Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion.

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12- hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.

Allelic variation of BBX24 is a dominant determinant controlling red coloration and dwarfism in pear.

Variation in anthocyanin biosynthesis in pear fruit provides genetic germplasm resources for breeding, while dwarfing is an important agronomic trait, which is beneficial to reduce the management costs and allow for the implementation of high-density cultivation. Here, we combined bulked segregant analysis (BSA), quantitative trait loci (QTL), and structural variation (SV) analysis to identify a 14-bp deletion which caused a frame shift mutation and resulted in the premature translation termination of a B-box (BBX) family of zinc transcription factor, PyBBX24, and its allelic variation termed PyBBX24ΔN14. PyBBX24ΔN14 overexpression promotes anthocyanin biosynthesis in pear, strawberry, Arabidopsis, tobacco, and tomato, while that of PyBBX24 did not. PyBBX24ΔN14 directly activates the transcription of PyUFGT and PyMYB10 through interaction with PyHY5. Moreover, stable overexpression of PyBBX24ΔN14 exhibits a dwarfing phenotype in Arabidopsis, tobacco, and tomato plants. PyBBX24ΔN14 can activate the expression of PyGA2ox8 via directly binding to its promoter, thereby deactivating bioactive GAs and reducing the plant height. However, the nuclear localization signal (NLS) and Valine-Proline (VP) motifs in the C-terminus of PyBBX24 reverse these effects. Interestingly, mutations leading to premature termination of PyBBX24 were also identified in red sports of un-related European pear varieties. We conclude that mutations in PyBBX24 gene link both an increase in pigmentation and a decrease in plant height.

Vaccinium as a comparative system for understanding of complex flavonoid accumulation profiles and regulation in fruit.

The genus Vaccinium L. (Ericaceae) contains premium berryfruit crops, including blueberry, cranberry, bilberry, and lingonberry. Consumption of Vaccinium berries is strongly associated with various potential health benefits, many of which are attributed to the relatively high concentrations of flavonoids, including the anthocyanins that provide the attractive red and blue berry colors. Because these phytochemicals are increasingly appealing to consumers, they have become a crop breeding target. There has been substantial recent progress in Vaccinium genomics and genetics together with new functional data on the transcriptional regulation of flavonoids. This is helping to unravel the developmental control of flavonoids and identify genetic regions and genes that can be selected for to further improve Vaccinium crops and advance our understanding of flavonoid regulation and biosynthesis across a broader range of fruit crops. In this update we consider the recent progress in understanding flavonoid regulation in fruit crops, using Vaccinium as an example and highlighting the significant gains in both genomic tools and functional analysis.

Nitrophenol Reduction with Silver Oxide Nanostructures as a Sustainable Approach to Environmental Remediation.

We propose silver oxide as a cost-effective and sustainable alternative to noble metals for the catalytic reduction of nitroaromatics. In the present investigation, we adopt a facile and green synthetic route for the synthesis of silver oxide nanostructures. The prepared nanostructures were found to crystallize in the cuprite phase and exhibit absorbance across the entire visible range of the electromagnetic spectrum. The catalytic potential of the silver oxide was evaluated by following the kinetics of nitrophenol reduction under ambient conditions and is observed to follow pseudo-first order kinetics with the apparent rate constant k a p p = 4 . 24 × 10 - 3 ${{k}_{app}=4.24\ \times {10}^{-3}}$ s-1 at minimum concentration of the catalyst. We attribute the observed catalytic activity to the freshly generated catalytic surface featuring a partially reduced form of silver oxide during reaction. The findings highlight the efficacy of silver oxide in mitigating the environmental pollution originating from the recalcitrant nitroarenes.

The effect of a single closed-circuit rebreather decompression dive in extremely cold water to cardiac function.

