Search

Finding a directed acyclic graph (DAG) that best encodes the conditional inde-pendence statements observable from data is a central question within causality. Algorithms that greedily transform one candidate DAG into another given a fixed set of moves have been particularly successful, for example, the greedy equivalence search, greedy interventional equivalence search, and max-min hill climbing algorithms. In 2010, Studenty, Hemmecke, and Lindner introduced the char-acteristic imset (CIM) polytope, CIMp, whose vertices correspond to Markov equivalence classes, as a way of transforming causal discovery into a linear optimization problem. We show that the moves of the aforementioned algorithms are included within classes of edges of CIMp and that restrictions placed on the skeleton of the candidate DAGs correspond to faces of CIMp. Thus, we observe that greedy equivalence search, greedy interventional equivalence search, and max-min hill climbing all have geometric realizations as greedy edge-walks along CIMp. Furthermore, the identified edges of CIMp strictly generalize the moves of these algorithms. Exploiting this generalization, we introduce a greedy simplex-type algorithm called greedy CIM, and a hybrid variant, skeletal greedy CIM, that outperforms current competitors among hybrid and constraint-based algorithms., QC 20230425

Mental healthcare disparities are routinely documented, yet they remain wider than in most other areas of healthcare services and common mental disorders (depression and anxiety) continue to be one of the highest health burdens for older people of color. To address disparities in mental health services for older people of color, the narrative must move beyond simply documenting these inequities and attain a better understanding of the internalized, interpersonal, systemic, and medical racism that have harmed these communities and excluded them from its services in the first place. It is imperative that researchers, clinicians, and policymakers acknowledge the realities of racism and discrimination as leading causes of mental healthcare disparities. Therefore, this review is a call-to-action. Authors adopt an antiracist and health equity lens in evaluating the differing needs of Blacks/African-Americans, Asian Americans, and Latinos by exploring psychiatric comorbidity, experiences with seeking, accessing, and engaging in treatment, and the unique cultural and psychosocial factors that affect treatment outcomes for these diverse groups. Further, authors offer researchers and practitioners tangible tools for developing and implementing culturally-sensitive, mental health focused interventions for older people of color with special attention placed on cultural adaptations, models of care, prevention, and practical strategies that can be implemented to reduce disparities and increase equity in mental healthcare.

BackgroundA learning health system (LHS) is a health system in which patients and clinicians work together to choose care on the basis of best evidence and to drive discovery as a natural outgrowth of every clinical encounter to ensure the right care at the right time. An LHS for dentistry is now feasible, as an increased number of oral health care encounters are captured in electronic health records (EHRs).MethodsThe authors used EHRs data to track periodontal health outcomes at 3 large dental institutions. The 2 outcomes of interest were a new periodontitis case (for patients who had not received a diagnosis of periodontitis previously) and tooth loss due to progression of periodontal disease.ResultsThe authors assessed a total of 494,272 examinations (new periodontitis outcome: n = 168,442; new tooth loss outcome: n = 325,830), representing a total of 194,984 patients. Dynamic dashboards displaying performance on both measures over time allow users to compare demographic and risk factors for patients. The incidence of new periodontitis and tooth loss was 4.3% and 1.2%, respectively.ConclusionsPeriodontal disease, diagnosis, prevention, and treatment are particularly well suited for an LHS model. The results showed the feasibility of automated extraction and interpretation of critical data elements from the EHRs. The 2 outcome measures are being implemented as part of a dental LHS. The authors are using this knowledge to target the main drivers of poorer periodontal outcomes in a specific patient population, and they continue to use clinical health data for the purpose of learning and improvement.Practical implicationsDental institutions of any size can conduct contemporaneous self-evaluation and immediately implement targeted strategies to improve oral health outcomes.

Systemic sclerosis (SSc) is a rare, systemic autoimmune disease of unknown etiology. Among the systemic rheumatic diseases, SSc carries the highest mortality, in part due to the historical lack of disease modifying therapies. Recently, landmark randomized controlled trials (RCTs) have been conducted that have illustrated the heterogeneous nature of SSc and furthered our understanding of the key inflammatory and fibrotic pathways involved in SSc pathogenesis. Although SSc affects various organ systems, RCTs have focused on investigating treatments for diffuse cutaneous sclerosis (dcSSc) and interstitial lung disease (ILD). While recent RCTs for dcSSc have failed to demonstrate a treatment benefit, the outcomes of two RCTs led to the approval of two novel therapies for SSc-ILD: nintedanib and tocilizumab. This review summarizes the salient outcome data from recent SSc trials within a practical clinical framework and points out gaps in knowledge that may help inform the design of future SSc studies.

As opioid prescribing has declined, it is unclear how the landscape of prescription pain treatment across the U.S. has changed. We used nationally-representative data from the Medical Expenditure Health Survey, 2014 to 2018 to examine trends in prescriptions for opioid and non-opioid pain medications, including acetaminophen, non-steroidal anti-inflammatory drugs, gabapentinoids, and antidepressants among U.S. adults with self-reported pain. Overall, from 2014 to 2018, the percentage of participants receiving a prescription for opioids declined, (38.8% vs 32.8%), remained stable for non-steroidal anti-inflammatory drugs (26.8% vs 27.7%), and increased for acetaminophen (1.6% vs 2.3%), antidepressants (9.6% vs 12.0%) and gabapentinoids (13.2% vs 19.0%). In this period, the adjusted odds of receiving an opioid prescription decreased (aOR = .93, 95% CI = .90-.96), while the adjusted odds of receiving antidepressant, gabapentinoid and acetaminophen prescriptions increased (antidepressants: aOR = 1.08, 95% CI = 1.03-1.13 gabapentinoids: aOR = 1.11, 95% CI = 1.06-1.17; acetaminophen: aOR = 1.10, 95% CI: 1.02-1.20). Secondary analyses stratifiying within the 2014 to 2016 and 2016 to 2018 periods revealed particular increases in prescriptions for gabapentinoids (aOR = 1.13, 95% CI = 1.05-1.21) and antidepressants (aOR = 1.23, 95% CI = 1.12-1.35) since 2016. PERSPECTIVE: These data demonstrate that physicians are increasingly turning to CDC-recommended non-opioid medications for pain management, particularly antidepressants and gabapentinoids. However, evidence for these medications' efficacy in treating numerous common pain conditions, including low back pain, remains limited.

