Urinary biomarkers associated with acute kidney injury in pediatric mechanical circulatory support patients.

BACKGROUND: In patients requiring mechanical circulatory support (MCS), the incidence of acute kidney injury (AKI) is between 37 and 63%. In this study, we performed an exploratory analysis evaluating the relationship of multiple urine biomarkers with AKI development in pediatric MCS patients. METHODS: This is a single center retrospective study in a pediatric cohort receiving MCS from August 2014 to November 2020. We measured 14 urine biomarkers of kidney injury on day 1 following MCS initiation and analyzed their association with development of AKI in the first 7 days of MCS initiation. RESULTS: Sixty patients met inclusion criteria. Patients with AKI were more likely to be supported by venoarterial extracorporeal membrane oxygenation (65% vs. 8.3%, p < 0.001), compared to the no AKI group and less likely to have ventricular assist devices (10% vs. 50%, p < 0.001). There was a significant increase in the median urine albumin and urine osteoactivin in the AKI group, compared to the no AKI group (p = 0.020 and p = 0.018, respectively). When normalized to urine creatinine (UCr), an increased log osteoactivin/UCr was associated with higher odds of AKI development (OR: 2.05; 95% CI: 1.07, 4.44; p = 0.028), and higher log epidermal growth factor (EGF)/UCr (OR: 0.41; 95% CI: 0.15, 0.96) was associated with decreased odds of AKI. CONCLUSIONS: Early increase in urine osteoactivin is associated with AKI development within 7 days of MCS initiation in pediatric patients. Contrary, an increased urine EGF is associated with kidney protection. A higher resolution version of the Graphical abstract is available as Supplementary information.

Food deprivation reduces sensitivity of liver Igf1 synthesis pathways to growth hormone in juvenile gopher rockfish (Sebastes carnatus).

Growth hormone (Gh) regulates growth in part by stimulating the liver to synthesize and release insulin-like growth factor-1 (Igf1), which then promotes somatic growth. However, for fish experiencing food limitation, elevated blood Gh can occur even with low circulating Igf1 and slow growth, suggesting that nutritional stress can alter the sensitivity of liver Igf1 synthesis pathways to Gh. Here, we examined how recent feeding experience affected Gh regulation of liver Igf1 synthesis pathways in juvenile gopher rockfish (Sebastes carnatus) to illuminate mechanisms underlying the nutritional modulation of Igf1 production. Juvenile gopher rockfish were maintained under conditions of feeding or complete food deprivation (fasting) for 14 d and then treated with recombinant sea bream (Sparus aurata) Gh or saline control. Gh upregulated hepatic igf1 mRNA levels in fed fish but not in fasted fish. The liver of fasted rockfish also showed a lower relative abundance of gene transcripts encoding teleost Gh receptors 1 (ghr1) and 2 (ghr2), as well as reduced protein levels of phosphorylated janus tyrosine kinase 2 (pJak2) and signal transducer and activator of transcription 5 (pStat5), which function to induce igf1 gene transcription following Gh binding to Gh receptors. Relative hepatic mRNA levels for suppressors of cytokine signaling (Socs) genes socs2, socs3a, and socs3b were also lower in fasted rockfish. Socs2 can suppress Gh activation of Jak2/Stat5, and fasting-related variation in socs expression may reflect modulated inhibitory control of igf1 gene transcription. Fasted rockfish also had elevated liver mRNA abundances for lipolytic hormone-sensitive lipase 1 (hsl1) and Igf binding proteins igfbp1a, -1b and -3a, reduced liver mRNAs encoding igfbp2b and an Igfbp acid labile subunit-like (igfals) gene, and higher transcript abundances for Igf1 receptors igf1ra and igf1rb in skeletal muscle. Together, these findings suggest that food deprivation impacts liver Igf1 responsiveness to Gh via multiple mechanisms that include a downregulation of hepatic Gh receptors, modulation of the intracellular Jak2/Stat5 transduction pathway, and possible shifts in Socs-inhibitory control of igf1 gene transcription, while also demonstrating that these changes occur in concert with shifts in liver Igfbp expression and muscle Gh/Igf1 signaling pathway components.

Insulin-like growth factor-1 (Igf1) signaling responses to food consumption after fasting in the Pacific rockfish Sebastes carnatus.

