Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Bacterial Cholecystitis and Cholangiohepatitis in Common Marmosets (Callithrix jacchus).

The common marmoset (Callithrix jacchus), a New World NHP, has emerged as important animal model in multiple areas of translational biomedical research. The quality of translational research in marmosets depends on early diagnosis, treatment, and prevention of their spontaneous diseases. Here, we characterize an outbreak of infectious cholangiohepatitis that affected 7 adult common marmosets in a single building over a 10-mo period. Marmosets presented for acute onset of lethargy, dull mentation, weight loss, dehydration, hyporexia, and hypothermia. Blood chemistries at presentation revealed markedly elevated hepatic and biliary enzymes, but mild neutrophilia was detected in only 1 of the 7. Affected marmosets were unresponsive to rigorous treatment and died or were euthanized within 48 h of presentation. Gross and histopathologic examinations revealed severe, necrosuppurative cholangiohepatitis and proliferative cholecystitis with bacterial colonies and an absence of gallstones. Perimortem and postmortem cultures revealed single or dual isolates of Escherichia coli and Pseudomonas aeruginosa. Other postmortem findings included bile duct hyperplasia, periportal hepatitis, bile peritonitis, ulcerative gastroenteritis, and typhlitis. Environmental contamination of water supply equipment with Pseudomonas spp. was identified as the source of infection, but pathogenesis remains unclear. This type of severe, infectious cholangiohepatitis with proliferative cholecystitis with Pseudomonas spp. had not been reported previously in marmosets, and we identified and here describe several contributing factors in addition to contaminated drinking water.

Examining the Effect of Interruptions at Different Breakpoints and Frequencies Within a Task.

OBJECTIVE: The purpose was to explore how event segmentation theory (EST) can be used to determine optimal moments for an interruption relying on hierarchical task analysis (HTA) to identify coarse and fine event boundaries. BACKGROUND: Research on the effects of interruptions shows that they can be either disruptive or beneficial, depending on which aspects of an interruption are manipulated. Two important aspects that contribute to these conflicting results concern when and how often interruptions occur. METHOD: Undergraduates completed a trip planning task divided into three subtasks. The within-subjects factor was interruption timing with three levels: none, coarse breakpoints, and fine breakpoints. The between-subjects factor was interruption frequency with two levels: one and three. The dependent measures included resumption lag, number of errors, mental workload, and frustration. RESULTS: Participants took longer to resume the primary task and reported higher mental workload when interruptions occurred at fine breakpoints. The effect of interruptions at coarse breakpoints was similar to completing the task without interruption. Interruption frequency had no effect on performance; however, participants spent significantly longer attending to interruptions in the initial task, and within a task, the first and second interruptions were attended to significantly longer than the third interruption. CONCLUSION: The disruptiveness of an interruption is tied to the point within the task hierarchy where it occurs. APPLICATION: The performance cost associated with interruptions must be considered within the task structure. Interruptions occurring at coarse breakpoints may not be disruptive or have a negative effect on mental workload.

The Common Marmoset-Biomedical Research Animal Model Applications and Common Spontaneous Diseases.

Marmosets are becoming more utilized in biomedical research due to multiple advantages including (1) a nonhuman primate of a smaller size with less cost for housing, (2) physiologic similarities to humans, (3) translatable hepatic metabolism, (4) higher numbers of litters per year, (5) genome is sequenced, molecular reagents are available, (6) immunologically similar to humans, (7) transgenic marmosets with germline transmission have been produced, and (8) are naturally occurring hematopoietic chimeras. With more use of marmosets, disease surveillance over a wide range of ages of marmosets has been performed. This has led to a better understanding of the disease management of spontaneous diseases that can occur in colonies. Knowledge of clinical signs and histologic lesions can assist in maximizing the colony's health, allowing for improved outcomes in translational studies within biomedical research. Here, we describe some basic husbandry, biology, common spontaneous diseases, and animal model applications for the common marmoset in biomedical research.

Organic dry pea (Pisum sativum L.) biofortification for better human health.

