Diastolic Blood Pressure Alleles Improve Congenital Heart Defect Repair Outcomes.

BACKGROUND: Congenital heart defects (CHDs) affect 40 000 US births per year, half of which require surgical intervention. Individual differences in surgical outcomes including mortality and complications are not well understood but may be due to genetic variability. We hypothesized that polygenic risk scores (PRSs) for blood pressure in adults are associated with treatments and postsurgical outcomes in children with CHD, as CHD survivors are at higher risk of negative cardiometabolic disease. METHODS: We used imputed genotype data from pediatric participants requiring surgery for CHD (median age at surgery, 201 days; nmax=2498). Base data for the systolic and diastolic blood pressure PRSs (nmax=760 226) came from published genome-wide association study. The blood pressure PRSs were tested for association with postsurgical outcomes. All effects presented are per SD increase in PRS and adjusted for age, sex, body mass index, surgical complexity score, and first 10 principal components of ancestry. RESULTS: A higher diastolic blood pressure PRS was associated with decreased in-hospital mortality risk (odds ratio, 0.57 [0.39-0.82]; P=0.0022). Additional analyses suggest an interaction between diastolic blood pressure PRS and vasopressor dose. Those with a diastolic blood pressure PRS 1 SD above the mean, receiving a vasopressor dose in the top tertile, were estimated to have 52% (32%-66%) lower risk of in-hospital mortality compared with those with a vasopressor dose in the bottom tertile. CONCLUSIONS: These results suggest a genetically determined postsurgical survival advantage for CHD patients with blood pressure increasing alleles. Further study may reveal novel mechanisms contributing to postoperative morbidity and mortality, and this approach may assist in early identification of children at risk for adverse postoperative outcomes.

Explant of an infected, endo-trashed IVC filter in an immunosuppressed patient with chronically occluded iliocaval stents.

BACKGROUND: In the absence of a contiguous bowel perforation or intraabdominal source, infection of a retained vena cava filter in an occluded IVC has never been described. OBJECTIVE: To describe a case of an infected IVC filter in a chronically occluded iliocaval segment. METHODS: Here we present a case of an immunosuppressed 35-year-old female with chronically occluded iliocaval stents and an extensive staphylococcus hominis infection of a previously endo-trashed Bard Eclipse® filter. Particular attention is paid to supportive imaging in establishing the diagnosis and technical aspects of successful device explant and retroperitoneal debridement. RESULTS: At 6 months postoperatively, the patient was doing well without evidence of recurrent infection. Her lower extremity edema was controlled with compression alone. CONCLUSIONS: The main objective of this operation was source control with debridement of the infection and removal of the filter and as much of the iliac vein as safely possible. Superinfection of a previously placed iliocaval stents and inferior vena cava filter remains a concern in patients with retroperitoneal infection and chronic iliocaval occlusion. Operative explant and debridement can be safely performed in patients with favorable cardiopulmonary risk.

Cryptic community structure and metabolic interactions among the heritable facultative symbionts of the pea aphid.

Most insects harbour influential, yet non-essential heritable microbes in their hemocoel. Communities of these symbionts exhibit low diversity. But their frequent multi-species nature raises intriguing questions on roles for symbiont-symbiont synergies in host adaptation, and on the stability of the symbiont communities, themselves. In this study, we build on knowledge of species-defined symbiont community structure across US populations of the pea aphid, Acyrthosiphon pisum. Through extensive symbiont genotyping, we show that pea aphids' microbiomes can be more precisely defined at the symbiont strain level, with strain variability shaping five out of nine previously reported co-infection trends. Field data provide a mixture of evidence for synergistic fitness effects and symbiont hitchhiking, revealing causes and consequences of these co-infection trends. To test whether within-host metabolic interactions predict common versus rare strain-defined communities, we leveraged the high relatedness of our dominant, community-defined symbiont strains vs. 12 pea aphid-derived Gammaproteobacteria with sequenced genomes. Genomic inference, using metabolic complementarity indices, revealed high potential for cooperation among one pair of symbionts-Serratia symbiotica and Rickettsiella viridis. Applying the expansion network algorithm, through additional use of pea aphid and obligate Buchnera symbiont genomes, Serratia and Rickettsiella emerged as the only symbiont community requiring both parties to expand holobiont metabolism. Through their joint expansion of the biotin biosynthesis pathway, these symbionts may span missing gaps, creating a multi-party mutualism within their nutrient-limited, phloem-feeding hosts. Recent, complementary gene inactivation, within the biotin pathways of Serratia and Rickettsiella, raises further questions on the origins of mutualisms and host-symbiont interdependencies.