Fish adjust rates of somatic growth in the face of changing food consumption. As in other vertebrates, growth in fish is regulated by the growth hormone (Gh)/insulin-like growth factor-1 (Igf1) endocrine axis, and changes in food intake impact growth via alterations to Gh/Igf1 signaling. Understanding the time course by which the Gh/Igf1 axis responds to food consumption is crucial to predict how rapidly changes in food abundance might lead to altered growth dynamics. Here, we looked at the response times of plasma Igf1 and liver Igf1 signaling-associated gene expression to refeeding after food deprivation in juvenile gopher rockfish (Sebastes carnatus), one of several species of northern Pacific Ocean Sebastes rockfishes targeted by fisheries or utilized for aquaculture. Gopher rockfish were fasted for 30 d, after which a subset was fed to satiation for 2 h, while other rockfish continued to be fasted. Refed fish exhibited higher hepatosomatic index (HSI) values and increased Igf1 after food consumption. Gene transcripts for Gh receptor 1 (ghr1), but not ghr2, increased in the liver 2-4 d after eating. Transcripts encoding igf1also increased in the liver of refed fish by 4 d after feeding, only to return to levels similar as continually fasted rockfish by 9 d after feeding. Liver mRNA abundances for Igf binding protein (Igfbp) genes igfbp1a, igfbp1b, and igfbp3a declined within 2 d of feeding. These findings provide evidence that circulating Igf1 in rockfish reflects a fish's feeding experience within the previous few days, and suggest that feeding-induced increases in Igf1 are being mediated in part by altered liver sensitivity to Gh due to upregulated Gh receptor 1 expression.

Effects of food deprivation on plasma insulin-like growth factor-1 (Igf1) and Igf binding protein (Igfbp) gene transcription in juvenile cabezon (Scorpaenichthys marmoratus).

The growth hormone (GH)/insulin-like growth factor (Igf) endocrine axis regulates somatic growth in the face of changing environmental conditions. In actinopterygian fishes, food availability is a key modulator of the somatotropic axis, with lower food intake generally depressing liver Igf1 release to diminish growth. Igf1 signaling, however, also involves several distinct IGF binding proteins (Igfbps), and the functional roles of many of these Igfbps in affecting growth during shifting food availability remain uncertain. Here, we tested how complete food deprivation (fasting) affected gene transcription for paralogs of all six types of Igfbps in the liver and fast-twitch skeletal muscle of cabezon (Scorpaenichthys marmoratus), a nearshore marine fish important for recreational fisheries in the eastern North Pacific Ocean. Juvenile cabezon were maintained as either fed (6% mass food⋅g fish wet mass-1⋅d-1) or fasted for 14 d. Fasted fish exhibited a lower body condition (K), a depressed mass-specific growth rate (SGR), and reduced plasma concentrations of Igf1. In the liver, fasting reduced the relative abundance of gene transcripts encoding Igfbps igfbp2a and igfbp2b, while significantly elevating mRNA levels for igfbp1a, igfbp1b, igfbp3b, and igfbp4. Fasting also reduced hepatic mRNA levels of GH receptor-1 (ghr1) - but not GH receptor-2 (ghr2) - supporting the idea that changes in liver sensitivity to GH may underlie the decline in plasma Igf1 during food deprivation. In skeletal muscle, fasting downregulated gene transcripts encoding igf1, igfbp2b, igfbp5b, and igfbp6b, while also upregulating mRNAs for igf2 and ghr2. These data demonstrate isoform-specific regulation of Igfbps in liver and skeletal muscle in cabezon experiencing food deprivation and reinforce the idea that the repertoire of duplicated Igfbp genes that evolved in actinopterygian fishes supports a diverse scope of endocrine and paracrine functions.

Interactions of long-term food ration variation and short-term fasting on insulin-like growth factor-1 (IGF-1) pathways in copper rockfish (Sebastes caurinus).