Errors have been conceptualized as internal forms of threat that can cause harm in unpredictable ways. An index of error processing is the error-related negativity (ERN), an event-related potential reflecting variability in the sensitivity to errors. Prior work has shown the relationship between psychopathology symptoms and the ERN is unclear, and may be moderated by intolerance of uncertainty (IU), a trait that captures how people react to unpredictability. IU includes two subfactors of prospective IU (active seeking of predictability) and inhibitory IU (behavioral paralysis). In the present study, 188 undergraduates performed an Eriksen flanker task designed to elicit the ERN, while brain activity was recorded using electroencephalography (EEG). Participants completed the Intolerance of Uncertainty Scale, Short Form (IUS-12), and other measures of anxiety, depression and worry. Total IU explained 5 % of the variance in correct-response negativity (CRN), but was not associated with the ERN in our sample. In contrast to previous findings, the IU subfactors did not predict the ERN or post-error slowing (PES), nor did total IU and depression interact to predict the ERN. Exploratory analyses also showed that total IU did not moderate the relationship between trait anxiety and the ERN. Small samples may have previously exaggerated the links between self-reported IU and the ERN. As such, further high-powered replications are required to confirm if, and how, they are related.

We provide a computer-assisted proof of one of the central open questions in one-dimensional renormalization theory - universality of the golden-mean Siegel disks. We further show that for every function in the stable manifold of the golden-mean renormalization fxed point the boundary of the Siegel disk is a quasicircle which coincides with the closure of the critical orbit, and that the dynamics on the boundary of the Siegel disk is rigid. Furthermore, we extend the renormalization from one-dimensional analytic maps with a golden-mean Siegel disk to two-dimensional dissi-pative He acute accent non-like maps and show that the renormalization hyperbolicity result still holds in this setting.

Acute coronary syndrome (ACS) is frequently complicated by evidence of heart failure (HF). Those at highest risk for acute decompensated HF in the setting of ACS (ACS-HF) are older, female, and have preexisting heart disease, type 2 diabetes mellitus, hypertension, and/or kidney disease. The presence of ACS-HF is strongly associated with higher mortality and more frequent readmissions, especially for HF. Low implementation of guideline-directed medical therapy has further complicated the clinical care of this high-risk population. Improved utilization of current therapies, coupled with further investigation of strategies to manage ACS-HF, is desperately needed to improve outcomes in this vulnerable population, and the results of currently ongoing or recently concluded ACS-HF studies in this population are of great interest. In this review, we explore the pathophysiology, epidemiology, risk factors, and outcomes for patients with ACS-HF, and describe both existing evidence for management of this challenging condition and areas requiring further research. (J Am Coll Cardiol HF 2022;10:404-414) (c) 2022 by the American College of Cardiology Foundation.

Undetectable attacks are an important class of malicious attacks threatening the security of cyber-physical systems, which can modify a system's state but leave the system output measurements unaffected and hence cannot be detected from the output. This paper studies undetectable attacks on cone-invariant systems and multi-agent systems. We first provide a general characterization of zero-dynamics attacks, which characterizes fully undetectable attacks targeting the nonminimum phase zeros of a system. This geometrical characterization makes it possible to develop a defense strategy seeking to place a minimal number of sensors to detect and counter the zero-dynamics attacks on the system's actuators. The detect and defense scheme amounts to computing a set containing potentially vulnerable actuator locations and nodes and a defense union for feasible placement of sensors based on the geometrical properties of the cones under consideration., QC 20230222

In this article we introduce line Smoothness-Increasing Accuracy-Conserving Multi -Resolution Analysis. This is a procedure for exploiting convolution kernel post-processors for ob-taining more accurate multidimensional multiresolution analysis in terms of error reduction. This filtering-projection tool allows for the transition of data between different resolutions while simultane-ously decreasing errors in the fine grid approximation. It specifically allows for defining detail multi -wavelet coefficients when translating coarse data onto finer meshes. These coefficients are usually not defined in such cases. We show how to analytically evaluate the resulting convolutions and express the filtered approximation in a new basis. This is done by combining the filtering procedure with projection operators that allow for computational implementation of this scale transition procedure. Further, this procedure can be applied to piecewise constant approximations to functions, as it pro-vides error reduction. We demonstrate the effectiveness of this technique in two and three dimensions., QC 20230612

We prove the existence of real analytic Hamiltonians with topologically unstable quasi -periodic invariant tori. Using various versions of our examples, we solve the following problems in the stability theory of analytic quasi-periodic motion:(1) Show the existence of topologically unstable tori of arbitrary frequency. Moreover, the Birkhoff Normal Form at the invariant torus can be chosen to be convergent, equal to a planar or non -planar polynomial.(2) Show the optimality of the exponential stability for Diophantine tori.(3) Show the existence of real analytic Hamiltonians that are integrable on half of the phase space, and such that all orbits on the other half accumulate at infinity.(4) For sufficiently Liouville vectors, obtain invariant tori that are not accumulated by a positive measure set of quasi-periodic invariant tori., QC 20221118