PURPOSE: Dive-induced cardiac and hemodynamic changes are caused by various mechanisms, and they are aggravated by cold water. Therefore, aging divers with pre-existing cardiovascular conditions may be at risk of acute myocardial infarction, heart failure, or arrhythmias while diving. The aim of this study was to assess the effect of a single decompression CCR dive in arctic cold water on cardiac function in Finnish technical divers. METHODS: Thirty-nine divers performed one identical 45 mfw CCR dive in 2-4 °C water. Hydration and cardiac functions were assessed before and after the dive. Detection of venous gas embolization was performed within 120 min after the dive. RESULTS: The divers were affected by both cold-water-induced hemodynamic changes and immersion-related fluid loss. Both systolic and diastolic functions were impaired after the dive although the changes in cardiac functions were subtle. Venous inert gas bubbles were detected in all divers except for one. Venous gas embolism did not affect systolic or diastolic function. CONCLUSION: A single trimix CCR dive in arctic cold water seemed to debilitate both systolic and diastolic function. Although the changes were subtle, they appeared parallel over several parameters. This indicates a real post-dive deterioration in cardiac function instead of only volume-dependent changes. These changes are without a clinical significance in healthy divers. However, in a population with pre-existing or underlying heart problems, such changes may provoke symptomatic problems during or after the dive.

Antimicrobial resistance of Escherichia coli from dairy farms participating in an antimicrobial stewardship educational program for farm employees.

Antimicrobial use in food-producing animals is under increasing scrutiny due to the potential effect on the selection of antimicrobial-resistant bacteria that may be transmitted to humans by direct contact, with the food chain, or the environment. Novel data monitoring commensal Escherichia coli from dairy farms is essential for understanding antimicrobial resistance (AMR) patterns and their association with herd health management practices. The objectives of this study were to: (1) compare the prevalence of antimicrobial resistance in the E. coli isolates from the hospital, fresh, and mid-lactation pens from 18 conventional dairy farms participating in an educational training program in antimicrobial stewardship practices in California and Ohio, and (2) to characterize the prevalence of antimicrobial resistance of commensal E. coli isolated from pooled fecal pat samples before and 3 mo after participating in the educational training program. Pooled fecal pat samples were collected from the hospital pen, the fresh pen (1 to 5 DIM), and the mid-lactation pens (90 to 150 DIM) on conventional dairies in CA (n = 9) and OH (n = 9). Fecal samples were collected as part of a larger study using a quasi-experimental design that assigned farms to the training intervention group (TG; 6 per state) or the control group (CG; 3 per state). For the TG, farm worker(s) identified as having the task of diagnosis and treatment of adult cows on the farm participated in a training program on antimicrobial stewardship practices. Pooled fecal samples (n = 7) were collected at enrollment and 3 mo after completing the intervention on each of the participating farms (n = 18), followed by culture for E. coli isolation and antimicrobial sensitivity testing using the broth microdilution methodology. Logistic regression models were used to evaluate the association between E. coli antimicrobial resistance patterns with the training intervention and farm-level factors. No effect was observed in the prevalence of resistant isolates between the control and intervention farms after the training was delivered. Isolates from the hospital pens were 2.48 (95% CI: 1.06-6.22, P = 0.03) and 5.61 (95% CI: 1.94-16.91, P < 0.001) times, more likely to be resistant to streptomycin and chloramphenicol, respectively, than isolates from the mid-lactation pens. Our findings indicate there was a higher prevalence of AMR in E. coli associated with the hospital pen within the farm, while the training program for 3 mo did not affect the prevalence of AMR in E. coli on the farms participating in the program. Further research efforts should be conducted to identify factors driving AMR at the pen level, as well as approaches that could be used to reduce the risk of disseminating AMR from sick pens to animals being housed and to other pens on the farm.

Computing leaky Lamb waves for waveguides between elastic half-spaces using spectral collocation.