Variation in food intake affects somatic growth by altering the expression of hormones in the somatotropic endocrine axis including insulin-like growth factor-1 (IGF-1). Here, we examined IGF-1 pathway responses to long- and short-term variation in food availability in copper rockfish (Sebastes caurinus), a nearshore Pacific rockfish important for commercial and recreational fisheries. Juvenile copper rockfish were raised under differing ration amounts (3% or 9% mass feed·g-1 fish wet mass·day-1) for 140 d to simulate 'long-term' feeding variation, after which some fish from both rations were fasted for 12 d to generate 'short-term' conditions of food deprivation. Rockfish on the 9% ration treatment grew more quickly than those on the 3% ration and were larger in mass, length, and body condition (k) after 152 d. Fish on the 9% ration had higher blood glucose than those on the 3% ration, with fasting decreasing blood glucose in both ration treatments, indicating that both long-term and short-term feed treatments altered energy status. Plasma IGF-1 was higher in rockfish from the 9% ration than those in the 3% ration and was also higher in fed fish than fasted fish. Additionally, plasma IGF-1 related positively to individual variation in specific growth rate (SGR). The positive association between IGF-1 and SGR showed discordance in fish that had experienced different levels of food and growth over the long-term but not short-term, suggesting that long-term nutritional experience can influence the relationship between IGF-1 and growth in this species. Rockfish on the 3% ration showed a lower relative abundance of gene transcripts encoding igf1 in the liver, but higher hepatic mRNAs for IGF binding proteins igfbp1a and igfbp1b. Fasting similarly decreased the abundance of igf1 mRNAs in the liver of fish reared under both the 9% and 3% rations, while concurrently increasing mRNAs encoding the IGF binding proteins igfbp1a, -1b, and -3a. Hepatic mRNAs for igfbp2b, -5a, and -5b were lower with long-term ration variation (3% ration) and fasting. Fish that experienced long-term reduced rations also had higher mRNA levels for igfbp3a, -3b, and IGF receptors isoforms A (igf1rA) and B (igf1rB) in skeletal muscle, but lower mRNA levels for igf1. Fasting increased muscle mRNA abundance for igfbp3a, igf1rA, and igf1rB, and decreased levels for igfbp2a and igf1. These data show that a positive relationship between circulating IGF-1 and individual growth rate is maintained in copper rockfish even when that growth variation relates to differences in food consumption across varying time scales, but that long- and short-term variation in food quantity can shift basal concentrations of circulating IGF-1 in this species.

Utilization of an endocrine growth index, insulin-like growth factor binding protein (IGFBP)-1b, for postsmolt coho salmon in the Strait of Georgia, British Columbia, Canada.

Monitoring the growth of salmon during their early marine phase provides insights into prey availability, and growth rates may be linked to risks of size-dependent mortality. However, the measurement of growth rate is challenging for free-living salmon in the ocean. Insulin-like growth factor (IGF)-I is a growth-promoting hormone that is emerging as a useful index of growth in salmon. In addition, laboratory-based studies using coho salmon have shown that one of circulating IGF-binding proteins (IGFBPs), IGFBP-1b, is induced by fasting and thus could be used as an inverse index of growth and/or catabolic state in salmon. However, few studies have measured plasma levels of IGFBP-1b in salmon in the wild. We measured plasma IGFBP-1b levels for postsmolt coho salmon collected in the Strait of Georgia and surrounding waters, British Columbia, Canada, and compared regional differences in IGFBP-1b to ecological information such as seawater temperature and stomach fullness. Plasma IGFBP-1b levels were the highest in fish from Eastern Johnstone Strait and relatively high in Queen Charlotte Strait and Western Johnstone Strait, which was in good agreement with the poor ocean conditions for salmon hypothesized to occur in that region. The molar ratio of plasma IGF-I to IGFBP-1b, a theoretical parameter of IGF-I availability to the receptor, discriminated differences among regions better than IGF-I or IGFBP-1b alone. Our data suggest that plasma IGFBP-1b reflects catabolic status in postsmolt coho salmon, as highlighted in fish in Eastern Johnston Strait, and is a useful tool to monitor negative aspects of salmon growth in the ocean.

Response of the insulin-like growth factor-1 (Igf1) system to nutritional status and growth rate variation in olive rockfish (Sebastes serranoides).

