Fractional myocardial blood volume by ferumoxytol-enhanced MRI: Estimation of ischemic burden.

PURPOSE: To investigate model-fitted fractional myocardial blood volume (fMBV) derived from ferumoxytol-enhanced MRI as a measure of myocardial tissue hypoperfusion at rest. METHODS: We artificially induced moderate to severe focal coronary stenosis in the left anterior descending artery of 19 swine by percutaneous delivery of a 3D-printed coronary implant. Using the MOLLI pulse sequence, we acquired T1 maps at 3 T after multiple incremental ferumoxytol doses (0.0-4.0 mg/kg). We computed pixel-wise fMBV using a multi-compartmental modeling approach in 19 ischemic swine and 4 healthy swine. RESULTS: Ischemic myocardial segments showed a mean MRI-fMBV of 11.72 ± 3.00%, compared with 8.23 ± 2.12% in remote segments and 8.38 ± 2.23% in normal segments. Ischemic segments showed a restricted transvascular water-exchange rate (ki  = 15.32 ± 8.69 s-1 ) relative to remote segments (ki  = 17.78 [11.60, 26.36] s-1 ). A mixed-effects model found significant difference in fMBV (p = 0.002) and water-exchange rate (p < 0.001) between ischemic and remote myocardial regions after adjusting for biological sex and slice location. Analysis of fMBV as a predictor of impaired myocardial contractility using receiver operating characteristics showed an area under the curve of 0.89 (95% confidence interval [CI] 0.80, 0.95). An MRI-fMBV threshold of 9.60% has a specificity of 90.0% (95% CI 76.3, 97.2) and a sensitivity of 72.5% (95% CI 56.1, 83.4) for prediction of impaired myocardial contractility. CONCLUSIONS: Model-fitted fMBV derived from ferumoxytol-enhanced MRI can distinguish regions of ischemia from remote myocardium in a swine model of myocardial hypoperfusion.

Journal Initiatives to Enhance Preclinical Research: Analyses of Stroke, Nature Medicine, Science Translational Medicine.

Background and Purpose- Preclinical research using animals often informs clinical trials. However, its value is dependent on its scientific validity and reproducibility, which are, in turn, dependent on rigorous study design and reporting. In 2011, Stroke introduced a Basic Science Checklist to enhance the reporting and methodology of its preclinical studies. Except for Nature and Science journals, few others have implemented similar initiatives. We sought to estimate the impact of these journal interventions on the quality of their published reports. Methods- All articles published in Stroke, Nature Medicine, and Science Translational Medicine over 9 to 18 years and in 2 control journals without analogous interventions over a corresponding 11.5 years were reviewed to identify reports of experiments in nonhuman mammals with proposed clinical relevance. The effect of journal interventions on the reporting and use of key study design elements was estimated via interrupted time-series analyses. Results- Of 33 009 articles screened, 4162 studies met inclusion criteria. In the 3.5 to 12 years preceding each journal's intervention, the proportions of studies reporting and using key study design elements were stable except for blinding in Stroke and randomization in Science Translational Medicine, which were both increasing. Post-intervention, abrupt and often marked increases were seen in the reporting of randomization status (level change: +17% to +44%, P≤0.005), blinding (level change: +20% to +40%, P≤0.008), and sample size estimation (level change: 0% to +40%, P≤0.002 in 2 journals). Significant but more modest improvements in the use of these study design elements were also observed. These improvements were not seen in control journals. Conclusions- Journal interventions such as Stroke's author submission checklist can meaningfully improve the quality of published preclinical research and should be considered to enhance study transparency and design. However, such interventions are alone insufficient to fully address widespread shortcomings in preclinical research practices.

Reduced arterial compliance along the cerebrovascular tree predicts cognitive slowing in multiple sclerosis: Evidence for a neurovascular uncoupling hypothesis.

BACKGROUND: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. OBJECTIVE: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. METHODS: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. RESULTS: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. CONCLUSION: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS.

Evaluation of an in vitro coronary stent thrombosis model for preclinical assessment.