In non-destructive evaluation guided wave inspections, the elastic structure to be inspected is often embedded within other elastic media and the ensuing leaky waves are complex and non-trivial to compute; we consider the canonical example of an elastic waveguide surrounded by other elastic materials that demonstrates the fundamental issues with calculating the leaky waves in such systems. Due to the complex wavenumber solutions required to represent them, leaky waves pose significant challenges to existing numerical methods, with methods that spatially discretise the field to retrieve them suffering from the exponential growth of their amplitude far into the surrounding media. We present a spectral collocation method yielding an accurate and efficient identification of these modes, leaking into elastic half-spaces. We discretise the elastic domains and, depending on the exterior bulk wavespeeds, select appropriate mappings of the discretised domain to complex paths, in which the numerical solution decays and the physics of the problem are preserved. By iterating through all possible radiation cases, the full set of dispersion and attenuation curves are successfully retrieved and validated, where possible, against the commercially available software disperse. As an independent validation, dispersion curves are obtained from finite element simulations of time-dependent waves using Fourier analysis.

Person-specific differences in ubiquitin-proteasome mediated proteostasis in human neurons.

BACKGROUND: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)-derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation-prone proteins such as tau. HIGHLIGHTS: Polygenic risk score for AD is associated with the ubiquitin-proteasome system (UPS) in neurons. Basal proteasome activity correlates with aggregation-prone protein levels in neurons. Genetic variation affects the response to proteasome inhibition in neurons. Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis. Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge.

The Response of Growth and Transcriptome Profiles of Tea Grey Blight Disease Pathogen Pestalotiopsis theae to the Variation of Exogenous L-Theanine.

Tea grey blight disease is one of the most destructive diseases that infects tea and is caused by the pathogen Pestalotiopsis theae (Sawada) Steyaert. L-theanine is a unique non-protein amino acid of the tea plant. Different concentrations of L-theanine exhibit significant inhibitory effects on the growth and sporulation ability of the pathogen causing tea grey blight disease. To understand the effect mechanism of L-theanine on P. theae, transcriptome profiling was performed on the pathogenic mycelium treated with three different concentrations of L-theanine: no L-theanine treatment (TH0), 20 mg/mL theanine treatment (TH2), and 40 mg/mL theanine treatment (TH4). The colony growths were significantly lower in the treatment with L-theanine than those without L-theanine. The strain cultured with a high concentration of L-theanine produced no spores or only a few spores. In total, 2344, 3263, and 1158 differentially expressed genes (DEGs) were detected by RNA-sequencing in the three comparisons, Th2 vs. Th0, Th4 vs. Th0, and Th4 vs. Th2, respectively. All DEGs were categorized into 24 distinct clusters. According to GO analysis, low concentrations of L-theanine primarily affected molecular functions, while high concentrations of L-theanine predominantly affected biological processes including external encapsulating structure organization, cell wall organization or biogenesis, and cellular amino acid metabolic process. Based on KEGG, the DEGs of Th2 vs. Th0 were primarily involved in pentose and glucuronate interconversions, histidine metabolism, and tryptophan metabolism. The DEGs of Th4 vs. Th0 were mainly involved in starch and sucrose metabolism, amino sugar, and nucleotide sugar metabolism. This study indicated that L-theanine has a significant impact on the growth and sporulation of the pathogen of tea grey blight disease and mainly affects amino acid metabolism, carbohydrate metabolism, and cellular structure-related biosynthesis processes of pathogenic fungi. This work provides insights into the direct control effect of L-theanine on pathogenic growth and also reveals the molecular mechanisms of inhibition of L-theanine to P. theae.

Emergence and Genomic Characterization of a spa Type t4407 ST6-SCCmec Type IVa Methicillin-Resistant Staphylococcus aureus Strain Isolated from Al-Karak Hospital, Jordan.