Growth performance in vertebrates is regulated by environmental factors including the quality and quantity of food, which influence growth via endocrine pathways such as the growth hormone (GH)/insulin-like growth factor somatotropic axis. In several teleost fishes, circulating concentrations of insulin-like growth factor-1 (Igf1) correlate positively with growth rate, and it has been proposed that plasma Igf1 levels may serve as an indicator of growth variation for fisheries and aquaculture applications. This study tested whether plasma Igf1 concentrations might serve as an indicator of somatic growth in olive rockfish (Sebastes serranoides), one species among dozens of rockfishes important to commercial and recreational fisheries in the Northern Pacific Ocean. Juvenile olive rockfish were reared under food ration treatments of 1% or 4% wet mass per d for 98 d to experimentally generate variation in growth. Juvenile rockfish in the 4% ration grew 60% more quickly in mass and 22% faster in length than fish in the 1% ration. Plasma Igf1 levels were elevated in rockfish under the 4% ration, and individual Igf1 levels correlated positively with growth rate, as well as with individual variation in hepatic igf1 mRNA levels. Transcripts encoding the Igf binding proteins (Igfbps) igfbp1a and igfbp1b were also at higher abundance in the liver of rockfish in the 1% ration treatment, while mRNAs for igfbp5a and igfbp5b were elevated in the skeletal muscle of 4% ration fish. These findings support the use of plasma Igf1 as a physiological index of growth rate variation in rockfish.

Growth and endocrine effect of growth hormone transgene dosage in diploid and triploid coho salmon.

Growth-hormone transgene dosage, polyploidy, and parental effects on growth and endocrine responses have been assessed in coho salmon. Diploid fry with one or two transgene doses grew equally, whereas later-stage juvenile homozygotes grew faster than hemizygotes. In contrast, homozygotes and hemizygotes grew equally after smoltification, both in sea water and fresh water. Triploid transgenic salmon showed impaired growth which could not be fully overcome with additional transgene copies. Levels of muscle GH mRNA were elevated in two vs. one transgene dose diploids, but in triploids, a dosage effect was observed in muscle but not for animals carrying three transgene doses. IGF-I mRNA levels were elevated in transgenic vs. non-transgenic animals, but a dosage effect was not observed. Diploids and triploids with two transgenes had higher plasma GH levels than one-dose animals, but three-dose triploids showed no further elevation. Circulating IGF-I levels also showed a dosage effect in diploids, but not among any transgene doses in triploids. The present study reveals complex interactions among transgene dosage, maternal effects, developmental stage, and ploidy on growth and endocrine parameters in GH transgenic coho salmon. Specifically, GH transgenes do not always express nor have effects on growth that are directly correlated with the number of transgenes. Further, the reduced growth rate seen in triploid transgenic animals could not be fully overcome by increasing transgene dosage. The findings have relevance for understanding growth physiology, transgene function, and for environmental risk assessments that require understanding phenotypes of hemizygous vs. homozygous transgenic animals in populations.

Development of a multiplex gene expression assay for components of the endocrine growth axis in coho salmon.

This study explores the efficacy of the Quantigene plex (QGP) technology for measuring a panel of endocrine growth-related transcripts in coho salmon, Oncorhynchus kisutch. The QGP technology permits the simultaneous quantification of multiple targeted mRNAs within a single tissue homogenate using sequence-specific probes and requires no reverse transcription (RT) or amplification as is required for RT-quantitative PCR (RT-qPCR). Using liver homogenates from coho salmon under fed and fasted conditions, we compared the detectable fold differences of steady-state mRNA levels between the QGP and probe-based RT-qPCR assays for insulin-like growth factors (igf1 and igf2), insulin-like growth factor binding proteins (igfbp1b, igfbp2a, and igfbp2b), somatolactin receptor (slr), and growth hormone receptors (ghr1 and ghr2). Significant, positive correlations for all genes between the two assays were found. In addition, the relatively low variance of results from the QGP assay suggests that this is a suitable method for a comprehensive analysis of endocrine growth-related transcripts and could potentially be used to develop assays for other gene networks in teleosts.

A correlation between seasonally changing photoperiod, whole body lipid, and condition factor in juvenile spring Chinook salmon (Oncorhynchus tshawytscha).