Stent thrombosis remains an infrequent but significant complication following percutaneous coronary intervention. Preclinical models to rapidly screen and validate therapeutic compounds for efficacy are lacking. Herein, we describe a reproducible, high throughput and cost-effective method to evaluate candidate therapeutics and devices for either treatment or propensity to develop stent thrombosis in an in vitro bench-top model. Increasing degree of stent malapposition (0.00 mm, 0.10 mm, 0.25 mm and 0.50 mm) was associated with increasing thrombosis and luminal area occlusion (4.1 ± 0.5%, 6.3 ± 0.5%, 19.7 ± 4.5%, and 92.6 ± 7.4%, p < 0.0001, respectively). Differences in stent design in the form of bare-metal, drug-eluting, and bioresorbable vascular scaffolds demonstrated differences in stent thrombus burden (14.7 ± 3.8% vs. 20.5 ± 3.1% vs. 86.8 ± 5.3%, p < 0.01, respectively). Finally, thrombus burden was significantly reduced when healthy blood samples were incubated with Heparin, ASA/Ticagrelor (DAPT), and Heparin+DAPT compared to control (DMSO) at 4.1 ± 0.6%, 6.9 ± 1.7%, 4.5 ± 1.2%, and 12.1 ± 1.8%, respectively (p < 0.01). The reported model produces high throughput reproducible thrombosis results across a spectrum of antithrombotic agents, stent design, and degrees of apposition. Importantly, performance recapitulates clinical observations of antiplatelet/antithrombotic regimens as well as device and deployment characteristics. Accordingly, this model may serve as a screening tool for candidate therapies in preclinical evaluation.

Perioperative Interdisciplinary Intervention Contributes to Improved Outcomes of Adolescents Treated With Hip Preservation Surgery.

BACKGROUND: Adolescent hip preservation surgery (HPS) candidates typically present with chronic pain, which can negatively affect psychological function and surgical outcomes. A previous study demonstrated high rates of psychological symptoms and maladaptive behaviors in this population. This study quantified psychological and functional improvements in these patients from preoperative presentation to postoperative follow-up. An integrated interdisciplinary approach is also described. METHODS: A total of 67 patients undergoing HPS were evaluated preoperatively and postoperatively at 1 year by staff psychologists. Perioperative psychological intervention consisted of education, counseling, and administration of self-report measures. Self-report measure scores were compared preoperatively and postoperatively, grouped by orthopaedic diagnoses. Frequency analysis, correlational analysis, and analysis of variance were conducted. RESULTS: Psychological function improved significantly at follow-up: decreased emotional symptomatology (46.1 to 43.6, P=0.013), anxiety (49.6 to 45.8, P<0.001), school problems (46.6 to 44.7, P=0.035), internalizing problems (46.3 to 44.1, P=0.015), social stress (44.5 to 42.3, P=0.024), sense of inadequacy (49.0 to 46.0, P=0.004), and increased self-concept (51.1 to 54.1, P=0.003). Resiliency factors also significantly improved: increased mastery (50.3 to 52.9, P=0.001) and resourcefulness (49.7 to 52.0, P=0.046), decreased emotional reactivity (46.3 to 42.9, P=0.001), and vulnerability (47.7 to 44.7, P=0.011). Physical function and return to activity also significantly improved (University of California-Los Angeles: 7.1 to 8.7, P=0.017; modified Harris Hip Score: 67.3 to 83.8, P<0.001). Return to activity positively correlated with optimism and self-efficacy (P=0.041). Femoroacetabular impingement and hip dysplasia patients consistently reported feeling less depressed (P=0.036), having fewer somatic complaints (P=0.023), fewer internalized problems (P=0.037), and exhibiting fewer atypical behaviors (P=0.036) at follow-up. Slipped capital femoral epiphysis patients did not demonstrate improvements in psychological functioning postoperatively. CONCLUSIONS: Perioperative psychological education and counseling, in combination with HPS, improved postoperative psychological and physical function. Patients reported reduced anxiety, school problems, and social stress, with marked increase in resilience. Increased mobility and return to activity significantly correlated with improved optimism and self-efficacy. LEVEL OF EVIDENCE: Level II-therapeutic studies-investigating the results of treatment.

Clinical Implications of Psychosocial Factors on Pediatric External Fixation Treatment and Recommendations.