Background and Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a major concern in Jordanian hospitals in terms of infection control. The purpose of this study was to identify the resistance patterns of Staphylococcus aureus strains isolated from surfaces of critical locations within the Al-Karak Governmental Hospital in 2019. Additionally, the study aimed to conduct whole-genome sequencing on the isolates. Materials and Methods: In February 2019, fourteen S. aureus strains were isolated from surfaces in critical sites in the Al-Karak Governmental Hospital. These isolates underwent antibiogram testing to determine their resistance profile. Genome sequencing using the Illumina MiSeq platform was applied to the extracted DNA from these isolates. The genomic data, including coding sequences, were analyzed to identify lineage, resistance genes, and plasmids. Results: The antibiogram results revealed that 11 of the 14 isolates were resistant to oxacillin, 6 to linezolid, and 1 to rifampicin, while none showed resistance to chloramphenicol. Eleven isolates were identified as MRSA, with a novel spa type (t4407) not previously reported in Jordan. High-quality sequencing data were obtained for only one isolate, i.e., A29, the genome showed 2,789,641 bp with a 32.7% GC content and contained 2650 coding sequences. Genomic analysis indicated the ST6 lineage, mecA gene (SCCmec type IVa(2B)), and a hybrid plasmid (pJOR_blaZ) carrying the blaZ gene for ß-lactam resistance. Genomic data were deposited in NCBI (CP104989). The A29 genome closely resembled an MRSA genome isolated from a Danish hospital in 2011. The SNP analysis revealed identical antimicrobial resistance genes in these two genomes. Conclusions: This study unveils the first genomic sequence of an MRSA isolate from Jordan, marked by distinctive genotypic traits. The findings enhance our understanding of the MRSA types circulating in Jordan and the region and substantiate the phenomenon of intercontinental MRSA transmission.

Addressing sex-based disparities in solid organ transplantation in the United States - a conference report.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

Establishment of a diverse head and neck squamous cancer cell bank using conditional reprogramming culture methods.

Most laboratory models of head and neck squamous cell cancer (HNSCC) rely on established immortalized cell lines, which carry inherent bias due to selection and clonality. We established a robust panel of HNSCC tumor cultures using a "conditional reprogramming" (CR) method, which utilizes a rho kinase inhibitor (Y-27632) and co-culture with irradiated fibroblast (J2 strain) feeder cells to support indefinite tumor cell survival. Sixteen CR cultures were successfully generated from 19 consecutively enrolled ethnically and racially diverse patients with HNSCC at a tertiary care center in the Bronx, NY. Of the 16 CR cultures, 9/16 were derived from the oral cavity, 4/16 were derived from the oropharynx, and 3/16 were from laryngeal carcinomas. Short tandem repeat (STR) profiling was used to validate culture against patient tumor tissue DNA. All CR cultures expressed ΔNp63 and cytokeratin 5/6, which are markers of squamous identity. Human papillomavirus (HPV) testing was assessed utilizing clinical p16 staining on primary tumors, reverse transcription polymerase chain reaction (RT-PCR) of HPV16/18-specific viral oncogenes E6 and E7 in RNA extracted from tumor samples, and HPV DNA sequencing. Three of four oropharyngeal tumors were p16 and HPV-positive and maintained HPV in culture. CR cultures were able to establish three-dimensional spheroid and murine flank and orthotopic tongue models. CR methods can be readily applied to all HNSCC tumors regardless of patient characteristics, disease site, and molecular background, providing a translational research model that properly includes patient and tumor diversity.

The apple BTB protein MdBT2 positively regulates MdCOP1 abundance to repress anthocyanin biosynthesis.

The ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) plays a central role in light-induced anthocyanin biosynthesis. However, the upstream regulatory factors of COP1 remain poorly understood, particularly in horticultural plants. Here, we identified an MdCOP1-interacting protein, BROAD-COMPLEX, TRAMTRACK AND BRIC A BRAC2 (MdBT2), in apple (Malus domestica). MdBT2 is a BTB protein that directly interacts with and stabilizes MdCOP1 by inhibiting self-ubiquitination. Fluorescence observation and cell fractionation assays showed that MdBT2 increased the abundance of MdCOP1 in the nucleus. Moreover, a series of phenotypic analyses indicated that MdBT2 promoted MdCOP1-mediated ubiquitination and degradation of the MdMYB1 transcription factor, inhibiting the expression of anthocyanin biosynthesis genes and anthocyanin accumulation. Overall, our findings reveal a molecular mechanism by which MdBT2 positively regulates MdCOP1, providing insight into MdCOP1-mediated anthocyanin biosynthesis.

