assessed in 67 coronary lesions of 53 patients. Pressure guidewire–based FFR <0.80 served as the reference standard to define hemodynamically significant stenosis and assess the diagnostic performance of CT-based FFR compared with standard evaluation of cCTA (luminal diameter stenosis of ≥50%). We recorded the time needed for derivation of CT-based FFR. On a per-lesion and per-patient basis, CT-based FFR resulted in a sensitivity of 85% and 94%, a specificity of 85% and 84%, a positive predictive value of 71% and 71%, and a negative predictive value of 93% and 97%, respectively. The area under the receiver operating characteristic curve on a per-lesion basis was significantly greater for CT-based FFR compared with standard evaluation of cCTA (0.92 vs 0.72, p = 0.0049). A similar trend, albeit not statistically significant, was observed on per-patient analysis (0.91 vs 0.78, p = 0.078). Mean total time for CT-based FFR was 37.5 ± 13.8 minutes. In conclusion, the CT-based FFR algorithm evaluated here outperforms standard evaluation of cCTA for the detection of hemodynamically significant stenoses while allowing on-site application within clinically viable time frames.
•We investigated the diagnostic performance of a computed tomography (CT)–based fractional flow reserve (FFR) algorithm.•Hemodynamically indeterminate coronary lesions were evaluated.•CT-based FFR resulted in a sensitivity of 85% and 94% and specificity of 85% and 84%.•CT-based FFR algorithm allows application within clinically viable time frames.
Journal Article
Youth well-being predicts later academic success
Young people worldwide face new challenges as climate change and complex family structures disrupt societies. These challenges impact on youth’s subjective well-being, with evidence of decline across many countries. While the burden of negative well-being on productivity is widely examined amongst adults, its cost among youth remains understudied. The current research comprehensively investigates the relationship between youth subjective well-being and standardized academic test scores. We use highly controlled machine learning models on a moderately-sized high-school student sample (
N
~ 3400), with a composite subjective well-being index (composed of depression, anxiety and positive affect), to show that students with greater well-being are more likely to have higher academic scores 7–8 months later (on Numeracy: β* = .033,
p
= .020). This effect emerges while also accounting for previous test scores and other confounding factors. Further analyses with each well-being measure, suggests that youth who experience greater depression have lower academic achievement (Numeracy: β* = − .045,
p
= .013; Reading: β* = − .033,
p
= .028). By quantifying the impact of youth well-being, and in particular of lowering depression, this research highlights its importance for the next generation's health and productivity.
Journal Article
Drivers and implications of alternative routes to fuels decarbonization in net-zero energy systems
Energy transition scenarios are characterized by increasing electrification and improving efficiency of energy end uses, rapid decarbonization of the electric power sector, and deployment of carbon dioxide removal (CDR) technologies to offset remaining emissions. Although hydrocarbon fuels typically decline in such scenarios, significant volumes remain in many scenarios even at the time of net-zero emissions. While scenarios rely on different approaches for decarbonizing remaining fuels, the underlying drivers for these differences are unclear. Here we develop several illustrative net-zero systems in a simple structural energy model and show that, for a given set of final energy demands, assumptions about the use of biomass and CO
2
sequestration drive key differences in how emissions from remaining fuels are mitigated. Limiting one resource may increase reliance on another, implying that decisions about using or restricting resources in pursuit of net-zero objectives could have significant tradeoffs that will need to be evaluated and managed.
Assumptions about the use of biomass and CO
2
sequestration drive key differences in how emissions from remaining fuels are mitigated in net-zero energy systems, with potentially significant tradeoffs that will need to be evaluated and managed.
Journal Article
Modeling genetic epileptic encephalopathies using brain organoids
Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain‐containing oxidoreductase (
WWOX
) are associated with a relatively mild autosomal recessive spinocerebellar ataxia‐12 (SCAR12) and a more severe early infantile
WWOX
‐related epileptic encephalopathy (WOREE). In this study, we generated an
in vitro
model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR‐engineered human ES cells and from patient‐derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic
WWOX
expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.