BACKGROUND: Pediatric limb reconstruction using circular external fixation is a prolonged treatment that interrupts patients' daily function. Patient personality characteristics and expectations may interfere with planned treatment, making complicated medical procedures more challenging. The aims of this study are to identify factors impacting treatment outcome and recommendations for preoperative evaluation and planning. QUESTIONS/PURPOSES: (1) Are there group differences between patients with and without a preexisting mental health condition(s) in terms of unplanned reoperations? (2) Does the number of surgical procedures before current external fixator placement correlate with the number of unplanned readmissions, unplanned reoperations, and days spent in circular external fixation? (3) Are there group differences between single- compared with two-parent households in terms of inpatient narcotic doses, length of inpatient stay, number of unplanned readmissions, length of readmission(s), and/or unplanned outpatient clinic visits? (4) Does patient age at the time of surgery have an impact on treatment duration, postoperative complications, and treatment outcome? METHODS: This is a retrospective chart review of pediatric patients who underwent limb reconstruction between 2008 and 2012. Patients with limb length discrepancy > 4 cm or severe angular deformity and who agreed to intervention were treated with circular external fixation. Sixty-seven patients were included; 16 patients were excluded. Statistical analyses included Pearson r correlation and t-test. RESULTS: Patients who reported preexisting mental health diagnosis (13%) had more unplanned reoperations than patients who did not (no mental health diagnosis; 87%) (mental health diagnosis 3.4 ± 10.3 versus no mental health diagnosis 0.2 ± 0.5 reoperation[s], p = 0.022). Number of previous surgical procedures correlated with number of unplanned reoperations (r = 0.448, p < 0.001), number of unplanned readmissions (r = 0.375, p < 0.001), and number of days in an apparatus (r = 0.275, p = 0.018). Compared with patients from two-parent households, patients from single-parent households received a greater number of inpatient narcotic doses (single-parent 129 ± 118 versus two-parent 73 ± 109 doses, p = 0.039), longer length of inpatient stay (single-parent 73 ± 63 versus two-parent 40 ± 65 days, p = 0.036), more unplanned readmissions (single-parent 0.4 ± 0.1 versus two-parent 0.2 ± 0.2 readmission, p = 0.024), longer hospitalization when readmitted (single-parent 5 ± 11 versus two-parent 1 ± 3 day(s), p = 0.025), and fewer unplanned outpatient visits (single-parent 0.2 ± 0.8 versus two-parent 0.9 ± 1.1 visit, p = 0.005). Apparatus applications with successful outcome had higher average age than those with poor outcome (successful outcome 16 ± 3 versus poor outcome 13 ± 4 years old, p = 0.011). Age at time of apparatus application correlated with number of prescribed antibiotics (r = 0.245, p = 0.036) and number of days in an apparatus (r = 0.233, p = 0.047). CONCLUSIONS: As a result of the inherent challenges of limb reconstruction, surgical candidates should be preoperatively assessed and mitigating psychosocial factors managed to maximize successful treatment outcome. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Preoperative psychological findings in adolescents undergoing hip preservation surgery.

BACKGROUND: Chronic pain is associated with increased anxiety, depression, and maladaptive behaviors, especially in adolescents. We hypothesized that adolescents with chronic hip pain selected for hip preservation surgery (HPS) would demonstrate increased anxiety and depression compared with same-age peers. We designed a study to assess the psychological state of adolescents before HPS. METHODS: We prospectively evaluated 58 patients (23 males, 35 females), average age 16.5 years (range, 11 to 19 y) before HPS. Their diagnoses included: femoroacetabular impingement (n=25), acetabular dysplasia (16), Perthes disease (11), and slipped capital femoral epiphysis (6). Psychological questionnaires included patient-completed and parent-completed Behavioral Assessment System for Children, Second Edition (BASC-2), Beck Youth Inventory, Second Edition (BYI-II), and Resiliency Scales. Self-reported functional questionnaires included the modified Harris hip score (mHHS, max 100) and the UCLA activity score. Psychological scores were compared between diagnoses, procedures performed, and self-reported functional scores with a Student t test and ANOVA. RESULTS: All patients reported pain, 52 (90%) reported pain >6 months with 28 (54%) >1 year. A total of 44 patients (76%) reported moderate or severe pain. All reported decreased function: average UCLA 7.25 (range, 2 to 10), average HHS 65.5 (range, 27.5 to 97.9). At presentation, 10 patients (17.2%) were receiving psychological intervention and 30% had a family history of mental illness. On the basis of the BYI-II scales, 10% and 31% of patients reported at-risk or clinically significant symptoms of anxiety and depression, respectively. Similarly, using the BASC-2 measure, 28% and 14% reported at-risk or clinically significant anxiety and depression, respectively. Resiliency scales demonstrated that 21% to 36% of patients report maladaptive behavior. There were no significant correlations between any psychological score and diagnosis, procedure, or preoperative functional score. CONCLUSIONS: Preoperative evaluation identified patients who reported at-risk or clinically significant symptoms of anxiety and/or depression, with up to one third of patients reporting maladaptive behavior that may significantly influence their postoperative outcomes. Preoperative psychological evaluation, with appropriate intervention and follow-up, if needed, should be considered before surgery selection as mental health conditions may be undiagnosed and will likely influence functional outcomes.

Genome sequences of seven bacterial isolates collected from soil as part of a microbiology lab course.

Soil is a source for diverse microbes that possess useful biotechnological capabilities. Here, we report the genome sequences of seven bacterial isolates from the species Exiguobacterium acetylicum, Rossellomorea marisflavi, Delftia acidovorans, Pseudomonas aeruginosa, Bacillus sp., and Bacillus toyonensis (two isolates) cultured from Dallas/Fort Worth metroplex soil samples.

