Citations

Abstract Studying cardiovascular senescence is crucial for understanding disease-related changes in the cardiovascular system and their impact on health and disease. To systematically investigate the heterogeneity of senescent vascular cells in atherosclerosis, we employed the senescence reporter mouse p16tdTomato+/-, overexpressed PCSK9 and fed a high-fat diet (HFD) to induce atherosclerosis, and treated them with the senolytic drug ABT-737. Whole-aorta, single-cell RNA-sequencing (scRNA-seq) and Gene Set Enrichment Analysis (GSEA) using the SenMayo panel uncovered 10 cell clusters displaying senescent features, although not ‘classical’ senescence markers, that were reduced by treatment with ABT-737. Unbiased subclustering revealed subsets of cells increasing by HFD and reduced by ABT-737 treatment that expressed unique transcripts Spp1, Ctsb, and Tnfrsf11b mRNAs. Spatial analysis of these RNAs identified senescent cells in the cap and core of brachiocephalic arteries from atherosclerotic mice. Our results uncover a vascular-specific transcriptomic signature that may be exploited for therapeutic targeting in age-related vascular diseases.

Background Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far. Methods As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals. Results The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families. Conclusion The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.

(1) Background: Acute kidney injury (AKI) kidneys have high non-utilization rates due to concerns regarding unfavorable outcomes. In this paper, we aimed to review the past, present, and future opinions on AKI kidneys. (2) Methods: A PubMed search was conducted for topics relevant to AKI kidney transplantation. (3) Results: Current short- and long-term data on AKI kidneys have demonstrated good outcomes including favorable graft function and survival. The role of procurement biopsies is controversial, but they have been shown to be beneficial in AKI kidneys by allowing clinicians to differentiate between reversible tubular injury and irreversible cortical necrosis. Machine perfusion has also been applied to AKI kidneys and has been shown to reduce delayed graft function (DGF). The incidence of DGF increases with AKI severity and its management can be challenging. Strategies employed to counteract this have included early initiation of dialysis after kidney transplantation, early targeting of adequate immunosuppression levels to minimize rejection risk, and establishment of outpatient dialysis. (4) Conclusions: Despite good outcomes, there continue to be barriers that impact AKI kidney utilization. Successful strategies have included use of procurement biopsies or machine perfusion and expectant management of DGF. With increasing experience, better use of AKI kidneys can result in additional opportunities to expand the donor pool.

Background: The identification of cancer driver genes and key molecular pathways has been the focus of large-scale cancer genome studies. Network-based methods detect significantly perturbed subnetworks as putative cancer pathways by incorporating genomics data with the topological information of PPI networks. However, commonly used PPI networks have distinct topological structures, making the results of the same method vary widely when applied to different networks. Furthermore, emerging context-specific PPI networks often have incomplete topological structures, which pose serious challenges for existing subnetwork detection algorithms. Methods: In this paper, we propose a novel method, referred to as MultiFDRnet, to address the above issues. The basic idea is to model a set of PPI networks as a multiplex network to preserve the topological structure of individual networks, while introducing dependencies among them, and, then, to detect significantly perturbed subnetworks on the modeled multiplex network using all the structural information simultaneously. Results: To illustrate the effectiveness of the proposed approach, an extensive benchmark analysis was conducted on both simulated and real cancer data. The experimental results showed that the proposed method is able to detect significantly perturbed subnetworks jointly supported by multiple PPI networks and to identify novel modular structures in context-specific PPI networks.

Pencil beam scanning delivered with continuous scanning has several advantages over conventional discrete spot scanning. Such advantages include improved beam delivery efficiency and reduced beam delivery time. However, a move dose is delivered between consecutive spots with continuous scanning, and current treatment planning systems do not take this into account. Therefore, continuous scanning and discrete spot plans have an inherent dose discrepancy. Using the operating parameters of the state-of-the-art particle therapy system, we conducted a proof-of-concept study in which we systematically generated 28 plans for cubic targets with different combinations of plan parameters and simulated the dose discrepancies between continuous scanning and a planned one. A nomograph to guide the selection of plan parameters was developed to reduce the dose discrepancy. The effectiveness of the nomograph was evaluated with two clinical cases (one prostate and one liver). Plans with parameters guided by the nomograph decreased dose discrepancy than those used standard plan parameters. Specifically, the 2%/2 mm gamma passing rate increased from 96.3% to 100% for the prostate case and from 97.8% to 99.7% for the liver case. The CTV DVH root mean square error decreased from 2.2% to 0.2% for the prostate case and from 1.8% to 0.9% for the liver case. The decreased dose discrepancy may allow the relaxing of the delivery constraint for some cases, leading to greater benefits in continuous scanning. Further investigation is warranted.