A primary criticism of organic agriculture is its lower yield and nutritional quality compared to conventional systems. Nutritionally, dry pea (Pisum sativum L.) is a rich source of low digestible carbohydrates, protein, and micronutrients. This study aimed to evaluate dry pea cultivars and advanced breeding lines using on-farm field selections to inform the development of biofortified organic cultivars with increased yield and nutritional quality. A total of 44 dry pea entries were grown in two USDA-certified organic on-farm locations in South Carolina (SC), United States of America (USA) for two years. Seed yield and protein for dry pea ranged from 61 to 3833 kg ha-1 and 12.6 to 34.2 g/100 g, respectively, with low heritability estimates. Total prebiotic carbohydrate concentration ranged from 14.7 to 26.6 g/100 g. A 100-g serving of organic dry pea provides 73.5 to 133% of the recommended daily allowance (%RDA) of prebiotic carbohydrates. Heritability estimates for individual prebiotic carbohydrates ranged from 0.27 to 0.82. Organic dry peas are rich in minerals [iron (Fe): 1.9-26.2 mg/100 g; zinc (Zn): 1.1-7.5 mg/100 g] and have low to moderate concentrations of phytic acid (PA:18.8-516 mg/100 g). The significant cultivar, location, and year effects were evident for grain yield, thousand seed weight (1000-seed weight), and protein, but results for other nutritional traits varied with genotype, environment, and interactions. "AAC Carver," "Jetset," and "Mystique" were the best-adapted cultivars with high yield, and "CDC Striker," "Fiddle," and "Hampton" had the highest protein concentration. These cultivars are the best performing cultivars that should be incorporated into organic dry pea breeding programs to develop cultivars suitable for organic production. In conclusion, organic dry pea has potential as a winter cash crop in southern climates. Still, it will require selecting diverse genetic material and location sourcing to develop improved cultivars with a higher yield, disease resistance, and nutritional quality.

Genome-wide association studies of mineral and phytic acid concentrations in pea (Pisum sativum L.) to evaluate biofortification potential.

Pea (Pisum sativum L.) is an important cool season food legume for sustainable food production and human nutrition due to its nitrogen fixation capabilities and nutrient-dense seed. However, minimal breeding research has been conducted to improve the nutritional quality of the seed for biofortification, and most genomic-assisted breeding studies utilize small populations with few single nucleotide polymorphisms (SNPs). Genomic resources for pea have lagged behind those of other grain crops, but the recent release of the Pea Single Plant Plus Collection (PSPPC) and the pea reference genome provide new tools to study nutritional traits for biofortification. Calcium, phosphorus, potassium, iron, zinc, and phytic acid concentrations were measured in a study population of 299 different accessions grown under greenhouse conditions. Broad phenotypic variation was detected for all parameters except phytic acid. Calcium exhibited moderate broad-sense heritability (H2) estimates, at 50%, while all other minerals exhibited low heritability. Of the accessions used, 267 were previously genotyped in the PSPPC release by the USDA, and we mapped the genotyping data to the pea reference genome for the first time. This study generated 54,344 high-quality SNPs used to investigate the population structure of the PSPPC and perform a genome-wide association study to identify genomic loci associated with mineral concentrations in mature pea seed. Overall, we were able to identify multiple significant SNPs and candidate genes for iron, phosphorus, and zinc. These results can be used for genetic improvement in pea for nutritional traits and biofortification, and the candidate genes provide insight into mineral metabolism.

Usability: Adoption, Measurement, Value.

OBJECTIVE: We searched for the application of usability in the literature with a focus on adoption, measurements employed, and demonstrated value. Five human factors domains served as a platform for our reflection, which included the last 20 years. BACKGROUND: As usability studies continue to accumulate, there has been only a little past reflection on usability and contributions across a variety of applications. Our research provides a background for general usability, and we target specific usability research subareas within transportation, aging populations, autistic populations, telehealth, and cybersecurity. METHOD: "Usability" research was explored across five different domains within human factors. The goal was not to perform an exhaustive review but, rather, sample usability practices within several specific subareas. We focused on answering three questions: How was usability adopted? How was it measured? How was it framed in terms of value? CONCLUSION: We found that usability is very domain specific. Usability benchmarking studies and empirical standards are rare. The value associated with improving usability ranged widely-from monetary benefits to saving lives. Thus, researchers are motivated to further improve usability practices. A number of data collection and interpretation challenges still call for solutions. APPLICATION: Findings offer insight into the development of usability, as applied across a variety of subdomains. Our reflection ought to inform future theory development efforts. We are concerned about the lack of established benchmarks, which can help ground data interpretation. Future research should address this gap in the literature. We note that our findings can be used to develop better training materials for future usability researchers.

Field pea (Pisum sativum L.) shows genetic variation in phosphorus use efficiency in different P environments.

Field pea is important to agriculture as a nutritionally dense legume, able to fix nitrogen from the atmosphere and supply it back to the soil. However, field pea requires more phosphorus (P) than other crops. Identifying field pea cultivars with high phosphorus use efficiency (PUE) is highly desirable for organic pulse crop biofortification. This study identified field pea accessions with high PUE by determining (1) the variation in P remobilization rate, (2) correlations between P and phytic acid (PA), and (3) broad-sense heritability estimates of P concentrations. Fifty field pea accessions were grown in a completely randomized design in a greenhouse with two replicates under normal (7551 ppm) and reduced (4459 ppm) P fertilizer conditions and harvested at two time points (mid-pod and full-pod). P concentrations ranged from 332 to 9520 ppm under normal P and from 83 to 8473 ppm under reduced P conditions across all tissues and both time points. Field pea accessions showed variation in remobilization rates, with PI 125840 and PI 137119 increasing remobilization of P under normal P conditions. Field pea accessions PI 411142 and PI 413683 increased P remobilization under the reduced P treatment. No correlation was evident between tissue P concentration and seed PA concentration (8-61 ppm). Finally, seed P concentration under limited P conditions was highly heritable (H2 = 0.85), as was mid-pod lower leaf P concentrations under normal P conditions (H2 = 0.81). In conclusion, breeding for PUE in field pea is possible by selecting for higher P remobilization accessions in low P soils with genetic and location sourcing.

