Natural channel design (NCD) and analytical channel design (ACD) are two competing approaches to stable channel design that share fundamental similarities in accounting for sediment transport ...processes with designs based on hybrid fluvial geomorphology and hydraulic engineering methods. In this paper, we highlight the linkage between ACD's capacity/supply ratio (CSR) and NCD's sediment capacity models (FLOWSED/POWERSED), illustrating how ACD and NCD have reached a point of convergent evolution within the stream restoration toolbox. We modified an existing CSR analytical spreadsheet tool which enabled us to predict relative channel stability using both conventional bed load transport equations and regional sediment regression curves. The stable channel design solutions based on measured data most closely matched the Parker (ACD) and/or Pagosa good/fair (NCD) relationships, which also showed the greatest CSR sensitivity in response to channel alterations. We found that CSR differences among the transport relationships became more extreme the further the design width deviated from the supply reach, suggesting that a stable upstream supply reach may serve as the best design analog. With this paper, we take a step toward resolving lingering controversy in the field of stream restoration, advancing the science and practice by reconciling key differences between ACD and NCD in the context of reach scale morphodynamics.
Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine ...whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer's disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a ...Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Purpose
To perform a systematic review and meta-analysis to quantify the technical success rate of adrenal venous sampling (AVS) with and without intraprocedural computed tomography (CT).
Methods
A ...systematic search of the Medline, Scopus, EMBASE, and Web of Science databases for comparative studies using intraprocedural CT was undertaken. More than 1,000 records were screened using titles and abstracts. Full texts of 121 studies were reviewed and 14 eligible studies were identified. Nine studies had adequate comparative data and were included in the meta-analysis.
Results
A research synthesis was performed and data from 809 patients were pooled in multiple random effect models. Overall success rate of AVS without and with intraprocedural CT was 72.7% (59.3–83.0%) and 92.5% (86.6–95.9), respectively. The addition of intraprocedural CT increased the technical success rate by 19.8% (
P
< 0.001), with an odds ratio (OR) of 5.5 (3.3–9.2;
P
< 0.01). In meta-regression, odds of success with intraprocedural CT was associated with younger age (beta: 0.16 ± 0.05;
P
:0.001), higher body mass index (BMI; beta:0.08 ± 0.03;
P
:0.002), and higher selectivity index (defined as the ratio of cortisol in the adrenal vein to that in the inferior vena cava; beta:0.35 ± 0.08,
P
< 0.001). We found a linear inverse association between operator’s success without CT and improved success with intraprocedural CT (
R
2
: 0.86).
Conclusions
Intraprocedural CT is not required for every case, but can be performed in difficult cases or when operators' success is limited. The benefit was more pronounced in younger patients with higher BMI, female gender, and with higher selectivity.
Level of evidence
III Systematic review and meta-analysis of non-randomized clinical trials.
To estimate the prevalence of and identify characteristics associated with the presence of aneurysms in a cohort of patients with hereditary hemorrhagic telangiectasia (HHT).
In the study ...institution's HHT database, 418 patients with a definite HHT diagnosis were identified based on the clinical Curaçao criteria and/or an HHT-associated genetic mutation. Regression modeling was used to evaluate the association between arterial aneurysms and older age, male sex, smoking, alcohol consumption, hypertension, hyperlipidemia, genetic mutations, the presence of arteriovenous malformations (AVMs) unrelated to the aneurysms, and HHT-related genetic mutations.
Forty-three (10.3%) patients had at least 1 aneurysm. Sixteen (3.8%) patients had multiple aneurysms. Of the variables analyzed, older age (odds ratio OR = 1.02; 95% confidence interval CI: 1.0-1.1), the presence of anatomically and flow-unrelated AVMs (OR = 3.2; 95% CI: 1.3-8.0), and the presence of activin A receptor type II-like 1 (ACVRL1) mutation (OR = 4.0; 95% CI: 1.5-10) were associated with the presence of at least 1 aneurysm.
In this cohort of patients with HHT, the prevalence of intracranial and visceral arterial aneurysms was estimated to be 10.3%. Older age, the presence of unrelated AVMs, and the presence of the ACVRL1 mutation were associated with the presence of arterial aneurysms. Further study is required to assess the clinical importance and risk of rupture of aneurysms in patients with HHT.
Recurrent croup (RC) is a common problem in the pediatric population. We theorize that reduced rhinorrhea and post-nasal drip as well as suppressed cough receptor activity by the anticholinergic, ...intranasal ipratropium bromide (IB), may lead to reduced inflammation and edema of the subglottis, decreasing RC symptoms. The aim of this study is to determine the effectiveness of IB in improving symptoms of RC and in reducing the need for alternative forms of management.
A retrospective chart review combined with survey data of patients with RC was conducted to assess demographic data, comorbidities, and treatment outcomes. Pediatric patients less than 10 years of age diagnosed with RC through the department of pediatric otolaryngology between 2018 and 2020 were included. Results were compared between one group treated with IB for RC and a second group treated with medications other than IB.
Among the 67 patients treated for RC, 34 completed survey data and were included in the study. Overall, patients who were treated with IB for RC had 1.83 less croup episodes per year (p = 0.046), a 0.5-point improvement in child symptoms (p = 0.017) and 1.3 fewer doses of steroids per year than the patients not treated with IB (p = 0.018). Patients treated with IB were significantly more likely to answer “yes,” that the use of medication helped improve symptoms (p < 0.01).