A Novel Technique and Outcomes for Transcaval Endoleak Embolization.

BACKGROUND: Strategies for embolization of type 2 endoleaks include translumbar, transgraft, transarterial, and transcaval approaches. The transcaval approach is limited by an inconsistent ability to access the aortic sac and the risk of puncturing and damaging the endograft or adjacent structures. We describe a novel technique for caval to aortic aneurysm sac access and report early outcomes. METHODS: A retrospective review of all patients who underwent transcaval embolization (TCE) at a tertiary referral center. From March 2019 to June 2021, 12 patients were identified to have undergone a novel approach to transcaval aortic sac access using a 0.014″ heavy weight tip wire guide and continuous current electrocautery to create the connection between the inferior vena cava and aortic aneurysm sac. The endoleak outflow vessel is then selectively embolized with coils or liquid embolic agents. When selective embolization was not possible, the aneurysm sac was instilled with liquid embolic agents to induce thrombosis. RESULTS: Twelve patients underwent transcaval embolization using this method over the 3-year period. The average patient age was 79.2 ± 6.2 years and 10/12 (83.3%) were male. A high rate of comorbidities was noted in the cohort. Transcaval access into the aortic sac was achieved in all patients, while selective cannulation of outflow vessels was accomplished in 2/12 (16%) target vessels. Of these, both cases had vessels embolized using detachable coils and liquid embolic agents. Nonselective embolization was performed using liquid embolic and thrombotic agents in the other 10/12 cases. There was one perioperative complication of minor bleeding (1/12, 8.3%). Two patients were observed in intensive care unit for back pain. A persistent endoleak was identified on postoperative imaging performed at 30 days in 4/12 (33.3%) patients. Sac enlargement > 5 mm following TCE was observed in 3/12 (25%) patients. Three patients underwent open conversion with endovascular aneurysm repair explant. One patient was explanted at 1 month after failure to embolize the endoleak flow channel using TCE. A second was explanted for persistent endoleak found to be a Type IIIb with aortic diameter growth > 5 mm at 15-month follow-up. The third explant was performed for aortic sac infection at 4 months postprocedure without endoleak. CONCLUSIONS: TCE is an adjunctive technique to treat endoleaks in patients who have either failed transarterial or translumbar access. An electrified 0.014″ chronic total occlusion wire technique for transcaval access to the aortic sac for endoleak embolization can be successful in all cases without significant acute morbidity or mortality. The transcaval approach is still limited by ability to steer catheters and microcatheters into the outflow vessels with a resultant persistent endoleak and eventual need for explant.

Hypogastric artery luminal diameter predicts common-external iliac stent patency and major adverse limb events in patients with aortoiliac occlusive disease.

OBJECTIVE: Hypogastric coverage may be required for occlusive disease at the iliac arterial bifurcation. In this study, we sought to determine patency rates of common-external iliac artery (C-EIA) bare metal stents (BMS) spanning the hypogastric origin in patients with aortoiliac occlusive disease (AIOD). In addition, we sought to identify predictors of C-EIA BMS patency loss and major adverse limb events (MALE) in patients requiring hypogastric coverage. We hypothesized that worsening stenosis of the hypogastric origin would negatively influence C-EIA stent patency and freedom from MALE. METHODS: This is a single center, retrospective review of consecutive patients undergoing elective, endovascular treatment of aortoiliac disease (AIOD) between 2010 and 2018. Only patients with C-EIA BMS coverage of a patent IIA origin were included in the study. Hypogastric luminal diameter was determined from preoperative CT angiography. Analysis was performed using Kaplan-Meier survival analysis, univariable and multivariable logistic regression, and receiver operator characteristics (ROC). RESULTS: There were 236 patients (318 limbs) who were included in the study. AIOD was TASC C/D in 236/318 (74.2%) of cases. C-EIA stent primary patency was 86.5% (95% confidence interval: 81.1, 91.9) at 2 years and 79.7% (72.8, 86.7) at 4 years. Freedom from ipsilateral MALE was 77.0% (71.1, 82.9) at 2 years and 68.7% (61.3, 76.2) at 4 years. Luminal diameter of the hypogastric origin was most strongly associated with loss of C-EIA BMS primary patency in multivariable analysis (hazard ratio: 0.81, p = .02). Insulin-dependent diabetes, Rutherford's class IV or above, and stenosis of the hypogastric origin were significantly predictive of MALE in both univariable and multivariable analyses. In ROC analysis, luminal diameter of the hypogastric origin was superior to chance in prediction of C-EIA primary patency loss and MALE. Hypogastric diameter >4.5 mm had a negative predictive value of 0.94 for C-EIA primary patency loss and 0.83 for MALE. CONCLUSIONS: Patency rates of C-EIA BMS are high. Hypogastric luminal diameter is an important and potentially modifiable predictor of C-EIA BMS patency and MALE in patients with AIOD.