The Value and Caveats of Interpreting Small Case Series: Implications for Patient Care.

PURPOSE: To discuss the value and limitations of interpreting small case series for the purpose of understanding the pathophysiology of conditions affecting the visual system and how they may influence patient care decision making. DESIGN: Selective review of English-language ophthalmic articles published in peer-reviewed journals since 1950. METHODS: Author-initiated PubMed Central query of small case series in glaucoma, pediatric neuro-ophthalmology, and diabetic retinopathy. RESULTS: A review of well-known ophthalmic case studies by Gass, Irvine, Brockhurst, and others shows that small samples can provide suggestions to the skilled clinician for adding steps to the examination process when uncovering rare or previously unknown associated complications, as is the case for this perspective's initiating studies by Groth and Brodsky. However, as shown by the now-retracted small case series in Lancet connecting measles-mumps-rubella vaccinations with autism, small case series do not replace the value of clinical trials, with rare exception, when considering impacts to widespread, common clinical practice. CONCLUSION: Small case series may contribute to an improved understanding of pathophysiology of rare ophthalmic conditions, but alone are insufficient to provide evidence for changing clinical practice of common eye diseases.

Checking Agriculture's Pulse: Field Pea (Pisum Sativum L.), Sustainability, and Phosphorus Use Efficiency.

Investigations regarding the incorporation of better sustainable production strategies into current agricultural-food systems are necessary to grow crops that reduce negative impacts on the environment yet will meet the production and nutritional demand of 10 billion people by 2050. The introduction of organic, alternative staple food crops, such as nutrient-dense field pea (Pisum sativum L.), to the everyday diet, may alleviate micronutrient malnutrition and incorporate more sustainable agriculture practices globally. Varieties are grown in organic systems currently yield less than conventionally produced foods, with less bioavailable nutrients, due to poor soil nutrient content. One of the most limiting nutrients for field pea is phosphorus (P) because this legume crop requires significant inputs for nodule formation. Therefore, P use efficiency (PUE) should be a breeding target for sustainable agriculture and biofortification efforts; the important role of the soil microbiome in nutrient acquisition should also be examined. The objectives of this review are to highlight the benefits of field pea for organic agriculture and human health, and discuss nutritional breeding strategies to increase field pea production in organic systems. Field pea and other pulse crops are underrepresented in agricultural research, yet are important crops for a sustainable future and better food systems. Furthermore, because field pea is consumed globally by both developed and at-risk populations, research efforts could help increase global health overall and combat micronutrient malnutrition.

A city-scale assessment reveals that native forest types and overstory species dominate New York City forests.

Cities are increasingly focused on expanding tree canopy cover as a means to improve the urban environment by, for example, reducing heat island effects, promoting better air quality, and protecting local habitat. The majority of efforts to expand canopy cover focus on planting street trees or on planting native tree species and removing nonnatives in natural areas through reforestation. Yet many urban canopy assessments conducted at the city-scale reveal co-dominance by nonnative trees, fueling debates about the value of urban forests and native-specific management targets. In contrast, assessments within cities at site or park scales find that some urban forest stands harbor predominantly native biodiversity. To resolve this apparent dichotomy in findings, about the extent to which urban forests are native dominated, between the city-scale canopy and site-level assessments, we measure forest structure and composition in 1,124 plots across 53 parks in New York City's 2,497 ha of natural area forest. That is, we assess urban forests at the city-scale and deliberately omit sampling trees existing outside of forest stands but which are enumerated in citywide canopy assessments. We find that on average forest stand canopy is comprised of 82% native species in New York City forests, suggesting that conclusions that the urban canopy is co-dominated by nonnatives likely results from predominantly sampling street trees in prior city-scale assessments. However, native tree species' proportion declines to 75% and 53% in the midstory and understory, respectively, suggesting potential threats to the future native dominance of urban forest canopies. Furthermore, we find that out of 57 unique forest types in New York City, the majority of stands (81%) are a native type. We find that stand structure in urban forest stands is more similar to rural forests in New York State than to stand structure reported for prior assessments of the urban canopy at the city scale. Our results suggest the need to measure urban forest stands apart from the entire urban canopy. Doing so will ensure that city-scale assessments return data that align with conservation policy and management strategies that focus on maintaining and growing native urban forests rather than individual trees.