The regulation of lipid stores is a central process for the physiology and ecology of fishes. Seasonal variation in lipid stores has been directly linked to survival of fishes across periods of food deprivation. We assessed whether a seasonally changing photoperiod was correlated to seasonal changes in energetic status to help better understand these important processes. Groups of first feeding Chinook salmon fry were introduced to a seasonal photoperiod cycle, but the point of entrance into the seasonal cycle varied from near the winter solstice (December), to either side of the spring equinox (February & May). Temperature and feeding rate were similar for all treatments. Subsequently, condition factor and whole body lipid content were assessed through a seasonal progression. Throughout most of the experiment, length and weight did not differ between the different photoperiod treatments, however whole body lipid and Fulton's condition factor did. Furthermore, changes in both whole body lipid and Fulton's condition factor in all treatment groups followed a similar seasonal pattern that was inversely related to day length (highest K and lipid levels found during days with the least light). These results suggest that regardless of age or size, there is a correlation between seasonal changes in photoperiod and changes in body composition in juvenile Chinook salmonids.

Creation of iPSC line NCHi004-A from a patient with down syndrome and congenital heart defects.

Down syndrome is a congenital disorder resulting from an extra full or partial chromosome 21, which is characterized by a spectrum of systemic developmental abnormalities, including those affecting the cardiovascular system. Here, we generated an iPSC line from peripheral blood mononuclear cells of a male adolescent with Down syndrome-associated congenital heart defects through Sendai virus-mediated transfection of 4 Yamanaka factors. This line exhibited normal morphology, expressed pluripotency markers, trisomy 21 karyotype, and could be differentiated into three germ layers. This iPSC line can be used for studying cellular and developmental etiologies of congenital heart defects induced by aneuploidy of chromosome 21.

Nutritional status affects Igf1 regulation of skeletal muscle myogenesis, myostatin, and myofibrillar protein degradation pathways in gopher rockfish (Sebastes carnatus).

Insulin-like growth factor-1 (Igf1) regulates skeletal muscle growth in fishes by increasing protein synthesis and promoting muscle hypertrophy. When fish experience periods of insufficient food intake, they undergo slower muscle growth or even muscle wasting, and those changes emerge in part from nutritional modulation of Igf1 signaling. Here, we examined how food deprivation (fasting) affects Igf1 regulation of liver and skeletal muscle gene expression in gopher rockfish (Sebastes carnatus), a nearshore rockfish of importance for commercial and recreational fisheries in the northeastern Pacific Ocean, to understand how food limitation impacts Igf regulation of muscle growth pathways. Rockfish were either fed or fasted for 14 d, after which a subset of fish from each group was treated with recombinant Igf1 from sea bream (Sparus aurata). Fish that were fasted lost body mass and had lower body condition, reduced hepatosomatic index, and lower plasma Igf1 concentrations, as well as a decreased abundance of igf1 gene transcripts in the liver, increased hepatic mRNAs for Igf binding proteins igfbp1a, igfbp1b, and igfbp3a, and decreased mRNA abundances for igfbp2b and a putative Igf acid labile subunit (igfals) gene. In skeletal muscle, fasted fish showed a reduced abundance of intramuscular igf1 mRNAs but elevated gene transcripts encoding Igf1 receptors A (igf1ra) and B (igf1rb), which also showed downregulation by Igf1. Fasting increased skeletal muscle mRNAs for myogenin and myostatin1, as well as ubiquitin ligase F-box only protein 32 (fbxo32) and muscle RING-finger protein-1 (murf1) genes involved in muscle atrophy, while concurrently downregulating mRNAs for myoblast determination protein 2 (myod2), myostatin2, and myogenic factors 5 (myf5) and 6 (myf6 encoding Mrf4). Treatment with Igf1 downregulated muscle myostatin1 and fbxo32 under both feeding conditions, but showed feeding-dependent effects on murf1, myf5, and myf6/Mrf4 gene expression indicating that Igf1 effects on muscle growth and atrophy pathways is contingent on recent food consumption experience.

Normalizing for biology: accounting for technical and biological variation in levels of reference gene and insulin-like growth factor 1 (igf1) transcripts in fish livers.