Activation of the cytosolic calcium-independent phospholipase A2 ß isoform contributes to TRPC6 externalization via release of arachidonic acid.

During vascular interventions, oxidized low-density lipoprotein and lysophosphatidylcholine (lysoPC) accumulate at the site of arterial injury, inhibiting endothelial cell (EC) migration and arterial healing. LysoPC activates canonical transient receptor potential 6 (TRPC6) channels, leading to a prolonged increase in intracellular calcium ion concentration that inhibits EC migration. However, an initial increase in intracellular calcium ion concentration is required to activate TRPC6, and this mechanism remains elusive. We hypothesized that lysoPC activates the lipid-cleaving enzyme phospholipase A2 (PLA2), which releases arachidonic acid (AA) from the cellular membrane to open arachidonate-regulated calcium channels, allowing calcium influx that promotes externalization and activation of TRPC6 channels. The focus of this study was to identify the roles of calcium-dependent and/or calcium-independent PLA2 in lysoPC-induced TRPC6 externalization. We show that lysoPC induced PLA2 enzymatic activity and caused AA release in bovine aortic ECs. To identify the specific subgroup and the isoform(s) of PLA2 involved in lysoPC-induced TRPC6 activation, transient knockdown studies were performed in the human endothelial cell line EA.hy926 using siRNA to inhibit the expression of genes encoding cPLA2α, cPLA2γ, iPLA2ß, or iPLA2γ. Downregulation of the ß isoform of iPLA2 blocked lysoPC-induced release of AA from EC membranes and TRPC6 externalization, as well as preserved EC migration in the presence of lysoPC. We propose that blocking TRPC6 activation and promoting endothelial healing could improve the outcomes for patients undergoing cardiovascular interventions.

Comparison of Aortobifemoral Bypass to Aortoiliac Stenting with Bifurcation Reconstruction for TASC II D Aortoiliac Occlusive Disease.

BACKGROUND: Long-segment stenting of the infrarenal aorta and bilateral iliac arteries, with or without femoral endarterectomy for diffuse disease, has been adopted for treatment of severe aortoiliac occlusive disease (AIOD). The objective of this study was to compare outcomes of this reconstruction, termed aortoiliac stenting with bifurcation reconstruction (AISBR), to aortobifemoral bypass (ABF) in patients with comparable TASC II D lesions. METHODS: This is a single-center, retrospective review of patients treated with ABF or AISBR for comparable TASC II D lesions between 2010 and 2018. ABF patients were included only if they were deemed anatomic candidates also for AISBR after review of preoperative imaging. Patients treated for acute limb ischemia and bypass graft infection were excluded. Statistics included Fisher exact test, Kaplan-Meier analysis, and Cox proportional hazards regression. RESULTS: There were 24 ABF and 75 AISBR included in the study. The primary indication for treatment was claudication in 55 (55.6%) patients, rest pain in 28 (28.3%), and tissue loss in 16 (16.2%). Patients undergoing AISBR were more likely to be female. Femoral endarterectomies were performed in 37/75 (49.3%) AISBR and 14/24 (58.3%) ABF (P = 0.44). AISBR were performed percutaneously in 34/75 (45.1%). No AISBR required conversion to ABF. Intraoperative blood loss, procedure time and hospital length of stay (LOS) were significantly less for AISBR compared to ABF. Surgical site infections (SSI) were less common in patients undergoing AISBR (AISBR: 6/75 (8.0%) vs. ABF: 9/24 (37.5%), (P< 0.01). One AISBR and two 2 ABF developed late SSI >30 days postoperatively. The reductions in blood loss, LOS and SSI remained significant after excluding percutaneous AISBR from the analysis. Five-year primary patency was 50.8% (95% CI: 33.3, 68.4%) for AISBR and 88.1% (72.7, 100.0%) for ABF (P= 0.04). Five-year survival was 76.5% (95% CI: 63.6, 89.5) for AISBR and 100% (95% CI: 100.0, 100.0) for ABF (P = 0.07). Five-year primary assisted patency, secondary patency, freedom from reintervention and major adverse limb events did not differ significantly between groups. CONCLUSIONS: AISBR is a viable option for management of TASC II D AIOD, with lower morbidity and acceptable durability when compared to traditional ABF.

Impact of obesity on post-operative arrhythmias after congenital heart surgery in children and young adults.