Regulated Capture of Vκ Gene Topologically Associating Domains by Transcription Factories.

Expression of vast repertoires of antigen receptors by lymphocytes, with each cell expressing a single receptor, requires stochastic activation of individual variable (V) genes for transcription and recombination. How this occurs remains unknown. Using single-cell RNA sequencing (scRNA-seq) and allelic variation, we show that individual pre-B cells monoallelically transcribe divergent arrays of Vκ genes, thereby opening stochastic repertoires for subsequent Vκ-Jκ recombination. Transcription occurs upon translocation of Vκ genes to RNA polymerase II arrayed on the nuclear matrix in transcription factories. Transcription is anchored by CTCF-bound sites or E2A-loaded Vκ promotors and continues over large genomic distances delimited only by topological associating domains (TADs). Prior to their monoallelic activation, Vκ loci are transcriptionally repressed by cyclin D3, which prevents capture of Vκ gene containing TADs by transcription factories. Cyclin D3 also represses protocadherin, olfactory, and other monoallelically expressed genes, suggesting a widely deployed mechanism for coupling monoallelic gene activation with cell cycle exit.

Effect of first cannulation time and dialysis machine blood flows on survival of arteriovenous fistulas.

Background: To study the effect of cannulation time on arteriovenous fistula (AVF) survival. Methods. Analysis of two prospective databases of access operations and dialysis sessions from 12 January 2002 through 4 January 2015 with follow-up until 4 January 2016. First cannulation time (FCT), defined from operation to first cannulation, was categorized as <2 weeks, 2-4 weeks, 4-8 weeks, 8-16 weeks and ≥16 weeks. Early cannulation was defined as FCT within 4 weeks. AVF survival was defined as the date until the AVF was abandoned. Maximum machine blood flow rate (BFR) for the first 29 dialysis sessions on AVF was analysed. Results: Altogether, 1167 AVF with functional dialysis use were analysed: 667 (57%) radial cephalic AVF, 383 (33%) brachiocephalic AVF and 117 (10%) brachiobasilic AVF. The 631 (54%) AVF created in on-dialysis patients were analysed separately from 536 (46%) AVF created in pre-dialysis patients. AVF survival was similar between cannulation categories for both pre-dialysis patients (P = 0.19) and on-dialysis patients (P = 0.83). Early cannulation was associated with similar AVF survival in both pre-dialysis patients (P = 0.82) and on-dialysis patients (P = 0.17). Six consecutive successful cannulations from the start were associated with improved AVF survival (P = 0.0002). A below-median BFR at the start of dialysis was associated with better AVF survival (P < 0.0001). A below-median increase in BFR in the first 2 months was associated with worse AVF survival (P = 0.007). The type of AVF, diabetes, pre-dialysis state at operation and six successful cannulations from the start were independent predictors for AVF survival. Conclusions: FCT is not associated with AVF survival. Failures to achieve six successful cannulations from the start of dialysis and higher machine BFR in the first week of dialysis are associated with decreased AVF survival.

Effect of ethnicity and socioeconomic status on vascular access provision and performance in an urban NHS hospital.

BACKGROUND: The aim of this study was to examine the effect of ethnicity, socioeconomic group (SEG) and comorbidities on provision of vascular access for haemodialysis (HD). METHODS: This was a retrospective review of two databases of HD sessions and access operations from 2003-11. Access modality of first HD session and details of transplanted patients were derived from the renal database. Follow-up was until 1 January 2015. Primary failure (PF) was defined as an arteriovenous fistula (AVF) used for fewer than six consecutive dialysis sessions. AVF survival was defined as being until the date the AVF was abandoned. Ethnicity was coded from hospital records. SEG was calculated from postcodes and 2011 census data from the Office of National Statistics. Comorbidities were calculated with the Charlson Comorbidity Index. RESULTS: Five hundred incident patients started chronic HD in the study period. Mode of starting HD was not associated with ethnicity (P = 0.27) or SEG (P = 0.45). Patients from ethnic minorities were younger when starting dialysis (P < 0.0001). Some 928 AVF patients' first AVF operations were analysed: 68% Caucasian, 26% Asian and 6% Afro-Caribbean. Half were in the most deprived SEG and 11% in the least deprived SEG. PF did not differ by ethnicity (P = 0.29), SEG (P = 0.75) or comorbidities (P = 0.54). AVF survival was not different according to ethnicity (P = 0.13) or SEG (P = 0.87). AVF survival was better for patients with a low comorbidity score (P = 0.04). The distribution of transplant recipients by ethnic group and SEG was similar to the distributions of all HD starters. CONCLUSION: Ethnicity and socioeconomic group had no effect on mode of starting HD, primary AVF failure rate or AVF survival. Ethnic minorities were younger at start of dialysis and at their first AVF operation.