The ionization region model (IRM) is applied to model high power impulse magnetron sputtering (HiPIMS) discharges with a Cu target. We apply the model to three discharges that were experimentally explored in the past, or applied to deposit thin copper films, with the aim to quantify internal plasma process parameters and thereby understand how these discharges differ from each other. The temporal variation of the various neutral and ionic species, the electron density and temperature, as well as internal discharge parameters, such as the ionization probability, back attraction probability, and ionized flux fraction of the sputtered species, are determined. We demonstrate that the Cu+ ions dominate the total ion current to the target surface and that all the discharges are dominated by self-sputter recycling to reach high discharge currents. Furthermore, the ion flux into the diffusion region is dominated by Cu+ ions, which represents roughly 80% of the total ion flux onto the substrate, in agreement with experimental findings. For the discharges operated with peak discharge current densities in the range 0.9 - 1.3 A cm-2, the ion back-attraction probability of the Cu+ ion (beta t) is low compared to previously investigated HiPIMS discharges, or in the range 44 - 50%, while the ionization probability (alpha t) is in the range 61 - 69%, and the ionized flux fraction is in the range 32 - 40%. It is, furthermore, found that operating these Cu HiPIMS discharges at lower working gas pressures (in the present case around 0.5 Pa) is beneficial in terms of optimizing ionization of the sputtered species., QC 20220728

BackgroundWith rising United States health care expenditure, estimating current spending for patients with heart failure (HF) informs the value of preventative health interventions.ObjectivesThe purpose of this study was to estimate current health care expenditure growth for patients with HF in the United States.MethodsThe authors pooled MEPS (Medical Expenditure Panel Survey) data from 2009-2018 to calculate total HF-related expenditure across clinical settings in the United States. A 2-part model adjusted for demographics, comorbidities, and year was used to estimate annual mean and incremental expenditures associated with HF.ResultsIn the United States, an average of $28,950 (2018 inflation-adjusted dollars) is spent per year for health care-related expenditure for individuals with HF compared with $5,727 for individuals without HF. After adjusting for demographics and comorbidities, a diagnosis of HF was associated with $3,594 in annual incremental expenditure compared with those without HF. HF-related expenditure increased from $26,864 annual per person in 2009-2010 to $32,955 in 2017-2018, representing a 23% rise over 10 years. In comparison, expenditure on myocardial infarction, type 2 diabetes mellitus, and cancer grew by 16%, 28%, and 16%, respectively. Most of the cost was related to hospitalization: $12,569 per year. Outpatient office-based care and prescription medications saw the greatest growth in cost over the period, 41% and 24%, respectively. Estimated incremental national expenditure for HF per year was $22.3 billion; total annual expenditure for adults with HF was $179.5 billion.ConclusionsHF is a costly condition for which expenditure is growing faster than that of other chronic conditions.

ObjectiveHealthcare disparities are widely described in adults, but barriers affecting access to care for pediatric patients with moyamoya disease (MMD) are unknown. Understanding socioeconomic factors impacting hospital access and outcomes is necessary to address pediatric healthcare disparities.MethodsIn this cross-sectional observational study, the Kids' Inpatient Database was used to identify patients admitted with a primary diagnosis of MMD from 2003 to 2016. Patients ≤ 18 years with a primary diagnosis of MMD based on International Classification of Diseases (ICD) codes were included. Hospital admissions were queried for use of cerebral revascularization based on ICD procedure codes.ResultsQuery of the KID yielded 1449 MMD hospitalizations. After multivariable regression, Hispanic ethnicity (OR 0.52 [95% CI 0.33-0.81], p = 0.004) was associated with lack of surgical revascularization. Private insurance (OR 1.56 [95% CI 1.15-2.13], p = 0.004), admissions at medium- and high-volume centers (OR 2.01 [95% CI 1.42-2.83], p < 0.001 and OR 2.84 [95% CI 1.95-4.14], p < 0.001, respectively), and elective hospitalization (OR 3.37 [95% CI 2.46-4.64], p < 0.001) were positively associated with revascularization. Compared with Caucasian race, Hispanic ethnicity was associated with increased mean (± SEM) length of stay by 2.01 ± 0.70 days (p = 0.004) and increased hospital charges by $24,333.61 ± $7918.20 (p = 0.002), despite the decreased utilization of surgical revascularization. Private insurance was associated with elective admission (OR 1.50 [95% CI 1.10-2.05], p = 0.01) and admission to high-volume centers (OR 1.90 [95% CI 1.26-2.88], p = 0.002). African American race was associated with the development of in-hospital complications (OR 2.52 [95% CI 1.38-4.59], p = 0.003).ConclusionsAmong pediatric MMD hospitalizations, multiple socioeconomic factors were associated with access to care, whether surgical treatment is provided, and whether in-hospital complicati

