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 CO2 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.

Emissions and energy impacts of the Inflation Reduction Act.

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.

Resolvin D1 improves allograft osteointegration and directly enhances osteoblasts differentiation.

Introduction: Allografts are the most common bone grafts for repairing osseous defects. However, their use is associated with an increased risk for infections, donor disease transmission and osteointegration deficiency. Resolvin D1 (RvD1) is an endogenous lipid with a scientifically proven pivotal role in inflammation resolution and osteoclastogenesis inhibition. Yet, its biological relevance as a potential bone regenerative drug has been scarcely studied. Here, we aim to investigate the RvD1 effect on allograft osteointegration in the alveolar bone regeneration (ABR) murine model. Methods: ABR model consisted of osseous defects that were generated by the extraction of the maxillary first molar in C57BL/6 mice. The sockets were filled with allograft and analyzed via RNA sequencing. Then they were locally injected with either RvD1 or saline via single or repeated administrations. The mice were sacrificed 2W after the procedure, and regenerated sites were analyzed using µCT and histology. First, MC3T3-E1 preosteoblasts were plated with IL-17 pro-inflammatory medium, and RANKL/OPG ratio was measured. Secondly, the MC3T3-E1 were cultured w/o RvD1, for 3W. Osteoblasts' markers were evaluated in different days, using qRT-PCR and Alizarin Red staining for calcified matrix. Results: In vivo, neither allograft alone nor single RvD1 administration promote bone regeneration in comparison to the control of spontaneous healing and even triggered an elevation in NR1D1 and IL1RL1 expression, markers associated with inflammation and inhibition of bone cell differentiation. However, repeated RvD1 treatment increased bone content by 135.92% ± 45.98% compared to its specific control, repeated sham, and by 39.12% ± 26.3% when compared to the spontaneous healing control group (n=7/group). Histologically, repeated RvD1 reduced the number of TRAP-positive cells, and enhanced allograft osteointegration with new bone formation. In vitro, RvD1 rescued OPG expression and decreased RANKL/OPG ratio in IL-17 pro-inflammatory conditions. Furthermore, RvD1 increased the expression of RUNX2, OSX, BSP and OC/BGLAP2 and the mineralized extracellular matrix during MC3T3-E1 osteoblasts differentiation. Conclusions: Repeated administrations of RvD1 promote bone regeneration via a dual mechanism: directly, via enhancement of osteoblasts' differentiation and indirectly, through reduction of osteoclastogenesis and RANKL/OPG ratio. This suggests that RvD1 may be a potential therapeutic bioagent for osseous regeneration following allograft implantation.

In former smokers with COPD, HEPA and carbon filter air cleaners improved moderate exacerbations but not QoL.

SOURCE CITATION: Hansel NN, Putcha N, Woo H, et al. Randomized clinical trial of air cleaners to improve indoor air quality and chronic obstructive pulmonary disease health: results of the CLEAN AIR study. Am J Respir Crit Care Med. 2022;205:421-30. 34449285.

CT in Transcatheter-delivered Treatment of Valvular Heart Disease.

Minimally invasive strategies to treat valvular heart disease have emerged over the past 2 decades. The use of transcatheter aortic valve replacement in the treatment of severe aortic stenosis, for example, has recently expanded from high- to low-risk patients and became an alternative treatment for those with prohibitive surgical risk. With the increase in transcatheter strategies, multimodality imaging, including echocardiography, CT, fluoroscopy, and cardiac MRI, are used. Strategies for preprocedural imaging strategies vary depending on the targeted valve. Herein, an overview of preprocedural imaging strategies and their postprocessing approaches is provided, with a focus on CT. Transcatheter aortic valve replacement is reviewed, as well as less established minimally invasive treatments of the mitral and tricuspid valves. In addition, device-specific details and the goals of CT imaging are discussed. Future imaging developments, such as peri-procedural fusion imaging, machine learning for image processing, and mixed reality applications, are presented.