BACKGROUND: Obesity increases the risk of post-operative arrhythmias in adults undergoing cardiac surgery, but little is known regarding the impact of obesity on post-operative arrhythmias after CHD surgery. METHODS: Patients undergoing CHD surgery from 2007 to 2019 were prospectively enrolled in the parent study. Telemetry was assessed daily, with documentation of all arrhythmias. Patients aged 2-20 years were categorised by body mass index percentile for age and sex (underweight <5, normal 5-85, overweight 85-95, and obese >95). Patients aged >20 years were categorised using absolute body mass index. We investigated the impact of body mass index category on arrhythmias using univariate and multivariate analysis. RESULTS: There were 1250 operative cases: 12% underweight, 65% normal weight, 12% overweight, and 11% obese. Post-operative arrhythmias were observed in 38%. Body mass index was significantly higher in those with arrhythmias (18.8 versus 17.8, p = 0.003). There was a linear relationship between body mass index category and incidence of arrhythmias: underweight 33%, normal 38%, overweight 42%, and obese 45% (p = 0.017 for trend). In multivariate analysis, body mass index category was independently associated with post-operative arrhythmias (p = 0.021), with odds ratio 1.64 in obese patients as compared to normal-weight patients (p = 0.036). In addition, aortic cross-clamp time (OR 1.007, p = 0.002) and maximal vasoactive-inotropic score in the first 48 hours (OR 1.03, p = 0.04) were associated with post-operative arrhythmias. CONCLUSION: Body mass index is independently associated with incidence of post-operative arrhythmias in children after CHD surgery.

Inhibition of P110α and P110δ catalytic subunits of PI3 kinase reverses impaired arterial healing after injury in hypercholesterolemic male mice.

Endothelial cell (EC) migration is critical for healing arterial injuries, such as those that occur with angioplasty. Impaired re-endothelialization following arterial injury contributes to vessel thrombogenicity, intimal hyperplasia, and restenosis. Oxidized lipid products, including lysophosphatidylcholine (lysoPC), induce canonical transient receptor potential 6 (TRPC6) externalization leading to increased [Ca2+]i, activation of calpains, and alterations of the EC cytoskeletal structure that inhibit migration. The p110α and p110δ catalytic subunit isoforms of phosphatidylinositol 3-kinase (PI3K) regulate lysoPC-induced TRPC6 externalization in vitro. The goal of this study was to assess the in vivo relevance of those in vitro findings to arterial healing following a denuding injury in hypercholesterolemic mice treated with pharmacologic inhibitors of the p110α and p110δ isoforms of PI3K and a general PI3K inhibitor. Pharmacologic inhibition of the p110α or the p110δ isoform of PI3K partially preserves healing in hypercholesterolemic male mice, similar to a general PI3K inhibitor. Interestingly, the p110α, p110δ, and the general PI3K inhibitor do not improve arterial healing after injury in hypercholesterolemic female mice. These results indicate a potential new role for isoform-specific PI3K inhibitors in male patients following arterial injury/intervention. The results also identify significant sex differences in the response to PI3K inhibition in the cardiovascular system, where female sex generally has a cardioprotective effect. This study provides a foundation to investigate the mechanism for the sex differences in response to PI3K inhibition to develop a more generally applicable treatment option.

P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization.

Lipid oxidation products, including lysophosphatidylcholine (lysoPC) inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo, in part by activating phosphatidylinositol 3-kinase (PI3K), which increases the externalization of canonical transient receptor potential 6 (TRPC6) channels and the subsequent increase in intracellular calcium. Inhibition of PI3K is a potential method to decrease TRPC6 activation and restore migration, but PI3K is involved in multiple intracellular signaling pathways and has multiple downstream effectors. The goal of this study is to identify the specific p110 catalytic subunit isoforms responsible for lysoPC-induced TRPC6 externalization to identify a target for intervention while minimizing impact on alternative signaling pathways. Down-regulation of the p110α and p110δ isoforms, but not the p110ß or p110γ isoforms, with small interfering RNA significantly decreased phosphatidylinositol (3,4,5)-trisphosphate production and TRPC6 externalization, and significantly improved EC migration in the presence of lysoPC. These results identify an additional role of p110α in EC and reveal for the first time a specific role of p110δ in EC, providing a foundation for subsequent in vivo studies to investigate the impact of p110 isoform inhibition on arterial healing after injury.

Utilization of ICU Rehabilitation Services in Pediatric Patients With a Prolonged ICU Stay.