The purpose of this study was to compare external workloads between collegiate men’s (MLAX) and women’s lacrosse (WLAX) matches and examine positional differences across the season. Athletes (MLAX: n = 10; WLAX: n = 13) wore a global positional system device during all matches. External load metrics included in the analysis were total distance (TD), sprint distance (SD), accelerations (>3 m/s2), sprint efforts, player load per minute (PL/min), top speed, and distances spent in various speed zones. WLAX had higher TD (p = 0.001), SD (p < 0.001), distances in SZs 2–5 (p < 0.001), PL (p < 0.001), and sprint efforts (p < 0.001) compared to MLAX. However, MLAX performed more acceleration (p < 0.001) and deceleration (p < 0.001) efforts. WLAX midfielders (M) and defenders (D) reached higher top speeds and performed more accelerations than attackers (p < 0.001). Midfielders covered the greatest distance at high speeds (p = 0.011) and the smallest distance at low speeds (<0.001) for WLAX. For MLAX, midfielders performed the highest SDs, top speeds, accelerations, decelerations, and distances in higher speed zones (p < 0.001) compared to attackers and defenders. Results indicate that there are significant gender and positional differences in external workload demands during match play, specifically for volume- and intensity-derived workload parameters, between men’s and women’s lacrosse. Therefore, sports performance coaches should create gender- and position-specific conditioning programs to prepare athletes for match demands.

Background The impact of changes in Doppler‐derived kidney venous flow in heart failure (HF) is not well studied. We aimed to investigate the association of Doppler‐derived kidney venous stasis index (KVSI) and intrakidney venous‐flow (IKVF) patterns with adverse cardiorenal outcomes in patients with HF. Methods and Results In this observational cohort study, consecutive inpatients with HF referred to a nephrologist because of a history of diuretic resistance and abnormal kidney function (n=216) underwent spectral kidney assessments after admission (Doppler 1) and 25 to 35 days later (Doppler 2) to identify IKVF patterns (continuous/pulsatile/biphasic/monophasic) and KVSI levels. Cox proportional hazard regression models were used to evaluate the associations between KVSI/IKVF patterns at Doppler 1 as well as changes from Doppler 1 to Doppler 2 and risk of cardiorenal events up to 18 months after admission. Worsening HF or death occurred in 126 patients. Both baseline KVSI (hazard ratio [HR], 1.49 [95% CI, 1.37–1.61] per 0.1‐unit increase) and baseline IKVF pattern (HR, 2.47 [95% CI, 2.01–3.04] per 1 pattern severity increase) were significantly associated with worsening HF/death. Increases in both KVSI and IKVF pattern severity from Doppler 1 to 2 were also associated with an increased risk of worsening HF/death (HR, 3.00 [95% CI, 2.08–4.32] per 0.1‐unit increase change; and HR, 6.73 [95% CI, 3.27–13.86] per 1 pattern increase in severity change, respectively). Similar results were observed for kidney outcomes. Conclusions Baseline kidney venous flow predicted adverse cardiorenal events, and inclusion of serial kidney venous flow in cardiorenal risk stratification could facilitate clinical decision‐making for patients with HF. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03039959.

To date, biventricular pacing (BiVP) has been the standard pacing modality for cardiac resynchronisation therapy. However, it is non-physiological, with the activation spreading between the left ventricular epicardium and right ventricular endocardium. Up to one-third of patients with heart failure who are eligible for cardiac resynchronisation therapy do not derive benefit from BiVP. Conduction system pacing (CSP), which includes His bundle pacing and left bundle branch area pacing, has emerged as an alternative to BiVP for cardiac resynchronisation. There is mounting evidence supporting the benefits of CSP in achieving synchronous ventricular activation and repolarisation. The aim of this review is to summarise the current options and outcomes of CSP when used for cardiac resynchronisation in patients with heart failure.

In response to the social inequities that exist in health care, the NIH-funded Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee to examine systemic racism and implicit bias in the care and research of eosinophilic gastrointestinal diseases (EGIDs). Herein, we describe our process, highlighting milestones and issues addressed since the committee’s inception, which we hope will inspire other researchers to enhance diversity, equity, inclusion, and accessibility (DEIA) in their fields. Our journey began by establishing mission and vision statements to define the purpose of the committee. Regular discussion of diversity-related topics was incorporated into existing meetings and web-based materials were shared. This was followed by educational initiatives, including establishing a library of relevant publications and a speaker series to address DEIA topics. We then established a research agenda focused on the following actionable items: (1) to define what is known about the demographics of EGIDs by systematic review of population-based studies; (2) to develop a practical tool for reporting participant demographics to reduce bias in EGID literature; (3) to examine health disparities in the care of individuals with eosinophilic esophagitis who present to the emergency department with an esophageal food impaction; (4) to examine how access to a gastroenterologist affects the conclusions of published research examining the prevalence of pediatric eosinophilic esophagitis; and (5) to develop a model for examining the dimensions of diversity, and provide a framework for CEGIR’s ongoing projects and data capture. In addition to promoting consciousness of DEIA, this initiative has fostered inclusivity among CEGIR members and will continue to inspire positive changes in EGID care and research.