Although stem cell-derived extracellular vesicles (EVs) have remarkable therapeutic potential for various diseases, the therapeutic efficacy of EVs is limited due to their degradation and rapid diffusion after administration, hindering their translational applications. Here, we developed a new generation of collagen-binding EVs, by chemically conjugating a collagen-binding peptide SILY to EVs (SILY-EVs), which were designed to bind to collagen in the extracellular matrix (ECM) and form an EV-ECM complex to improve EVs' in situ retention and therapeutic efficacy after transplantation. Methods: SILY was conjugated to the surface of mesenchymal stem/stromal cell (MSC)-derived EVs by using click chemistry to construct SILY-EVs. Nanoparticle tracking analysis (NTA), ExoView analysis, cryogenic electron microscopy (cryo-EM) and western-blot analysis were used to characterize the SILY-EVs. Fluorescence imaging (FLI), MTS assay, ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the collagen binding and biological functions of SILY-EVs in vitro. In a mouse hind limb ischemia model, the in vivo imaging system (IVIS), laser doppler perfusion imaging (LDPI), micro-CT, FLI and RT-qPCR were used to determine the SILY-EV retention, inflammatory response, blood perfusion, gene expression, and tissue regeneration. Results: In vitro, the SILY conjugation significantly enhanced EV adhesion to the collagen surface and did not alter the EVs' biological functions. In the mouse hind limb ischemia model, SILY-EVs presented longer in situ retention, suppressed inflammatory responses, and significantly augmented muscle regeneration and vascularization, compared to the unmodified EVs. Conclusion: With the broad distribution of collagen in various tissues and organs, SILY-EVs hold promise to improve the therapeutic efficacy of EV-mediated treatment in a wide range of diseases and disorders. Moreover, SILY-EVs possess the potential to functio

ObjectiveSporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.MethodsThe authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.ResultsThe authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.ConclusionsThe authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

SignificanceThe mature capsids of HIV-1 are transiently stable complexes that self-assemble around the viral genome during maturation, and uncoat to release preintegration complexes that archive a double-stranded DNA copy of the virus in the host cell genome. However, a detailed view of how HIV cores rupture remains lacking. Here, we elucidate the physical properties involved in capsid rupture using a combination of large-scale all-atom molecular dynamics simulations and cryo-electron tomography. We find that intrinsic strain on the capsid forms highly correlated patterns along the capsid surface, along which cracks propagate. Capsid rigidity also increases with high strain. Our findings provide fundamental insight into viral capsid uncoating.

Bacteria are efficient colonizers of a wide range of secluded microhabitats, such as soil pores, skin follicles, or intestinal crypts. How the structural diversity of these habitats modulates microbial self-organization remains poorly understood, in part because of the difficulty to precisely manipulate the physical structure of microbial environments. Using a microfluidic device to grow bacteria in crypt-like incubation chambers of systematically varied lengths, we show that small variations in the physical structure of the microhabitat can drastically alter bacterial colonization success and resistance against invaders. Small crypts are uncolonizable; intermediately sized crypts can stably support dilute populations, while beyond a second critical length scale, populations phase separate into a dilute region and a jammed region. The jammed state is characterized by extreme colonization resistance, even if the resident strain is suppressed by an antibiotic. Combined with a flexible biophysical model, we demonstrate that colonization resistance and associated priority effects can be explained by a crowding-induced phase transition, which results from a competition between proliferation and density-dependent cell leakage. The emerging sensitivity to scale underscores the need to control for scale in microbial ecology experiments. Systematic flow-adjustable length-scale variations may serve as a promising strategy to elucidate further scale-sensitive tipping points and to rationally modulate the stability and resilience of microbial colonizers.

The dissolution of sulfide minerals can lead to hazardous arsenic levels in groundwater. This study investigates the oxidative dissolution of natural As-bearing sulfide minerals and the related release of arsenic under flow-through conditions. Column experiments were performed using reactive As-bearing sulfide minerals (arsenopyrite and löllingite) embedded in a sandy matrix and injecting oxic solutions into the initially anoxic porous media to trigger the mineral dissolution. Noninvasive oxygen measurements, analyses of ionic species at the outlet, and scanning electron microscopy allowed tracking the propagation of the oxidative dissolution fronts, the mineral dissolution progress, and the change in mineral surface composition. Process-based reactive transport simulations were performed to quantitatively interpret the geochemical processes. The experimental and modeling outcomes show that pore-water acidity exerts a key control on the dissolution of sulfide minerals and arsenic release since it determines the precipitation of secondary mineral phases causing the sequestration of arsenic and the passivation of the reactive mineral surfaces. The impact of surface passivation strongly depends on the flow velocity and on the spatial distribution of the reactive minerals. These results highlight the fundamental interplay of reactive mineral distribution and hydrochemical and hydrodynamic conditions on the mobilization of arsenic from sulfide minerals in flow-through systems.

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

PurposeSleep is vital to cognition, yet underlying mechanisms remain unclear. Although sleep duration and continuity are two well-established contributors, additional factors-including homeostatic sleep drive processes-may also underlie cognition-related sleep restoration. This study investigates the relative contributions of sleep EEG factors to psychomotor functioning in adults with insomnia and healthy controls (HC) to identify the most significant sleep factors supporting psychomotor functioning.Materials and methodsAdults with insomnia (n = 37) and HC (n = 39) completed 3 nights of polysomnography and a complex psychomotor task (switching attention task; SAT). Univariate correlations identified the most significant predictors (traditional PSG, spectral EEG, initial delta peak, and overnight delta decline) of SAT performance, which were then entered into multivariable linear regressions examining whether predictors remained significant after accounting for shortened/fragmented sleep and whether relationships differed across groups.ResultsIn addition to greater wake after sleep onset (WASO; r = 0.33), a slower overnight delta decline (r = 0.50) and a lower initial delta peak (r = -0.38) were the most significant predictors of poorer SAT performance. Both overnight delta decline (F(7, 68) = 12.52, p < 0.001) and initial delta peak (F(7, 68) = 7.85, p = 0.007) remained significant predictors after controlling for demographics, total sleep time, and WASO. Relationships were analogous across subject groups.ConclusionFindings suggest that, in addition to sleep duration and continuity, processes related to recovery from and dissipation of homeostatic sleep drive may support psychomotor performance and broadly support daytime functioning in individuals with and without insomnia. Future research may examine overnight delta dynamics as transdiagnostic processes supporting cognition-related sleep restoration across a range of clinical populations.

Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.

To support the dynamic composition of various devices/apps into a medical system at point-of-care, a set of communication patterns to describe the communication needs of devices has been proposed. To address timing requirements, each pattern breaks common timing properties into finer ones that can be enforced locally by the components. Common timing requirements for the underlying communication substrate are derived from these local properties. The local properties of devices are assured by the vendors at the development time. Although organizations procure devices that are compatible in terms of their local properties and middleware, they may not operate as desired. The latency of the organization network interacts with the local properties of devices. To validate the interaction among the timing properties of components and the network, we formally specify such systems in Timed Rebeca. We use model checking to verify the derived timing requirements of the communication substrate in terms of the network and device models. We provide a set of templates as a guideline to specify medical systems in terms of the formal model of patterns. A composite medical system using several devices is subject to state-space explosion. We extend the reduction technique of Timed Rebeca based on the static properties of patterns. We prove that our reduction is sound and show the applicability of our approach in reducing the state space by modeling two clinical scenarios made of several instances of patterns.

Although stem cell-derived extracellular vesicles (EVs) have remarkable therapeutic potential for various diseases, the therapeutic efficacy of EVs is limited due to their degradation and rapid diffusion after administration, hindering their translational applications. Here, we developed a new generation of collagen-binding EVs, by chemically conjugating a collagen-binding peptide SILY to EVs (SILY-EVs), which were designed to bind to collagen in the extracellular matrix (ECM) and form an EV-ECM complex to improve EVs' in situ retention and therapeutic efficacy after transplantation. Methods: SILY was conjugated to the surface of mesenchymal stem/stromal cell (MSC)-derived EVs by using click chemistry to construct SILY-EVs. Nanoparticle tracking analysis (NTA), ExoView analysis, cryogenic electron microscopy (cryo-EM) and western-blot analysis were used to characterize the SILY-EVs. Fluorescence imaging (FLI), MTS assay, ELISA and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to evaluate the collagen binding and biological functions of SILY-EVs in vitro. In a mouse hind limb ischemia model, the in vivo imaging system (IVIS), laser doppler perfusion imaging (LDPI), micro-CT, FLI and RT-qPCR were used to determine the SILY-EV retention, inflammatory response, blood perfusion, gene expression, and tissue regeneration. Results: In vitro, the SILY conjugation significantly enhanced EV adhesion to the collagen surface and did not alter the EVs' biological functions. In the mouse hind limb ischemia model, SILY-EVs presented longer in situ retention, suppressed inflammatory responses, and significantly augmented muscle regeneration and vascularization, compared to the unmodified EVs. Conclusion: With the broad distribution of collagen in various tissues and organs, SILY-EVs hold promise to improve the therapeutic efficacy of EV-mediated treatment in a wide range of diseases and disorders. Moreover, SILY-EVs possess the potential to functio

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

In this paper, we consider several possible ways to set up Heterogeneous Multiscale Methods for the Landau-Lifshitz equation with a highly oscillatory diffusion coefficient, which can be seen as a means to modeling rapidly varying ferromagnetic materials. We then prove estimates for the errors introduced when approximating the relevant quantity in each of the models given a periodic problem, using averaging in time and space of the solution to a corresponding micro problem. In our setup, the Landau-Lifshitz equation with a highly oscillatory coefficient is chosen as the micro problem for all models. We then show that the averaging errors only depend on \varepsilon and the size of the microscopic oscillations, as well as the size of the averaging domain in time and space and the choice of averaging kernels., QC 20220323No duplicate with DiVA 1611064

Bacteria are efficient colonizers of a wide range of secluded microhabitats, such as soil pores, skin follicles, or intestinal crypts. How the structural diversity of these habitats modulates microbial self-organization remains poorly understood, in part because of the difficulty to precisely manipulate the physical structure of microbial environments. Using a microfluidic device to grow bacteria in crypt-like incubation chambers of systematically varied lengths, we show that small variations in the physical structure of the microhabitat can drastically alter bacterial colonization success and resistance against invaders. Small crypts are uncolonizable; intermediately sized crypts can stably support dilute populations, while beyond a second critical length scale, populations phase separate into a dilute region and a jammed region. The jammed state is characterized by extreme colonization resistance, even if the resident strain is suppressed by an antibiotic. Combined with a flexible biophysical model, we demonstrate that colonization resistance and associated priority effects can be explained by a crowding-induced phase transition, which results from a competition between proliferation and density-dependent cell leakage. The emerging sensitivity to scale underscores the need to control for scale in microbial ecology experiments. Systematic flow-adjustable length-scale variations may serve as a promising strategy to elucidate further scale-sensitive tipping points and to rationally modulate the stability and resilience of microbial colonizers.

ObjectiveSporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.MethodsThe authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.ResultsThe authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.ConclusionsThe authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

Unambiguous identification of the superconducting order parameter symmetry in [Formula: see text] has remained elusive for more than a quarter century. While a chiral p-wave ground state analogue to superfluid 3He-A was ruled out only very recently, other proposed triplet-pairing scenarios are still viable. Establishing the condensate magnetic susceptibility reveals a sharp distinction between even-parity (singlet) and odd-parity (triplet) pairing since the superconducting condensate is magnetically polarizable only in the latter case. Here field-dependent 17O Knight shift measurements, being sensitive to the spin polarization, are compared to previously reported specific heat measurements for the purpose of distinguishing the condensate contribution from that due to quasiparticles. We conclude that the shift results can be accounted for entirely by the expected field-induced quasiparticle response. An upper bound for the condensate magnetic response of <10% of the normal state susceptibility is sufficient to exclude all purely odd-parity candidates.