SYNOPSIS
Mutations in the human
WWOX
gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions.
At early stages of development
WWOX
is highly expressed in neural stem cells called ventricular radial glia (vRGs).
WWOX
‐mutated brain organoids have imbalanced levels of excitatory and inhibitory neurons and are hyperexcitable, demonstrating epileptiform activity upon electrophysiological recordings.
WWOX
mutations cause increased astrogenesis and cortical dysplasia.
WOREE‐modeled organoids have impaired DNA damage response and chronic activation of the Wnt‐signaling pathway.
WWOX
gene reintroduction could benefit patients suffering from
WWOX
mutations.
Graphical Abstract
Mutations in the human
WWOX
gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions.
Journal Article
WWOX-Related Neurodevelopmental Disorders: Models and Future Perspectives
The WW domain-containing oxidoreductase (WWOX) gene was originally discovered as a putative tumor suppressor spanning the common fragile site FRA16D, but as time has progressed the extent of its pleiotropic function has become apparent. At present, WWOX is a major source of interest in the context of neurological disorders, and more specifically developmental and epileptic encephalopathies (DEEs). This review article aims to introduce the many model systems used through the years to study its function and roles in neuropathies. Similarities and fundamental differences between rodent and human models are discussed. Finally, future perspectives and promising research avenues are suggested.
Journal Article
Exploring the market for third-party-owned residential photovoltaic systems: insights from lease and power-purchase agreement contract structures and costs in California
Over the past several years, third-party-ownership (TPO) structures for residential photovoltaic (PV) systems have become the predominant ownership model in the US residential market. Under a TPO contract, the PV system host typically makes payments to the third-party owner of the system. Anecdotal evidence suggests that the total TPO contract payments made by the customer can differ significantly from payments in which the system host directly purchases the system. Furthermore, payments can vary depending on TPO contract structure. To date, a paucity of data on TPO contracts has precluded studies evaluating trends in TPO contract cost. This study relies on a sample of 1113 contracts for residential PV systems installed in 2010-2012 under the California Solar Initiative to evaluate how the timing of payments under a TPO contract impacts the ultimate cost of the system to the customer. Furthermore, we evaluate how the total cost of TPO systems to customers has changed through time, and the degree to which contract costs have tracked trends in the installed costs of a PV system. We find that the structure of the contract and the timing of the payments have financial implications for the customer: (1) power-purchase contracts, on average, cost more than leases, (2) no-money-down contracts are more costly than prepaid contracts, assuming a customer's discount rate is lower than 17% and (3) contracts that include escalator clauses cost more, for both power-purchase agreements and leases, at most plausible discount rates. In addition, all contract costs exhibit a wide range, and do not parallel trends in installed costs over time.
Journal Article
OCD Taboo Thoughts and Stigmatizing Attitudes in Clinicians
Individuals who suffer from obsessive–compulsive disorder have persistent intrusive thoughts that cause severe distress that impairs daily functioning. These individuals often conceal their intrusive thoughts and delay help-seeking for fear of being stigmatized. Stigma can be problematic when it is present among mental health professionals because they may distance themselves from their clients and have a negative outlook on treatment outcome. To date there has not been any research that focuses on stigma that clinician’s may hold towards obsessive–compulsive disorder or specific obsessions; however, there is evidence that mental health professionals may have prejudices towards individuals who suffer from other mental illnesses. The current study aimed to explore clinician and student clinician attitudes about obsessional content from varying symptom dimensions. Results indicated participants were more likely to socially reject or be concerned by individuals with obsessions related to contamination, harming, and sexual obsessions than those with scrupulous obsessions, and that they would be less likely to reveal sexual obsessions to others if they were experiencing them than the other three types of obsessions.
Journal Article