OBJECTIVES: To describe rehabilitation practice patterns among critically ill children with prolonged ICU stays and explore the association between institution-level utilization of rehabilitative services and patient outcomes. DESIGN: Retrospective cohort study using an administrative database of inpatient clinical and resource utilization data from participating pediatric hospitals in the United States. Center-level utilization of physical therapy and occupational therapy among critically ill patients was used to divide hospitals by quartile into high utilization centers or standard utilization centers. SETTING: Fifty-one pediatric hospitals in the United States. PATIENTS: Critically ill pediatric patients with prolonged critical illness (defined as an ICU length of stay of at least 7 d) discharged from July 2016 to June 2017. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Seventeen thousand four hundred seventy encounters met criteria for study inclusion. Of those, 6,040 (35%) were not charged for either physical therapy or occupational therapy services. There was wide variability in center-level utilization of rehabilitative services while in the ICU, ranging from 81% utilization of physical therapy or occupational therapy services among high utilization centers to 46% utilization among centers within the lowest quartile. In univariate analyses, children cared for at an high utilization center were less likely to require discharge to an inpatient rehabilitation facility (1.7% vs 3.5%; p < 0.001) and less likely to incur a new pressure injury (2.2% vs 3.1%; p = 0.001). In multivariable analyses, the direction and magnitude of effects remained similar, although the effect was no longer statistically significant (discharge to inpatient rehabilitation facility: odds ratio, 0.64; 95% CI, 0.18-2.26; pressure injury: odds ratio, 0.77; 95% CI, 0.48-1.24). CONCLUSIONS: Institutional use of rehabilitative services for children with prolonged critical illness varies greatly in the United States. Further research is needed into the potential benefits for patients cared for at centers with high usage of rehabilitation services in the ICU during prolonged critical illness.

Epidemiology of Acute Kidney Injury After Neonatal Cardiac Surgery: A Report From the Multicenter Neonatal and Pediatric Heart and Renal Outcomes Network.

OBJECTIVES: Cardiac surgery-associated acute kidney injury occurs commonly following congenital heart surgery and is associated with adverse outcomes. This study represents the first multicenter study of neonatal cardiac surgery-associated acute kidney injury. We aimed to describe the epidemiology, including perioperative predictors and associated outcomes of this important complication. DESIGN: This Neonatal and Pediatric Heart and Renal Outcomes Network study is a multicenter, retrospective cohort study of consecutive neonates less than 30 days. Neonatal modification of The Kidney Disease Improving Global Outcomes criteria was used. Associations between cardiac surgery-associated acute kidney injury stage and outcomes (mortality, length of stay, and duration of mechanical ventilation) were assessed through multivariable regression. SETTING: Twenty-two hospitals participating in Pediatric Cardiac Critical Care Consortium. PATIENTS: Twenty-two-thousand forty neonates who underwent major cardiac surgery from September 2015 to January 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cardiac surgery-associated acute kidney injury occurred in 1,207 patients (53.8%); 983 of 1,657 in cardiopulmonary bypass patients (59.3%) and 224 of 583 in noncardiopulmonary bypass patients (38.4%). Seven-hundred two (31.3%) had maximum stage 1, 302 (13.5%) stage 2, 203 (9.1%) stage 3; prevalence of cardiac surgery-associated acute kidney injury peaked on postoperative day 1. Cardiac surgery-associated acute kidney injury rates varied greatly (27-86%) across institutions. Preoperative enteral feeding (odds ratio = 0.68; 0.52-0.9) and open sternum (odds ratio = 0.76; 0.61-0.96) were associated with less cardiac surgery-associated acute kidney injury; cardiopulmonary bypass was associated with increased cardiac surgery-associated acute kidney injury (odds ratio = 1.53; 1.01-2.32). Duration of cardiopulmonary bypass was not associated with cardiac surgery-associated acute kidney injury in the cardiopulmonary bypass cohort. Stage 3 cardiac surgery-associated acute kidney injury was independently associated with hospital mortality (odds ratio = 2.44; 1.3-4.61). No cardiac surgery-associated acute kidney injury stage was associated with duration of mechanical ventilation or length of stay. CONCLUSIONS: Cardiac surgery-associated acute kidney injury occurs frequently after neonatal cardiac surgery in both cardiopulmonary bypass and noncardiopulmonary bypass patients. Rates vary significantly across hospitals. Only stage 3 cardiac surgery-associated acute kidney injury is associated with mortality. Cardiac surgery-associated acute kidney injury was not associated with any other outcomes. Kidney Disease Improving Global Outcomes criteria may not precisely define a clinically meaningful renal injury phenotype in this population.