Feeding, fasting and re-feeding is a common experimental paradigm for studying growth endocrinology. Herein we demonstrate dynamic changes in the livers of coho salmon under these conditions and how changes in liver composition can influence quantification and interpretation of liver gene expression data. A three-week fast resulted in decreases in hepatosomatic index (liver size), liver glycogen content, and liver DNA concentration. In addition, significant differences were found in liver transcript levels from fed and fasted fish for the reference genes, arp and ef1a, when these were normalized to total RNA. We took the additional step of normalizing reference gene transcript levels to the liver homogenate RNA/DNA ratio to account for differences in RNA yield/cell and the number of cells sampled, normalizing to transcript number per cell rather than transcript number per unit RNA. After this additional step no significant differences in liver transcript levels of reference genes were found. The significance of these results was illustrated by normalizing liver transcript levels of insulin-like growth factor 1 (igf1) to ef1a transcript levels or ef1a transcript levels by RNA/DNA. The different normalization strategies resulted in differing patterns of change in igf1 transcript levels between fed and fasted fish. The novelty of this work rests in a two-step normalization process, attempting to account for both 1) technical errors in reverse transcription and qPCR reactions, and 2) biological variance in liver samples.

Utility of Follow-Up Echocardiograms in Uncomplicated PDA Device Closures Performed After Infancy.

INTRODUCTION: Guidelines recommend lifelong follow-up with transthoracic echocardiograms (TTE) for patients who had a patent ductus arteriosus (PDA) device closure via catheterization. The goal of this study was to determine the utility of follow-up TTE in patients who underwent an uncomplicated PDA device closure after infancy. METHODS: Chart review was performed on patients who had a PDA closure ≥ 1 year of age between 1/1/2002 and 6/1/2020. Patients were excluded if they had other congenital heart disease, did not have a follow-up TTE ≥ 6 months after procedure, had a residual PDA or velocity > 2.0 m/s in the left pulmonary artery (LPA) or descending aorta (DAo) on the first TTE ≥ 6 months after device placement. Time points included the initial TTE after the procedure, first TTE ≥ 6 months after procedure, and the most recent TTE. RESULTS: A total of 189 patients met the study criteria. The median age and weight at initial procedure were 2.7 (1.0-64.7) years and 12.5 (3.4-69.2) kg. Most recent TTE was performed 2.0 (0.4-17.0) years after PDA closure. There were no significant differences in fractional shortening (36.4 ± 5.0% vs. 36.9 ± 5.6%) or LPA velocity (1.1 ± 0.4 m/s vs. 1.1 ± 0.4 m/s) from initial to most recent TTE, respectively. Left ventricular internal diastolic diameter Z-score significantly decreased (1.4 ± 1.8 vs. - 0.01 ± 1.2, p < 0.01) and DAo peak velocity significantly increased (1.2 ± 0.3 m/s vs. 1.3 ± 0.3 m/s, p = 0.02) from initial to most recent TTE, respectively. No patient died or underwent an intervention on the LPA or DAo for stenosis. Seventy-five patients had a total of 208 repeat TTE > 1 year after PDA procedure with no change in clinical management. CONCLUSIONS: In patients who underwent an uncomplicated PDA closure after infancy, TTE parameters improved or stayed within normal limits on the most recent TTE. Repeat lifetime TTEs after 1-year post-device placement in this population may not necessarily be needed if there are no clinical concerns.

Utility of Follow-Up Echocardiograms in Uncomplicated PDA Device Closures Performed During Infancy.

INTRODUCTION: Guidelines recommend lifelong follow-up with transthoracic echocardiograms (TTE) for patients who had a patent ductus arteriosus (PDA) device closure via catheterization. The goal of this study was to determine the utility of follow-up TTE in patients who underwent an uncomplicated PDA device closure during infancy. METHODS: Chart review was performed on patients who had a PDA closure at not more than 1 year of age between January 1, 2002 and June 1, 2020. Patients were excluded if they had other congenital heart disease, did not have a follow-up TTE at least 3 months after procedure, or had a velocity greater than 2.0 m/s in the left pulmonary artery (LPA) or descending aorta (DAo) on the first TTE at least 3 months after device placement. Time points included the first TTE after the procedure, first TTE at least 3 months after procedure, and the most recent TTE. RESULTS: Total of 147 infants met the inclusion criteria. Age and weight at initial procedure were 141 ± 217 days and 4.2 ± 2.8 kg. There was no significant difference in DAo velocity between initial and most recent TTE. LPA velocity and left ventricular diastolic Z score significantly decreased between initial and most recent TTE. Seventy-eight patients had repeat echocardiograms more than 1 year after PDA procedure with no change in clinical management. No patient underwent an intervention on the LPA or DAo for stenosis. CONCLUSION: In patients who underwent an uncomplicated PDA closure during infancy, TTE parameters either stayed stable or improved over time. These findings need to be corroborated in larger studies with longer follow-up. If verified, the long-term TTE guidelines may need to be simplified for this patient population.

