GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1.

Bromodomains are acetyl-lysine binding modules that are found in different classes of chromatin-interacting proteins. Among these are large chromatin remodeling complexes such as BAF and PBAF (variants of human SWI/SNF). Previous work has identified chemical probes targeting a subset of the bromodomains present in the BAF and PBAF complexes. Selective inhibitors of the individual bromodomains have proven challenging to discover, as the domains are highly similar. Here, elaboration of an aminopyridazine scaffold used previously to develop probes for the bromodomains of SMARCA2, SMARCA4, and the fifth bromodomain of PBRM1 yielded compounds with both potency and unusual selectivity for the second bromodomain of PBRM1. One of these, GNE-235, and its enantiomer control GNE-234 are suggested for initial cellular investigations of the function of the second bromodomain of PBRM1.

Cost-effectiveness of ropeginterferon alfa-2b-njft for the treatment of polycythemia vera.

Aim: Patients with polycythemia vera (PV), a rare and chronic blood cancer, are at a higher risk for thromboembolic events, progression to myelofibrosis, and leukemic transformation. In 2021, ropeginterferon alfa-2b-njft (BESREMi®) was approved in the US to treat adults with PV. The purpose of this study is to estimate the cost-effectiveness of ropeginterferon alfa-2b-njft, used as a first- or second-line treatment, for the treatment of patients with PV in the US. Materials & methods: A Markov cohort model was developed from the healthcare system perspective in the United States. Model inputs were informed by the PROUD-PV and CONTINUATION-PV studies and published literature. The model population included both low-risk and high-risk patients with PV. The model compared ropeginterferon alfa-2b-njft used either as first- or second-line versus an alternative treatment pathway of first-line hydroxyurea followed by ruxolitinib. Results: Over the modeled lifetime, ropeginterferon alfa-2b-njft provided an additional 0.4 higher quality-adjusted life years (QALYs) and 0.4 life-years with an added cost of USD60,175, resulting in a cost per QALY of USD141,783. The model was sensitive to treatment costs, the percentage of patients who discontinue hydroxyurea, the percentage of ropeginterferon alfa-2b-njft users who switch to monthly dosing, the percentage of ropeginterferon alfa-2b-njft users as 2nd line treatment, and the treatment response rates. A younger patient age at baseline and a higher percentage of patients with low-risk disease improved the cost-effectiveness of ropeginterferon alfa-2b-njft. Conclusion: Ropeginterferon alfa-2b-njft is a cost-effective treatment option for a broad range of patients with PV, including both low- and high-risk patients and patients with and without prior cytoreductive treatment with hydroxyurea.

GNE-064: A Potent, Selective, and Orally Bioavailable Chemical Probe for the Bromodomains of SMARCA2 and SMARCA4 and the Fifth Bromodomain of PBRM1.

Bromodomains are acetyllysine recognition domains present in a variety of human proteins. Bromodomains also bind small molecules that compete with acetyllysine, and therefore bromodomains have been targets for drug discovery efforts. Highly potent and selective ligands with good cellular permeability have been proposed as chemical probes for use in exploring the functions of many of the bromodomain proteins. We report here the discovery of a class of such inhibitors targeting the family VIII bromodomains of SMARCA2 (BRM) and SMARCA4 (BRG1), and PBRM1 (polybromo-1) bromodomain 5. We propose one example from this series, GNE-064, as a chemical probe for the bromodomains SMARCA2, SMARCA4, and PBRM1(5) with the potential for in vivo use.

Endoscopic Gluteus Medius Repair Replicates Open, Knotless Repair With Similar Cyclic Loading Properties: A Cadaveric Study.