Does getting defensive get you anywhere?-Seasonal balancing selection, temperature, and parasitoids shape real-world, protective endosymbiont dynamics in the pea aphid.

Facultative, heritable endosymbionts are found at intermediate prevalence within most insect species, playing frequent roles in their hosts' defence against environmental pressures. Focusing on Hamiltonella defensa, a common bacterial endosymbiont of aphids, we tested the hypothesis that such pressures impose seasonal balancing selection, shaping a widespread infection polymorphism. In our studied pea aphid (Acyrthosiphon pisum) population, Hamiltonella frequencies ranged from 23.2% to 68.1% across a six-month longitudinal survey. Rapid spikes and declines were often consistent across fields, and we estimated that selection coefficients for Hamiltonella-infected aphids changed sign within this field season. Prior laboratory research suggested antiparasitoid defence as the major Hamiltonella benefit, and costs under parasitoid absence. While a prior field study suggested these forces can sometimes act as counter-weights in a regime of seasonal balancing selection, our present survey showed no significant relationship between parasitoid wasps and Hamiltonella prevalence. Field cage experiments provided some explanation: parasitoids drove modest ~10% boosts to Hamiltonella frequencies that would be hard to detect under less controlled conditions. They also showed that Hamiltonella was not always costly under parasitoid exclusion, contradicting another prediction. Instead, our longitudinal survey - and two overwintering studies - showed temperature to be the strongest predictor of Hamiltonella prevalence. Matching some prior lab discoveries, this suggested that thermally sensitive costs and benefits, unrelated to parasitism, can shape Hamiltonella dynamics. These results add to a growing body of evidence for rapid, seasonal adaptation in multivoltine organisms, suggesting that such adaptation can be mediated through the diverse impacts of heritable bacterial endosymbionts.

Outcomes of Hypogastric Coverage and Occlusion during Endovascular Treatment of Aortoiliac Occlusive Disease.

BACKGROUND: The risk of hypogastric occlusion (HO) following bare-metal stent (BMS) coverage of the hypogastric origin during endovascular treatment of aortoiliac occlusive disease (AIOD) is unclear. This study sought to determine the rate and clinical significance of HO following BMS coverage during iliac stenting for complex AIOD. METHODS: Consecutive patients undergoing elective iliac stenting for AIOD from 2010-2018 at Cleveland Clinic were reviewed. Patients with BMS coverage of a patent hypogastric origin were included. Rate of HO were determined by review of intraoperative angiography and follow up imaging. Predictors of HO were identified by univariable and multivariable logistic regression. Outcomes were compared between those who did and did not develop HO. RESULTS: There were 251 patients (338 limbs) with BMS coverage of the hypogastric origin during treatment of AIOD. Lesion severity was classified as TASC C/D in 249/338 (73.7%) of cases. Bilateral hypogastric coverage occurred in 93/251 (37.1%) patients. Hypogastric patency was 78.1% at 24-months following coverage. Recanalization of an ipsilateral external iliac artery (EIA) occlusion was predictive of HO (HR 3.12, 95% CI: 1.33, 7.34; P= 0.009). Increased luminal diameter of the hypogastric origin protected against HO (HR 0.64; 95% CI: 0.47, 0.88; P= 0.006). Perioperative outcomes were no different between patients with and without HO. There were no cases of gluteal necrosis, spinal cord ischemia, or pelvic organ ischemia. Four-year mortality and limb salvage were not affected by HO. HO was associated with decreased primary patency of ipsilateral iliac stents and increased risk of ipsilateral reintervention (HR 5.49; 95% CI: 1.82, 16.58; P= 0.002). CONCLUSIONS: HO is relatively infrequent following BMS coverage during treatment of AIOD. Luminal diameter of the hypogastric origin and ipsilateral EIA occlusion are associated with occlusion. HO is well tolerated in AIOD, though it is potentially associated with increased risk iliac stent occlusion and reintervention.

Superoxide-induced Type I collagen secretion depends on prolyl 4-hydroxylases.