Data-driven computational models of ventricular-arterial hemodynamics in pediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a complex disease involving increased resistance in the pulmonary arteries and subsequent right ventricular (RV) remodeling. Ventricular-arterial interactions are fundamental to PAH pathophysiology but are rarely captured in computational models. It is important to identify metrics that capture and quantify these interactions to inform our understanding of this disease as well as potentially facilitate patient stratification. Towards this end, we developed and calibrated two multi-scale high-resolution closed-loop computational models using open-source software: a high-resolution arterial model implemented using CRIMSON, and a high-resolution ventricular model implemented using FEniCS. Models were constructed with clinical data including non-invasive imaging and invasive hemodynamic measurements from a cohort of pediatric PAH patients. A contribution of this work is the discussion of inconsistencies in anatomical and hemodynamic data routinely acquired in PAH patients. We proposed and implemented strategies to mitigate these inconsistencies, and subsequently use this data to inform and calibrate computational models of the ventricles and large arteries. Computational models based on adjusted clinical data were calibrated until the simulated results for the high-resolution arterial models matched within 10% of adjusted data consisting of pressure and flow, whereas the high-resolution ventricular models were calibrated until simulation results matched adjusted data of volume and pressure waveforms within 10%. A statistical analysis was performed to correlate numerous data-derived and model-derived metrics with clinically assessed disease severity. Several model-derived metrics were strongly correlated with clinically assessed disease severity, suggesting that computational models may aid in assessing PAH severity.

Perspectives on concordant and discordant relations between insulin-like growth factor 1 (IGF1) and growth in fishes.

Many physiological processes are modulated by the endocrine system, including growth. Insulin-like growth factor 1 is one of the primary hormones involved in growth regulation in vertebrates, including fishes. Current work on IGF1 in fishes is driven both by a desire to better understand mechanisms of growth as well as to develop a reliable index of growth rate. A review of studies relating IGF1 to growth broadly reveals positive and significant relations between IGF1 and growth; however, relations found in individual studies range from no correlation to highly significant correlations. Potential sources for this variation include both biological and methodological issues and range from differences in how growth is defined (changes in length or weight), the duration of growth assessed (weeks to months) and how growth is calculated (total change, rate, percent change); yet, these methodological concerns cannot account for all the variation found. A further review of the literature reveals a number of physiological conditions and environmental factors that might influence IGF1 level and the subsequent relation of that IGF1 level to growth rate. The term concordance is introduced to categorize factors that influence IGF1 and growth in a similar fashion, such that positive and significant relations between IGF1 and growth are maintained even though the factor stimulates changes in IGF1 level. Conversely, the term discordance is introduced to categorize factors that stimulate changes in the relations between IGF1 and growth, such that IGF1 is not an efficacious index of growth for both pre and post-stimulus fish combined. IGF1 and growth relations generally remain concordant after changes in nutrition (consumption rate or diet). Differences in IGF1 level of juvenile, maturing male and maturing female fish are common and IGF1-growth relations appear discordant between these groups. Acute changes in temperature and salinity induce discordant relations between IGF1 and growth but acclimation to persistent differences in environmental condition generally result in concordant relations. Overall, by discriminating between fish of differing physiological status and discerning and categorizing differences among environments one may effectively use IGF1 as a growth index for fishes.

Rheumatic Heart Disease in the United States: Forgotten But Not Gone: Results of a 10 Year Multicenter Review.