Native Coronary Artery Pseudoaneurysm after Coronary Artery Bypass Grafting.

Coronary artery pseudoaneurysms are extremely rare and most often occur after trauma or endovascular procedures [Aoki 2008; Kar 2017]. Delay in diagnosis or treatment may lead to coronary thrombosis with resultant ischemia or hemorrhage subsequent tamponade. Here, we present the case of a 66-year-old female who developed a coronary artery pseudoaneurysm of a non-grafted vessel three weeks after coronary artery bypass grafting. To avoid re-sternotomy, the pseudoaneurysm was successfully managed with a covered coronary stent and mini-left anterior thoracotomy to evacuate the hemopericardium and relieve tamponade.

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: ß* = .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: ß* = - .045, p = .013; Reading: ß* = - .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.

Intermittent Occlusion of the Superior Vena Cava to Improve Hemodynamics in Patients With Acutely Decompensated Heart Failure: The VENUS-HF Early Feasibility Study.

BACKGROUND: Reducing congestion remains a primary target of therapy for acutely decompensated heart failure. The VENUS-HF EFS (VENUS-Heart Failure Early Feasibility Study) is the first clinical trial testing intermittent occlusion of the superior vena cava with the preCARDIA system, a catheter mounted balloon and pump console, to improve decongestion in acutely decompensated heart failure. METHODS: In a multicenter, prospective, single-arm exploratory safety and feasibility trial, 30 patients with acutely decompensated heart failure were assigned to preCARDIA therapy for 12 or 24 hours. The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events through 30 days. Secondary end points included technical success defined as successful preCARDIA placement, treatment, and removal and reduction in right atrial and pulmonary capillary wedge pressure. Other efficacy measures included urine output and patient-reported symptoms. RESULTS: Thirty patients were enrolled and assigned to receive the preCARDIA system. Freedom from device- or procedure-related major adverse events was observed in 100% (n=30/30) of patients. The system was successfully placed, activated and removed after 12 (n=6) or 24 hours (n=23) in 97% (n=29/30) of patients. Compared with baseline values, right atrial pressure decreased by 34% (17±4 versus 11±5 mm Hg, P<0.001) and pulmonary capillary wedge pressure decreased by 27% (31±8 versus 22±9 mm Hg, P<0.001). Compared with pretreatment values, urine output and net fluid balance increased by 130% and 156%, respectively, with up to 24 hours of treatment (P<0.01). CONCLUSIONS: We report the first-in-human experience of intermittent superior vena cava occlusion using the preCARDIA system to reduce congestion in acutely decompensated heart failure. PreCARDIA treatment for up to 24 hours was well tolerated without device- or procedure-related serious or major adverse events and associated with reduced filling pressures and increased urine output. These results support future studies characterizing the clinical utility of the preCARDIA system. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03836079.

Coronary CT Fractional Flow Reserve before Transcatheter Aortic Valve Replacement: Clinical Outcomes.