BackgroundThere are currently no recommendations guiding when best to perform coronary artery calcium (CAC) scanning among young adults to identify those susceptible for developing premature atherosclerosis.ObjectivesThe purpose of this study was to determine the ideal age at which a first CAC scan has the highest utility according to atherosclerotic cardiovascular disease (ASCVD) risk factor profile.MethodsWe included 22,346 CAC Consortium participants aged 30-50 years who underwent noncontrast computed tomography. Sex-specific equations were derived from multivariable logistic modeling to estimate the expected probability of CAC >0 according to age and the presence of ASCVD risk factors.ResultsParticipants were on average 43.5 years of age, 25% were women, and 34% had CAC >0, in whom the median CAC score was 20. Compared with individuals without risk factors, those with diabetes developed CAC 6.4 years earlier on average, whereas smoking, hypertension, dyslipidemia, and a family history of coronary heart disease were individually associated with developing CAC 3.3-4.3 years earlier. Using a testing yield of 25% for detecting CAC >0, the optimal age for a potential first scan would be at 36.8 years (95% CI: 35.5-38.4 years) in men and 50.3 years (95% CI: 48.7-52.1 years) in women with diabetes, and 42.3 years (95% CI: 41.0-43.9 years) in men and 57.6 years (95% CI: 56.0-59.5 years) in women without risk factors.ConclusionsOur derived risk equations among health-seeking young adults enriched in ASCVD risk factors inform the expected prevalence of CAC >0 and can be used to determine an appropriate age to initiate clinical CAC testing to identify individuals most susceptible for early/premature atherosclerosis.

Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

Organic-inorganic layered perovskites, or Ruddlesden-Popper perovskites, are two-dimensional quantum wells with layers of lead-halide octahedra stacked between organic ligand barriers. The combination of their dielectric confinement and ionic sublattice results in excitonic excitations with substantial binding energies that are strongly coupled to the surrounding soft, polar lattice. However, the ligand environment in layered perovskites can significantly alter their optical properties due to the complex dynamic disorder of the soft perovskite lattice. Here, we infer dynamic disorder through phonon dephasing lifetimes initiated by resonant impulsive stimulated Raman photoexcitation followed by transient absorption probing for a variety of ligand substitutions. We demonstrate that vibrational relaxation in layered perovskite formed from flexible alkyl-amines as organic barriers is fast and relatively independent of the lattice temperature. Relaxation in layered perovskites spaced by aromatic amines is slower, although still fast relative to bulk inorganic lead bromide lattices, with a rate that is temperature dependent. Using molecular dynamics simulations, we explain the fast rates of relaxation by quantifying the large anharmonic coupling of the optical modes with the ligand layers and rationalize the temperature independence due to their amorphous packing. This work provides a molecular and time-domain depiction of the relaxation of nascent optical excitations and opens opportunities to understand how they couple to the complex layered perovskite lattice, elucidating design principles for optoelectronic devices.

Development has often been viewed as a constraining force on morphological adaptation, but its precise influence, especially on evolutionary rates, is poorly understood. Placental mammals provide a classic example of adaptive radiation, but the debate around rate and drivers of early placental evolution remains contentious. A hallmark of early dental evolution in many placental lineages was a transition from a triangular upper molar to a more complex upper molar with a rectangular cusp pattern better specialized for crushing. To examine how development influenced this transition, we simulated dental evolution on "landscapes" built from different parameters of a computational model of tooth morphogenesis. Among the parameters examined, we find that increases in the number of enamel knots, the developmental precursors of the tooth cusps, were primarily influenced by increased self-regulation of the molecular activator (activation), whereas the pattern of knots resulted from changes in both activation and biases in tooth bud growth. In simulations, increased activation facilitated accelerated evolutionary increases in knot number, creating a lateral knot arrangement that evolved at least ten times on placental upper molars. Relatively small increases in activation, superimposed on an ancestral tritubercular molar growth pattern, could recreate key changes leading to a rectangular upper molar cusp pattern. Tinkering with tooth bud geometry varied the way cusps initiated along the posterolingual molar margin, suggesting that small spatial variations in ancestral molar growth may have influenced how placental lineages acquired a hypocone cusp. We suggest that development could have enabled relatively fast higher-level divergence of the placental molar dentition.

CRISPR-based targeted modification of epigenetic marks such as DNA cytosine methylation is an important strategy to regulate the expression of genes and their associated phenotypes. Although plants have DNA methylation in all sequence contexts (CG, CHG, CHH, where H = A, T, C), methylation in the symmetric CG context is particularly important for gene silencing and is very efficiently maintained through mitotic and meiotic cell divisions. Tools that can directly add CG methylation to specific loci are therefore highly desirable but are currently lacking in plants. Here we have developed two CRISPR-based CG-specific targeted DNA methylation systems for plants using a variant of the bacterial CG-specific DNA methyltransferase MQ1 with reduced activity but high specificity. We demonstrate that the methylation added by MQ1 is highly target specific and can be heritably maintained in the absence of the effector. These tools should be valuable both in crop engineering and in plant genetic research.

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/ report/retroviridae.

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/ report/retroviridae.

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/ report/retroviridae.