Background Recent evaluation of rheumatic heart disease (RHD) mortality demonstrates disproportionate disease burden within the United States. However, there are few contemporary data on US children living with acute rheumatic fever (ARF) and RHD. Methods and Results Twenty-two US pediatric institutions participated in a 10-year review (2008-2018) of electronic medical records and echocardiographic databases of children 4 to 17 years diagnosed with ARF/RHD to determine demographics, diagnosis, and management. Geocoding was used to determine a census tract-based socioeconomic deprivation index. Descriptive statistics of patient characteristics and regression analysis of RHD classification, disease severity, and initial antibiotic prescription according to community deprivation were obtained. Data for 947 cases showed median age at diagnosis of 9 years; 51% and 56% identified as male and non-White, respectively. Most (89%) had health insurance and were first diagnosed in the United States (82%). Only 13% reported travel to an endemic region before diagnosis. Although 96% of patients were prescribed secondary prophylaxis, only 58% were prescribed intramuscular benzathine penicillin G. Higher deprivation was associated with increasing disease severity (odds ratio, 1.25; 95% CI, 1.08-1.46). Conclusions The majority of recent US cases of ARF and RHD are endemic rather than the result of foreign exposure. Children who live in more deprived communities are at risk for more severe disease. This study demonstrates a need to improve guideline-based treatment for ARF/RHD with respect to secondary prophylaxis and to increase research efforts to better understand ARF and RHD in the United States.

Changes in the plasma levels of insulin-like growth factor-I from the onset of spawning migration through upstream migration in chum salmon.

An increase in activity of the pituitary-gonadal axis (PG-axis) and gonadal development are essential for the onset of spawning migration of chum salmon from the Bering Sea. In the Bering Sea, fish with larger body sizes initiated gonadal development and commenced spawning migration to the natal river by the end of summer. We thus hypothesized that insulin-like growth factor-I (IGF-I), a somatotropic signal that interacts with the PG-axis, can be one of such factors responsible for the onset of migration, and examined changes in plasma levels and hepatic expression of IGF-I gene in oceanic and homing chum salmon in 2001-2003. The plasma IGF-I levels and corresponding body sizes in maturing adults, which had developing gonads, were significantly higher than those in immature fish in all years examined. Such increase in the plasma IGF-I levels in maturing fish was observed even in the Gulf of Alaska during February 2006, while coincident increase was not observed in the hepatic amounts of IGF-I mRNA. In autumn, the plasma IGF-I levels in homing adults decreased during upstream migration in the Ishikari River-Ishikari bay water system in Hokkaido, Japan. In conclusion, the plasma IGF-I levels increased with gonadal development when chum salmon migrated from the winter Gulf of Alaska to the summer Bering Sea. Circulating IGF-I may interact with the PG-axis and promote gonadal development that is inseparable from the onset of spawning migration. Circulating IGF-I levels were thereafter lowered in accordance with final maturation during upstream migration in the breeding season.

Postprandial changes in plasma growth hormone, insulin, insulin-like growth factor (IGF)-I, and IGF-binding proteins in coho salmon fasted for varying periods.

We examined postprandial changes in circulating growth hormone (GH), insulin, insulin-like growth factor (IGF)-I, and IGF-binding proteins (IGFBPs) in yearling coho salmon under different feeding regimes. Fish were initially fasted for 1 day, 1 wk, or 3 wk. Fasted fish were then fed, and blood was collected at 4-h intervals over 26 h. After the various periods of fasting, basal levels of insulin were relatively constant, whereas those of IGF-I, IGFBPs and GH changed in proportion to the duration of the fast. A single meal caused a rapid, large increase in the circulating insulin levels, but the degree of the increase was influenced by the fasting period. IGF-I showed a moderate increase 2 h after the meal but only in the regularly fed fish. Plasma levels of 41-kDa IGFBP were increased in all groups within 6 h after the single meal. The fasting period did not influence the response of 41-kDa IGFBP to the meal. IGFBP-1 and GH decreased after the meal to the same extent among groups regardless of the fasting period. The present study shows that insulin and IGF-I respond differently to long (weeks)- and short (hours)-term nutritional changes in salmon; insulin maintains its basal level but changes acutely in response to food intake, whereas IGF-I adjusts its basal levels to the long-term nutritional status and is less responsive to acute nutritional input. IGFBPs maintain their sensitivity to food intake, even after prolonged fasting, suggesting their critical role in the nutritional regulation of salmon growth.