Background The role of CT angiography-derived fractional flow reserve (CT-FFR) in pre-transcatheter aortic valve replacement (TAVR) assessment is uncertain. Purpose To evaluate the predictive value of on-site machine learning-based CT-FFR for adverse clinical outcomes in candidates for TAVR. Materials and Methods This observational retrospective study included patients with severe aortic stenosis referred to TAVR after coronary CT angiography (CCTA) between September 2014 and December 2019. Clinical end points comprised major adverse cardiac events (MACE) (nonfatal myocardial infarction, unstable angina, cardiac death, or heart failure admission) and all-cause mortality. CT-FFR was obtained semiautomatically using an on-site machine learning algorithm. The ability of CT-FFR (abnormal if ≤0.75) to predict outcomes and improve the predictive value of the current noninvasive work-up was assessed. Survival analysis was performed, and the C-index was used to assess the performance of each predictive model. To compare nested models, the likelihood ratio χ2 test was performed. Results A total of 196 patients (mean age ± standard deviation, 75 years ± 11; 110 women [56%]) were included; the median time of follow-up was 18 months. MACE occurred in 16% (31 of 196 patients) and all-cause mortality in 19% (38 of 196 patients). Univariable analysis revealed CT-FFR was predictive of MACE (hazard ratio [HR], 4.1; 95% CI: 1.6, 10.8; P = .01) but not all-cause mortality (HR, 1.2; 95% CI: 0.6, 2.2; P = .63). CT-FFR was independently associated with MACE (HR, 4.0; 95% CI: 1.5, 10.5; P = .01) when adjusting for potential confounders. Adding CT-FFR as a predictor to models that include CCTA and clinical data improved their predictive value for MACE (P = .002) but not all-cause mortality (P = .67), and it showed good discriminative ability for MACE (C-index, 0.71). Conclusion CT angiography-derived fractional flow reserve was associated with major adverse cardiac events in candidates for transcatheter aortic valve replacement and improved the predictive value of coronary CT angiography assessment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Choe in this issue.

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.

Real-Time Non-Invasive and Direct Determination of Lactate Dehydrogenase Activity in Cerebral Organoids-A New Method to Characterize the Metabolism of Brain Organoids?

Organoids are a powerful tool in the quest to understand human diseases. As the developing brain is extremely inaccessible in mammals, cerebral organoids (COs) provide a unique way to investigate neural development and related disorders. The aim of this study was to utilize hyperpolarized 13C NMR to investigate the metabolism of COs in real-time, in a non-destructive manner. The enzymatic activity of lactate dehydrogenase (LDH) was determined by quantifying the rate of [1-13C]lactate production from hyperpolarized [1-13C]pyruvate. Organoid development was assessed by immunofluorescence imaging. Organoid viability was confirmed using 31P NMR spectroscopy. A total of 15 organoids collated into 3 groups with a group total weight of 20-77 mg were used in this study. Two groups were at the age of 10 weeks and one was at the age of 33 weeks. The feasibility of this approach was demonstrated in both age groups, and the LDH activity rate was found to be 1.32 ± 0.75 nmol/s (n = 3 organoid batches). These results suggest that hyperpolarized NMR can be used to characterize the metabolism of brain organoids with a total tissue wet weight of as low as 20 mg (<3 mm3) and a diameter ranging from 3 to 6 mm.

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.

Neurological Disorders Associated with WWOX Germline Mutations-A Comprehensive Overview.

The transcriptional regulator WW domain-containing oxidoreductase (WWOX) is a key player in a number of cellular and biological processes including tumor suppression. Recent evidence has emerged associating WWOX with non-cancer disorders. Patients harboring pathogenic germline bi-allelic WWOX variants have been described with the rare devastating neurological syndromes autosomal recessive spinocerebellar ataxia 12 (SCAR12) (6 patients) and WWOX-related epileptic encephalopathy (DEE28 or WOREE syndrome) (56 patients). Individuals with these syndromes present with a highly heterogenous clinical spectrum, the most common clinical symptoms being severe epileptic encephalopathy and profound global developmental delay. Knowledge of the underlying pathophysiology of these syndromes, the range of variants of the WWOX gene and its genotype-phenotype correlations is limited, hampering therapeutic efforts. Therefore, there is a critical need to identify and consolidate all the reported variants in WWOX to distinguish between disease-causing alleles and their associated severity, and benign variants, with the aim of improving diagnosis and increasing therapeutic efforts. Here, we provide a comprehensive review of the literature on WWOX, and analyze the pathogenic variants from published and unpublished reports by collecting entries from the ClinVar, DECIPHER, VarSome, and PubMed databases to generate the largest dataset of WWOX pathogenic variants. We estimate the correlation between variant type and patient phenotype, and delineate the impact of each variant, and used GnomAD to cross reference these variants found in the general population. From these searches, we generated the largest published cohort of WWOX individuals. We conclude with a discussion on potential personalized medicine approaches to tackle the devastating disorders associated with WWOX mutations.

Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects.

WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2-4 years. The underlying mechanisms of WWOX actions are poorly understood. In the current study, we show that specific neuronal deletion of murine Wwox produces phenotypes typical of the Wwox-null mutation leading to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality. A significant decrease in transcript levels of genes involved in myelination was observed in mouse cortex and hippocampus. Wwox-mutant mice exhibited reduced maturation of oligodendrocytes, reduced myelinated axons and impaired axonal conductivity. Brain hyperexcitability and hypomyelination were also revealed in human brain organoids with a WWOX deletion. These findings provide cellular and molecular evidence for myelination defects and hyperexcitability in the WOREE syndrome linked to neuronal function of WWOX.

Ventricular septal defect complicating delayed presentation of acute myocardial infarction during COVID-19 lockdown: a case report.

BACKGROUND: Post-myocardial infarction ventricular septal defects (VSDs) have become rare in the reperfusion era but remain associated with very high morbidity and mortality. As patients defer prompt evaluation and management of acute coronary syndromes during the COVID-19 global pandemic, the incidence of these and other post-infarction mechanical complications is expected to increase. CASE SUMMARY: A 37-year-old gentleman with multiple coronary artery disease risk factors presented with intermittent chest discomfort and 1 week of heart failure symptoms. An echocardiogram demonstrated a large muscular VSD and coronary angiography confirmed the presence of an anterior wall infarction. He was subsequently referred for transcatheter VSD repair and showed rapid clinical improvement in his symptoms. DISCUSSION: Post-infarction VSDs remain associated with a high degree of morbidity and mortality. Surgical repair of acutely ruptured myocardium can be technically challenging, and transcatheter repair has emerged as a safe and effective alternative.

Clinical Guideline Highlights for the Hospitalist: Secondary Fracture Prevention for Hospitalized Patients.

GUIDELINE TITLE: Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition RELEASE DATE: September 20, 2019 PRIOR VERSION: Not applicable DEVELOPER: American Society for Bone and Mineral Research Task Force and Multistakeholder Coalition FUNDING SOURCE: American Society for Bone and Mineral Research and the Center for Medical Technology Policy TARGET POPULATION: Adults 65 years or older with a hip or vertebral fracture. This review will focus on the core recommendations and their application in the practice of hospital medicine.

In older patients with AF, low-dose edoxaban reduced stroke or systemic embolism without increasing major bleeding.

SOURCE CITATION: Okumura K, Akao M, Yoshida T, et al. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med. 2020;383:1735-45. 32865374.

Hemodynamic Impact of MitraClip Procedure for Systemic Tricuspid Regurgitation in Congenitally Corrected Transposition of Great Arteries: A Case Report.

Patients with congenitally-corrected transposition of the great arteries (ccTGA) commonly develop significant systemic tricuspid valve regurgitation and systemic right ventricular dysfunction in adulthood, both of which presenting a therapeutic dilemma for the care team. Here we describe the case of a 35-year-old male with congenitally-corrected transposition of the great arteries who presented with severe systemic tricuspid valve regurgitation, biventricular systolic failure, and pulmonary hypertension. Due to prohibitive surgical risk, he underwent percutaneous tricuspid valve repair via MitraClip placement. Post-procedure, he demonstrated rapidly improved symptoms and sustained echocardiographic and hemodynamic evaluations. Few reports exist describing the safety and feasibility of the MitraClip procedure on a systemic tricuspid valve, but to our knowledge, this is the first to describe invasive hemodynamic improvements in patients with this degree of cardiopulmonary sequelae from the congenital lesion. There may be optimism for the MitraClip procedure as "bridge to list" in patients with ccTGA otherwise initially ineligible for surgical valve intervention or transplant.