The role of environmental stress in fruit pigmentation.

For many fruit crops, the colour of the fruit outwardly defines its eating quality. Fruit pigments provide reproductive advantage for the plant as well as providing protection against unfavourable environmental conditions and pathogens. For consumers these colours are considered attractive and provide many of the dietary benefits derived from fruits. In the majority of species, the main pigments are either carotenoids and/or anthocyanins. They are produced in the fruit as part of the ripening process, orchestrated by phytohormones and an ensuing transcriptional cascade, culminating in pigment biosynthesis. Whilst this is a controlled developmental process, the production of pigments is also attuned to environmental conditions such as light quantity and quality, availability of water and ambient temperature. If these factors intensify to stress levels, fruit tissues respond by increasing (or ceasing) pigment production. In many cases, if the stress is not severe, this can have a positive outcome for fruit quality. Here, we focus on the principal environmental factors (light, temperature and water) that can influence fruit colour.

Secondary hypertension: evaluation and management.

PURPOSE OF REVIEW: Hypertension (HTN) that can be attributed to a particular source is known as secondary HTN (SH). Often, SH is difficult to control and thus referred to as resistant HTN, although the two terms are not mutually exclusive. RECENT FINDINGS: A common theme across several contributors to SH are coactivation of the sympathetic drive and hormonal changes, independent of hormonal axis activation. The key to effective management of SH is early recognition and treatment to avoid catastrophic cardiovascular disease effects and mortality. SUMMARY: This review article provides a contemporary summary of the conditions associated with SH and briefly reviews diagnostics and management.

APP and DYRK1A regulate axonal and synaptic vesicle protein networks and mediate Alzheimer's pathology in trisomy 21 neurons.

Trisomy 21 (T21) causes Down syndrome and an early-onset form of Alzheimer's disease (AD). Here, we used human induced pluripotent stem cells (hiPSCs) along with CRISPR-Cas9 gene editing to investigate the contribution of chromosome 21 candidate genes to AD-relevant neuronal phenotypes. We utilized a direct neuronal differentiation protocol to bypass neurodevelopmental cell fate phenotypes caused by T21 followed by unbiased proteomics and western blotting to define the proteins dysregulated in T21 postmitotic neurons. We show that normalization of copy number of APP and DYRK1A each rescue elevated tau phosphorylation in T21 neurons, while reductions of RCAN1 and SYNJ1 do not. To determine the T21 alterations relevant to early-onset AD, we identified common pathways altered in familial Alzheimer's disease neurons and determined which of these were rescued by normalization of APP and DYRK1A copy number in T21 neurons. These studies identified disruptions in T21 neurons in both the axonal cytoskeletal network and presynaptic proteins that play critical roles in axonal transport and synaptic vesicle cycling. These alterations in the proteomic profiles have functional consequences: fAD and T21 neurons exhibit dysregulated axonal trafficking and T21 neurons display enhanced synaptic vesicle release. Taken together, our findings provide insights into the initial molecular alterations within neurons that ultimately lead to synaptic loss and axonal degeneration in Down syndrome and early-onset AD.

Synthesis of Neocannabinoids Using Controlled Friedel-Crafts Reactions.

A one-step transformation to produce 8,9-dihydrocannabidiol (H2CBD) and related "neocannabinoids" via controlled Friedel-Crafts reactions is reported. Experimental and computational studies probing the mechanism of neocannabinoid synthesis from cyclic allylic alcohol and substituted resorcinol reaction partners provide understanding of the kinetic and thermodynamic factors driving regioselectivity for the reaction. Herein, we present the reaction scope for neocannabinoid synthesis including the production of both normal and abnormal isomers under both kinetic and thermodynamic control. Discovery and optimization of this one-step protocol between various allylic alcohols and resorcinol derivatives are discussed and supported with density functional theory calculations.