Evaluation of Plasma Adenosine as a Marker of Cardiovascular Risk: Analytical and Biological Considerations.

Background Adenosine is a ubiquitous regulatory molecule known to modulate signaling in many cells and processes vital to vascular homeostasis. While studies of adenosine receptors have dominated research in the field, quantification of adenosine systemically and locally remains limited owing largely to technical restrictions. Given the potential clinical implications of adenosine biology, there is a need for adequately powered studies examining the role of plasma adenosine in vascular health. We sought to describe the analytical and biological factors that affect quantification of adenosine in humans in a large, real-world cohort of patients undergoing evaluation for coronary artery disease. Methods and Results Between November 2016 and April 2018, we assessed 1141 patients undergoing angiography for evaluation of coronary artery disease. High-performance liquid chromatography was used for quantification of plasma adenosine concentration, yielding an analytical coefficient of variance (CVa) of 3.2%, intra-subject variance (CVi) 35.8% and inter-subject variance (CVg) 56.7%. Traditional cardiovascular risk factors, medications, and clinical presentation had no significant impact on adenosine levels. Conversely, increasing age (P=0.027) and the presence of obstructive coronary artery disease (P=0.026) were associated with lower adenosine levels. Adjusted multivariable analysis supported only age being inversely associated with adenosine levels (P=0.039). Conclusions Plasma adenosine is not significantly impacted by traditional cardiovascular risk factors; however, advancing age and presence of obstructive coronary artery disease may be associated with lower adenosine levels. The degree of intra- and inter-subject variance of adenosine has important implications for biomarker use as a prognosticator of cardiovascular outcomes and as an end point in clinical studies.

Head-to-Tail Cyclic Peptide Inhibitors of the Interaction between Human von†Willebrand Factor and Collagen.

The development of peptide-based therapeutics is on the rise, with macrocyclic compounds providing the added stability and drug-like characteristics sought after. Currently, therapies and preventatives for pathogenic thrombosis target platelet interactions at the site of the clot and have many complications. Herein we describe novel cyclic peptides as moderate inhibitors of the protein-protein interaction between von Willebrand factor (vWF) and collagen that initiates blood clot formation. We based our designs on two known disulfide-containing, peptide-based inhibitors of the vWF-collagen interaction. Replacing the disulfide with a head-to-tail cyclization strategy confers remarkable stability to the peptides when treated with a panel of proteases. Our peptides also showed moderate activity in our developed fluorescently linked immunosorbent assay (FLISA), similar to the most active disulfide-containing peptide. These peptides provide a springboard for future advances in exceptionally stable, active cyclic peptides as drugs.

School Scoliosis Screenings: Family Experiences and Potential Anxiety After Orthopaedic Referral.

STUDY DESIGN: Cross-sequential study design that used data from Texas Scottish Rite Hospital for Children (TSRHC). OBJECTIVE: Examine anxiety symptoms and family experiences subsequent to school scoliosis screening (SSS) referrals. SUMMARY OF BACKGROUND DATA: Use of SSS remains controversial. Prior research suggested that SSS programs may result in anxiety for both children and parents. Unfortunately, no study has examined the SSS referral processes and anxiety in families. METHODS: Study consisted of 2 groups-patients/parents from TSRHC evaluated for Adolescent Idiopathic Scoliosis (AIS) (n = 27) and control participants/parents (n = 27) between ages 9 and 17. All participants completed the primary outcome measure (State-Trait Anxiety Inventory) before and after the scoliosis evaluation or controlled wait time. Parents also rated experience and satisfaction with SSS. RESULTS: Compared with the control group, children/parents in patient group experienced significantly elevated levels of state-anxiety at preappointment. Children/parents in the patient group not diagnosed with AIS experienced a significant decline in state-anxiety. Children/parents in the patient group diagnosed with AIS continued to report elevated levels of anxiety. The control group remained consistent, reporting of low levels of anxiety pre to post. More than half (55.5%) of families indicated they received no information from the school about scoliosis. A third of the families who received information indicated it did not adequately address their concerns. Nonetheless, most families reported overall satisfaction with SSS. CONCLUSION: This study suggested that children and parents referred through the SSS program experienced significantly elevated levels of state-anxiety. This supports the subjective concerns of anxiety experiences in families voiced by researchers previously. However, families deemed the costs of the SSS referral process as worth the benefits. Though challengers of SSS programs were accurate in observing anxiety in families, it may not constitute significant burden to eliminate SSS programs altogether. Improvements to the current system may be warranted. LEVEL OF EVIDENCE: 3.