We study projective schemes arising from eigenvectors of tensors, called eigenschemes. After some general results, we give a birational description of the variety parametrizing eigenschemes of general ternary symmetric tensors, and we compute its dimension. Moreover, we characterize the locus of triples of homogeneous polynomials defining the eigenscheme of a ternary symmetric tensor. Our results allow us to implement algorithms to check whether a given set of points is the eigenscheme of a symmetric tensor and to reconstruct the tensor. Finally, we give a geometric characterization of all reduced zero-dimensional eigenschemes. The techniques we use rely on both classical and modern complex projective algebraic geometry., QC 20220119

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/ report/retroviridae.

This study analyzed kinorhynch communities from the southern portion of Mobile Bay and the near shore Alabama continental shelf. A multicorer was used to collect sediment samples from fourteen sites, specifically targeting the flow of freshwater efflux from the Mobile watershed. These sediment samples were analyzed for kinorhynch species, organic matter content, granulometry and trace metals. Kinorhynch specimens were examined via light microscopy and scanning electron microscopy and identified to species level for community analysis. Eleven species of kinorhynchs were recovered from thirteen sites. Four dominant species, Echinoderes augustae, E. bookhouti, E. spinifurca, and Leiocanthus langi were present, in agreement with an earlier survey of Alabama coastal kinorhynchs. Spearman correlations, PCA, and cluster analyses of kinorhynch communities, along with abiotic data, revealed a patchy distribution of kinorhynchs, organic matter and fine sediments in the path of freshwater efflux. Additionally, this study reports four new species records for the northern Gulf of Mexico.

Viruses in the family Retroviridae are found in a wide variety of vertebrate hosts. Enveloped virions are 80-100 nm in diameter with an inner core containing the viral genome and replicative enzymes. Core morphology is often characteristic for viruses within the same genus. Replication involves reverse transcription and integration into host cell DNA, resulting in a provirus. Integration into germline cells can result in a heritable provirus known as an endogenous retrovirus. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Retroviridae, which is available at ictv.global/ report/retroviridae.

Background & aims: Healthy diet has been associated with decreased mortality, but its impact on survival without disability is less clear. We aimed to investigate the association between the Nordic Prudent Diet Pattern (NPDP) and dementia-and disability-free survival, and to assess its interaction with other healthy lifestyle behaviors. Methods: Within the Swedish National Study on Aging and Care-Kungsholmen, 2290 dementia-and disability-free adults aged >60 were followed up to 12 years to detect survival free from dementia (standard criteria) and disability (Katz's Activities of Daily Living). NPDP index was assessed at baseline with a 98-item food frequency questionnaire (characterized mainly by more frequent intakes of vegetable, fruit, cooking, cereals, whole grains, fish, and water) and was further categorized into tertiles (low, moderate, or high). Information on lifestyle factors was collected via baseline questionnaire. A favorable (vs unfavorable) lifestyle profile was determined based on smoking status, social network and physical activity. Data were analyzed using Cox proportional hazard regression models and Laplace regression. Results: During the follow-up, 1074 participants survived without dementia and disability (614 died, 518 became disabled, and 84 developed dementia). Compared to low NPDP adherence, the hazard ratio (HR) of high NPDP adherence was 1.19 (95% CI 1.04-1.34) for dementia-and disability-free survival. High NPDP adherence prolonged lifespan without mental and physical disability by an average of 1.24 years (95% CI 0.11-2.37). Further, among participants with high NPDP adherence, a favorable lifestyle profile was associated with an even higher HR (1.96, 95% CI 1.52-2.42) of dementia-and disability-free survival, corresponding to an average of 3.80 (95% CI 2.25-5.35) years longer life compared to those with low NPDP adherence and an unfavorable lifestyle profile. Conclusion: High adherence to NPDP prolongs survival with good mental

CRISPR-based targeted modification of epigenetic marks such as DNA cytosine methylation is an important strategy to regulate the expression of genes and their associated phenotypes. Although plants have DNA methylation in all sequence contexts (CG, CHG, CHH, where H = A, T, C), methylation in the symmetric CG context is particularly important for gene silencing and is very efficiently maintained through mitotic and meiotic cell divisions. Tools that can directly add CG methylation to specific loci are therefore highly desirable but are currently lacking in plants. Here we have developed two CRISPR-based CG-specific targeted DNA methylation systems for plants using a variant of the bacterial CG-specific DNA methyltransferase MQ1 with reduced activity but high specificity. We demonstrate that the methylation added by MQ1 is highly target specific and can be heritably maintained in the absence of the effector. These tools should be valuable both in crop engineering and in plant genetic research.

Development has often been viewed as a constraining force on morphological adaptation, but its precise influence, especially on evolutionary rates, is poorly understood. Placental mammals provide a classic example of adaptive radiation, but the debate around rate and drivers of early placental evolution remains contentious. A hallmark of early dental evolution in many placental lineages was a transition from a triangular upper molar to a more complex upper molar with a rectangular cusp pattern better specialized for crushing. To examine how development influenced this transition, we simulated dental evolution on "landscapes" built from different parameters of a computational model of tooth morphogenesis. Among the parameters examined, we find that increases in the number of enamel knots, the developmental precursors of the tooth cusps, were primarily influenced by increased self-regulation of the molecular activator (activation), whereas the pattern of knots resulted from changes in both activation and biases in tooth bud growth. In simulations, increased activation facilitated accelerated evolutionary increases in knot number, creating a lateral knot arrangement that evolved at least ten times on placental upper molars. Relatively small increases in activation, superimposed on an ancestral tritubercular molar growth pattern, could recreate key changes leading to a rectangular upper molar cusp pattern. Tinkering with tooth bud geometry varied the way cusps initiated along the posterolingual molar margin, suggesting that small spatial variations in ancestral molar growth may have influenced how placental lineages acquired a hypocone cusp. We suggest that development could have enabled relatively fast higher-level divergence of the placental molar dentition.