Reactive oxygen species (ROS) including superoxide (O2•-) play an important role in a variety of diseases, including Alzheimer's Disease, cancer, and atherosclerosis. Early reports showed that O2•- is a stimulant for collagen synthesis. However, the mechanism remains incompletely understood. Here we showed that LY83583 (6-anilinoquinoline-5,8-quinone), a substance known to induce O2•- production by smooth muscle cell (SMC), increases Type I collagen secretion. This effect could be blocked by treating the cells with Tiron, a scavenger for O2•-. LY83583-induced Type I collagen secretion required P4HA1 and P4HA2. Knockout of either P4ha1 or P4ha2 greatly reduced LY83583-stimulated Type I collagen maturation whereas silencing of both P4ha1 and P4ha2 completely blocked LY83583-induced Type I collagen maturation. Although significantly more hydroxyproline on purified Type I collagen was detected from LY83583 treated mouse embryonic fibroblast (MEF) cells by mass spectrometry, the level of prolyl 4-hydroxylases was not altered. Thus, LY83583 might increase the enzymatic activity of prolyl 4-hydroxylases to increase Type I collagen maturation. In addition, we found that LY83583 activated prolyl 4-hydrolases differed from ascorbate-activated prolyl 4-hydroxylase in two aspects: (1) LY83583 activated both P4HA1 and P4HA2 involved in collagen maturation whereas ascorbate mainly stimulated P4HA1 in collagen maturation; (2) LY83583 did not induce N259 glycosylation on P4HA1 as ascorbate did. The mechanisms remain to be investigated.

Disorders of Adjustment, Mood, and Anxiety in Children and Adolescents Undergoing Heart Transplantation and the Association of Ventricular Assist Device Support.

OBJECTIVE: To assess the prevalence of psychiatric disorders and associated therapies in children during their heart transplantation admission. STUDY DESIGN: All pediatric heart transplant recipients (1999-2016) were included from a linked administrative and clinical registry database. Psychiatric disorders and associated therapies were identified using International Classification of Diseases or billing codes during the transplant admission. Data were analyzed using standard descriptive statistics. Multivariable logistic regression assessed factors independently associated with psychiatric disorders or therapies. RESULTS: A total of 3073 pediatric heart transplant recipients were included. Psychiatric disorders were present in 434 (14.1%) patients during the heart transplant admission, with adjustment disorders being the most common. Antidepressant therapy was prescribed to 212 patients (6.9%) and selective serotonin reuptake inhibitors were most commonly used. Psychiatric diagnoses (8.4% vs 18.1%; P < .001) and the use of antidepressants (4.5% vs 8.9%; P < .001) increased over time (era 1, 1999-2009 vs era 2, 2010-2016). Psychiatric disorders were present in 39.8% of patients ≥8 years of age requiring ventricular assist device support at heart transplantation. The need for ventricular assist device support was independently associated with psychiatric diagnoses (aOR, 1.57; 95% CI, 1.18-2.1; P = .002) and antidepressant therapy (aOR, 2.11; 95% CI. 1.43-3.12; P < .001). CONCLUSIONS: Psychiatric disorders are common in pediatric heart transplant recipients, especially among those bridged with ventricular assist device support. Psychiatric diagnoses and the use of antidepressants has increased over time, likely representing improved recognition of psychiatric comorbidities in this vulnerable population. Access to psychiatric services represents an important component of the multidisciplinary team caring for pediatric heart transplant recipients.

Ascorbate inducible N259 glycans on prolyl 4-hydroxylase subunit α1 promote hydroxylation and secretion of type I collagen.

Ascorbic acid (vitamin C, VC) increases the secretion of mature collagen by promoting the activity of prolyl 4-hydroxylase subunit α 1 (P4HA1). To explore the mechanism involved, we investigated the role of N-linked glycosylation, which can regulate enzyme activity. P4HA1 has two glycosylation sites, Asn (N) 113 and N259. Our studies show that glycosylation of N259, but not N113, by STT3B and magnesium transporter 1 (MAGT1) is augmented by VC. N259 glycosylation on P4HA1 correlates with enhanced pepsin-resistant collagen 1α2 secretion. Downregulation of Stt3b and Magt1 reduces N259 glycans on P4HA1. In collagen 1α2 purified from Stt3b-silenced fibroblasts, decreased hydroxylation is found at five specific proline residues, while significantly increased hydroxylation is noted at two proline residues. Similarly, in collagen 1α1, reduced proline hydroxylation is detected at eight sites and increased proline hydroxylation is found at four sites. These results suggest that N-linked glycosylation of P4HA1 can direct hydroxylation at specific proline residues and affect collagen maturation.

Evolving Management of Distal Anastomotic Technical Issues During Open Aortic Aneurysm Repair.