Antimicrobial stewardship on the dairy: Evaluating an on-farm framework for training farmworkers.

Dairy farmworkers are commonly responsible for disease diagnosis and routine treatment decisions for cattle. This highlights the importance of farmworkers' knowledge and skills to successfully implement judicious use of antimicrobials in livestock production systems. The main objectives of this project were to develop and evaluate an on-farm educational program for farmworkers in antimicrobial stewardship in adult dairy cattle. A longitudinal quasi-experimental study design was used, by enrolling 12 conventional dairy farms in the United States (6 in California and 6 in Ohio). Farmworkers responsible for treatment decisions on the farm (n = 25) participated in a didactic and hands-on 12-wk antimicrobial stewardship training program led by the investigators. All antimicrobial stewardship training materials were available in Spanish and English. Interactive short videos with audio were developed to cover the learning objectives for each of the 6 teaching modules: antimicrobial resistance, treatment protocols, visual identification of sick animals, clinical mastitis, puerperal metritis, and lameness. Pre- and post-training assessments were administered using an online training assessment tool to evaluate changes in knowledge and attitudes about antimicrobial stewardship practices. Cluster analysis and multiple correspondence analyses were conducted to evaluate the association among categorical variables for participants' level of change in knowledge and its association with language, farm size, and state. A 32% average increase in knowledge was observed through an assessment conducted after completing the antimicrobial stewardship training, compared with the pre-training assessment. A significant improvement in 7 of 13 attitude questions related to antimicrobial stewardship practices on the farm was observed. Knowledge and attitude scores of participants on antimicrobial stewardship and identification of sick animals significantly improved after completing the antimicrobial stewardship training. The results observed in this study support the relevance of antimicrobial stewardship training programs targeting farmworkers to improve antimicrobial drug use knowledge and skills.

Pediatric Heart Network Trial of Losartan vs. Atenolol in Children and Young Adults with Marfan Syndrome: Impact on Prescription Practices.

The Pediatric Heart Network (PHN) trial showed similar efficacy of ß-blockers (BB) and angiotensin receptor blockers (ARB) for aortic root dilation in Marfan syndrome, but the impact on prescription practices is unknown. We hypothesized BB and ARB prescriptions would increase after the trial results were published (2014). Prescription data (2007-2016) were obtained from outpatient encounters (IBM Marketscan) for Marfan syndrome patients (6 months-25 years old). Excluding 2014 as a washout period, we analyzed two intervals: 2007-2013 and 2015-2016. Medication categories included BB, ARB, angiotensin converting enzyme inhibitors (ACEI), combination (BB/ARB and/or BB/ACEI), and no drug. Interrupted time-series analysis assessed immediate level change after publication and change in slope for the trend pre- and post-publication. Odds ratios (OR) and 95% confidence intervals from logistic regressions and generalized estimating equation methods accounted for correlation of prescriptions within patients. In 1499 patients (age 14.1 ± 6.1 years, 59% female) seen 2007-2013, BB trended lower [OR 0.91 (0.89, 0.93), p < 0.001] and ARB trended higher [OR 1.12 (1.07, 1.18), p < 0.001], while combination, ACEI, and no drug remained stable. This trend persisted, but was not significant, for BB [OR 0.54 (0.27, 1.08), p = 0.37] and ARB [OR 1.91 (0.55, 6.69), p = 0.31] in 2015-2016. Combination, ACEI, and no drug remained similar. In short term follow-up, changes in prescription practices following publication of the PHN trial were not statistically significant. This may be due to a change seen prior to publication with early adoption of ARBs that was maintained after confirmation of their effectiveness.

The Fontan Udenafil Exercise Longitudinal Trial: Subgroup Analysis.

The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.