Organic-inorganic layered perovskites, or Ruddlesden-Popper perovskites, are two-dimensional quantum wells with layers of lead-halide octahedra stacked between organic ligand barriers. The combination of their dielectric confinement and ionic sublattice results in excitonic excitations with substantial binding energies that are strongly coupled to the surrounding soft, polar lattice. However, the ligand environment in layered perovskites can significantly alter their optical properties due to the complex dynamic disorder of the soft perovskite lattice. Here, we infer dynamic disorder through phonon dephasing lifetimes initiated by resonant impulsive stimulated Raman photoexcitation followed by transient absorption probing for a variety of ligand substitutions. We demonstrate that vibrational relaxation in layered perovskite formed from flexible alkyl-amines as organic barriers is fast and relatively independent of the lattice temperature. Relaxation in layered perovskites spaced by aromatic amines is slower, although still fast relative to bulk inorganic lead bromide lattices, with a rate that is temperature dependent. Using molecular dynamics simulations, we explain the fast rates of relaxation by quantifying the large anharmonic coupling of the optical modes with the ligand layers and rationalize the temperature independence due to their amorphous packing. This work provides a molecular and time-domain depiction of the relaxation of nascent optical excitations and opens opportunities to understand how they couple to the complex layered perovskite lattice, elucidating design principles for optoelectronic devices.

Acquisition and analysis of time-tagged events is a ubiquitous tool in scientific and industrial applications. With increasing time resolution, number of input channels, and acquired events, the amount of data can be overwhelming for standard processing techniques. We developed the Extensible Time-tag Analyzer (ETA), a powerful and versatile, yet easy to use software to efficiently analyze and display time-tagged data. Our tool allows for flexible extraction of correlation from time-tagged data beyond start-stop measurements that were traditionally used. A combination of state diagrams and simple code snippets allows for analysis of arbitrary complexity while keeping computational efficiency high., QC 20211015

Limiting gaseous nitrogen oxide (NOx) emissions is a major global concern due to their harmful effect on human health and the environment. During the past decade, low-temperature oxidation by ozone (O3) has emerged as a promising solution for NOx removal in the transportation and energy generation sectors. In the present study, three-dimensional (3D) large eddy simulations (LES) of the turbulent reacting flow inside a NOx-O3 reactor are performed. It is the first publication using LES and detailed finite rate chemistry for such a reactor. Additionally, plug-flow reactor (PFR) simulations are employed to identify the best performing chemical kinetic mechanisms among those available in the literature over the range of conditions studied. Furthermore, results from different experimental works are reviewed to analyze the variability in the literature. Additionally, this will aid in devising a strategy for validation. Time-averaged results obtained from PFR and combined LES-PFR simulations are observed to agree well with experimental results. The species correlation, distribution, and overall flow uniformity in the pure LES simulations are also assessed and the results highlight the benefits of a high mixing efficiency reactor geometry. Moreover, relevant features of the unsteady flow throughout the present reactor are studied. In particular, the analysis of coherent structures and the existence of regions with non-reacted gases and their relation to mixing and NOx oxidation efficiency are evaluated. The present simulations enable a novel understanding of the interplay between mixing and chemistry and highlight, for the first time, details of the oxidation of NOx by O3., QC 20210917

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis associated with asthma, anti-neutrophil cytoplasmic antibodies (ANCA) positivity, and tissue eosinophilia. Objective: To describe the presenting clinical features, significant biochemical alterations, and also potential pathogenic factors in adult patients diagnosed in our Center over a period of >20 years. Method: A retrospective study of EGPA patients diagnosed from 1994 to 2019 at ASST Grande Ospedale Metropolitano Niguarda Ca' Granda, Milan (Italy), which was performed according to the 1990 American College of Rheumatology criteria and Chapel Hill Consensus Conference definition. A dataset was compiled, registering demographic and clinical features, biochemical analysis at onset, and also the therapies received 3 months prior to EGPA diagnose. Statistical analyses were subsequently conducted dividing patients in 2 groups based on ANCA positivity and comparing them. Results: Two groups were clearly identified by ANCA serology and specific organ involvement in accordance with literature reports; however, our data underline for the first time the association between anti-leukotriene receptor antagonists (LTRAs) and ANCA positivity. The group of previously treated patients presents an OR of 6.42 to be ANCA positive. This finding could be attributed to an imbalanced stimulation of leukotriene receptors, inducing both mast cells activation and an increased neutrophil extracellular traps release from neutrophils. Conclusion: Despite the limitations of this retrospective study, the association between LTRAs and ANCA antibodies elucidates the mechanism by which innate immunity is directly involved in tolerance breakdown and autoantibodies production. Validation of our results with targeted studies could clarify the differences between ANCA-positive and ANCA-negative patients with important consequences on the use of some drug classes in the treatment of EGPA and asthmatic subjects.

Mixed vaginitis is defined as the simultaneous presence of at least two different vaginal pathogens, both contributing to an abnormal vaginal milieu leading to signs and symptoms. Pathogen coinfection occurs frequently in women with vaginitis, and both coinfection and mixed vaginitis have relevant clinical and therapeutic implications. Fenticonazole, an imidazole derivative with a broad spectrum of antimycotic and antimicrobial activity, appears at least as effective as other topical antifungals in the treatment of vulvovaginal candidiasis and can also have a major role in the treatment of mixed infections or coinfections of the lower genital tract. This paper will address the current role of topical fenticonazole as an empiric treatment of vulvovaginal infections, with a focus on the effectiveness in the treatment of mixed vaginitis and the possible implications of this.