BACKGROUND: Thrombosis of the iliac anastomosis is an important complication of open aortic aneurysm repair. We evaluated our evolving management of this complication to an endovascular approach and compared it with open revision to the common femoral artery. METHODS: Consecutive patients undergoing open aortic aneurysm repair from January 2009 through November 2016 at our institution were reviewed. Patients who developed iliac limb flow issues or thrombosis intraoperatively or within 48 hrs postoperatively were identified. Patients were grouped by management strategies of either 1) an endovascular approach including iliac angiography, thrombectomy if needed, and stenting or 2) open surgical revision of the iliac anastomosis with or without bypass to the common femoral artery. Demographics, comorbidities, operative variables, and outcomes were retrospectively analyzed between groups. Primary patency and mortality were assessed by Kaplan-Meier estimates. RESULTS: There were 711 patients who underwent aortoiliac aneurysm repair during the study period. 43/711 patients (6.0%) developed early perioperative iliac limb flow issues including thrombosis. Twenty-nine patients (31 limbs) were managed by an endovascular approach, and 14 patients (15 limbs) were managed by open surgical revision. The mean age of the cohort was 69 years, and 27 patients (62.8%) were male. Preoperative creatinine and diabetes frequency were higher in patients managed by an endovascular approach, although no other differences existed between preoperative comorbidities. Thrombosis or limb flow issues presented intraoperatively more commonly in the open surgical group and in the first 24 hrs postoperatively in the endovascular group. All patients had complete restoration of outflow as a result of the rescue procedure. Transfusion requirements and crystalloid replacement were significantly higher in the open surgical group. Length of stay, perioperative complications, and mortality were similar between groups. Overall, 21/31 limbs in the endovascular group and 9/15 limbs in the open surgical group had postoperative imaging, with mean follow-up of 35.0 and 55.6 months, respectively. Only one patient in the cohort lost patency: an iliofemoral jump graft that presented with late infection after postoperative wound infection, requiring staged extra-anatomic bypass and explant at 12 months. Three-year primary patency was 100% for the endovascular group and 85.7% for the surgical group by Kaplan-Meier method (P = 0.32). Endovascular management became our institution's primary salvage approach during the study. Whereas 8/15 limbs (53.3%) were managed by an endovascular approach from 2009-2011, 23/31 (74%) were managed by iliac stenting from 2012-2016. CONCLUSIONS: Endovascular management of iliac limb flow issues or thrombosis after open aneurysm repair is potentially a viable alternative to open surgical revision in the early postoperative period.

Rehospitalization Following Pediatric Heart Transplantation: Incidence, Indications, and Risk Factors.

Rehospitalization following pediatric heart transplantation is common. However, existing data remain somewhat limited. Using a novel linkage between administrative and clinical databases, pediatric heart transplant (HT) recipients from 29 centers who survived to discharge were retrospectively reviewed to determine the frequency, timing of, and indication for all-cause rehospitalizations in the year following transplant discharge. Of 2870 pediatric HT recipients, 1835 (63.9%) were rehospitalized in the first year post-discharge (5429 total readmissions). Rehospitalization rates varied significantly across centers (46% to 100%) and were inversely correlated to center transplant volume (r2 0.25, p < 0.01). The median number of rehospitalizations per patient was 2 (IQR 1-4) and the median time to first rehospitalization was 29 days (IQR 9-99 days). Independent risk factors for rehospitalization included younger age at HT (HR 0.99, 95% CI 0.97-0.99), congenital heart disease (HR 1.2, 95% CI 1.1-1.4), listing status 1B at transplant (HR 1.3, 95% CI 1.1-1.5), and post-transplant complications including rejection prior to discharge (HR 1.5 95% CI 1.3-1.8) and chylothorax (HR 1.3, 95% CI 1.0-1.6). Cardiac diagnoses were the most common indication for rehospitalization (n = 1600, 29.5%), followed by infection (n = 1367, 25.2%). These findings may serve to guide the development of interventions aimed at reducing post-HT hospitalizations.

Patterns and Correlates of Prescription Opioid Receipt Among US Veterans: A National, 18-Year Observational Cohort Study.

A better understanding of predisposition to transition to high-dose, long-term opioid therapy after initial opioid receipt could facilitate efforts to prevent opioid use disorder (OUD). We extracted data on 69,268 patients in the Veterans Aging Cohort Study who received any opioid prescription between 1998 and 2015. Using latent growth mixture modelling, we identified four distinguishable dose trajectories: low (53%), moderate (29%), escalating (13%), and rapidly escalating (5%). Compared to low dose trajectory, those in the rapidly escalating dose trajectory were proportionately more European-American (59% rapidly escalating vs. 38% low); had a higher prevalence of HIV (31% vs. 29%) and hepatitis C (18% vs. 12%); and during follow-up, had a higher incidence of OUD diagnoses (13% vs. 3%); were hospitalised more often [18.1/100 person-years (PYs) vs. 12.5/100 PY]; and had higher all-cause mortality (4.7/100 PY vs. 1.8/100 PY, all p < 0.0001). These measures can potentially be used in future prevention research, including genetic discovery.