Intranasal IB is a novel therapeutic option that may reduce RC events, improve patient symptoms and reduce steroid use. Further prospective studies are needed to definitively characterize the benefits of IB in the treatment of RC.
Uveal coloboma is a potentially blinding congenital ocular malformation caused by failure of the optic fissure to close during development. Although mutations in numerous genes have been described, ...these account for a minority of cases, complicating molecular diagnosis and genetic counseling. Here we describe a key role of aldh7a1 as a gene necessary for normal eye development. We show that morpholino knockdown of aldh7a1 in zebrafish causes uveal coloboma and misregulation of nlz1, another known contributor to the coloboma phenotype, as well as skeletal abnormalities. Knockdown of aldh7a1 leads to reduced cell proliferation in the optic cup of zebrafish, delaying the approximation of the edges of the optic fissure. The aldh7a1 morphant phenotype is partially rescued by co-injection of nlz1 mRNA suggesting that nlz1 is functionally downstream of aldh7a1 in regulating cell proliferation in the optic cup. These results support a role of aldh7a1 in ocular development and skeletal abnormalities in zebrafish.
To evaluate the racial and ethnic representation of transarterial therapy for hepatocellular carcinoma (HCC) clinical trials in the United States.
The ClinicalTrials.gov database was examined to ...identify all completed studies with transarterial therapies for the management of HCC in the United States and extract information about the observed number of participants for each racial and ethnic group (based on the Office of Management and Budget definitions). The expected number of participants was calculated by multiplying the total number of participants in a trial with the U.S.-population HCC-based proportion for each group. The effects of the study phase, funding source, number of centers involved in the study, and the location of the participating center on racial and ethnic distribution were explored.
Seventy-nine relevant studies were identified, of which 27 (34.2%) and 18 (22.8%) reported ethnic and race characteristics, respectively. Most study participants were White (81%, 1,591/1,964) by ethnicity and not Hispanic or Latino (93%, 937/1,008) by race. In terms of the observed-to-expected ratios by race and ethnicity in all trials, White and not Hispanic or Latino participants were overrepresented with a ratio of 1.22 (1.10-1.37) and 1.33 (1.26-1.41), respectively, and all other racial and ethnic groups were underrepresented. The enrollment of African Americans and Asian Americans varied by the study phase, and a higher enrollment of African Americans was noted in the National Institutes of Health-funded and multicenter studies (P < .05).
This cross-sectional study demonstrates that in HCC transarterial therapy clinical trials, racial and ethnic minorities were underrepresented and the majority of the studies identified failed to report this demographic information.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), the most severe pandemic in a century. The virus gains access to host cells ...when the viral spike protein (S-protein) binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2). Studies have attempted to understand SARS-CoV-2 S-protein interactions with vertebrate orthologs of ACE2 by expressing ACE2 orthologs in mammalian cells and measuring viral infection or S-protein binding. Often, these cells only transiently express ACE2 proteins, and the levels of ACE2 at the cell surface are not quantified. Here, we describe a cell-based assay that uses stably transfected cells expressing ACE2 proteins in a bicistronic vector with an easy-to-quantify reporter protein, Thy1.1. We found that both the binding of the S-protein receptor-binding domain (RBD) and infection with a SARS-CoV-2 pseudovirus are proportional to the amount of human ACE2 expressed at the cell surface, which can be inferred by quantifying the level of Thy1.1. We also compared different ACE2 orthologs, which were expressed in stably transfected cells expressing equivalent levels of Thy1.1. When ranked for either viral infectivity or RBD binding, mouse ACE2 had a weak to undetectable affinity for S-protein, while human ACE2 had the highest level detected, and feline ACE2 had an intermediate phenotype. The generation of stably transfected cells whose ACE2 level can be normalized for cross-ortholog comparisons allows us to create a reusable cellular library useful for measuring emerging SARS-CoV-2 variants' abilities to potentially infect different animals.
SARS-CoV-2 is a zoonotic virus responsible for the worst global pandemic in a century. An understanding of how the virus can infect other vertebrate species is important for controlling viral spread and understanding the natural history of the virus. Here, we describe a method to generate cells stably expressing different orthologs of ACE2, the receptor for SARS-CoV-2, on the surface of a human cell line. We find that both the binding of the viral spike protein receptor-binding domain (RBD) and infection of cells with a SARS-CoV-2 pseudovirus are proportional to the ACE2 levels at the cell surface. This method will allow the creation of a library of stably transfected cells expressing similar levels of different vertebrate ACE2 orthologs, which can be used repeatedly for identifying vertebrate species that may be susceptible to infection with SARS-CoV-2 and its many variants.
This study evaluated fundal arteriole angiographic revascularization after embolization with embolic microspheres of 3 different diameters in a swine model (16 swine, 31 arterioles). In the 50-μm ...group, 7 of 11 (64%) arterioles recanalized completely, 3 of 11 (27%) arterioles recanalized partially, and 1 of 11 (9%) arterioles had collateralization (no recanalization). In the 100- to 300-μm group, 7 of 10 (70%) arterioles recanalized completely and 3 of 10 (30%) arterioles) recanalized partially. In the 300- to 500-μm group, 7 of 10 (70%) arterioles recanalized completely, 1 of 10 (10%) arterioles recanalized partially, and 2 of 10 (20%) arterioles had collateralization. No difference was found between the groups in the degree of recanalization (P = .64). All embolized arterioles exhibited some degree of angiographic revascularization, irrespective of the microsphere size.
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