Purpose: To compare the repair strength, gap formation, and mode of failure between endoscopic and open double-row gluteus medius repairs in a cadaveric model. Methods: Six pairs of fresh-frozen human cadavers were used in this study. Gluteus medius tears were created in an open fashion and then repaired with either open or endoscopic techniques. Specimens were manually preloaded to 5 N, then cycled between 20-50 N for 150 cycles s. Then, a ramp to/s. Specimens were then returned to 10 N and ramped to failure at 1 mm/s. Gap formation and strengths of the construct were compared for the 2 techniques. Results: Biomechanical testing resulted in no significant differences in ultimate load (P = .86) or gap formation (P > .10) between groups. Ninety-two percent of specimens failed near the muscle origin on the ilium. Conclusions: This study shows that both open and endoscopic gluteus medius repairs are stronger than the muscle-bone interface in a cadaveric model and loaded biomechanically in tension between the ilium origin and femoral insertion. Further, endoscopic technique is able to replicate open, knotless gluteus medius repair technique in terms of gap formation in physiologic (i.e., subfailure) cyclic loading. Clinical Relevance: Gluteus medius tendinopathy is an increasingly common recognized etiology of lateral hip pain. When tears occur, debate exists over whether open or endoscopic repair procedures are optimal. Double-row endoscopic gluteus medius repair with knotless suture anchors may be an alternative to open repair.

Combined Orthopaedic and Vascular Injuries With Ischemia: A Multicenter Analysis.

OBJECTIVES: To review a large, multicenter experience to identify the current salvage and amputation rates of these combined injuries and, where possible, the variables that predict amputation. DESIGN: Retrospective. SETTING: Nine trauma centers. PATIENTS: This study involved 199 patients presenting to 9 trauma centers with orthopaedic and vascular injuries resulting in ischemic limbs for whom the orthopaedic service was involved with the decision for salvage versus amputation. RESULTS: We reviewed 199 patients, 17-85 years of age. One hundred seventy-two of the injuries were open. Thirty-eight patients (19%) were treated with amputation upon admission as they were deemed to be unsalvageable. Of the remaining 161 patients who had attempted salvage, 36 (30%) required late amputation. Closed injuries were successfully salvaged in 25 of 27 cases (93%). The highest rate of amputation was in tibia fractures with a combined amputation rate of 62%. In those attempted to be salvaged, 21 of 48 (44%) required amputation. The ischemia time for successful salvage was significantly less, P = 0.03. One hundred twenty-four patients had their definitive vascular repair before the bony reconstruction. There were 15 vascular complications, of which 13 (86%) had the definitive vascular repair performed before the definitive osseous repair, although this was not statistically significant. CONCLUSIONS: In this series of combined orthopaedic and vascular injuries, we found a high rate of acute and late amputations. It is possible that other protocols, such as shunting and stabilizing the osseous injury, before vascular repair may benefit limb salvage, although this needs more study. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Burden of pulmonary hypertension in patients with portal hypertension in the United States: a retrospective database study.

Patients with portal hypertension may develop pulmonary hypertension. The economic implications of these comorbidities have not been systematically assessed. We compared healthcare resource utilization and costs in the United States between patients with co-existing portal hypertension and pulmonary hypertension (pulmonary hypertension cohort) and a matched cohort of portal hypertension patients without pulmonary hypertension (control cohort). In this retrospective analysis, adult pulmonary hypertension and control patients were identified from the Optum® Clinformatics® Data Mart database between 1 July 2014 and 30 June 2018. All patients had ≥2 claims with diagnosis codes for portal hypertension; pulmonary hypertension patients had ≥2 claims with diagnosis codes for pulmonary hypertension; controls could not have pulmonary hypertension diagnoses or any claims for pulmonary arterial hypertension-specific medications. Controls were matched to pulmonary hypertension patients by age, sex, Charlson comorbidity index score, and liver diseases. We assessed 12-month healthcare resource utilization and costs. Each cohort included 146 patients. During follow-up, pulmonary hypertension cohort patients were more likely than controls to experience a hospitalization (51% vs. 32%, P = 0.0014) and an emergency room visit (55% vs. 41%, P = 0.026). The average annual total cost was higher in pulmonary hypertension patients than for matched controls ($119,912 vs. $81,839, P < 0.0001). After covariate adjustment, costs for pulmonary hypertension cohort patients were 1.47 times higher than those for controls (P = 0.0197). These findings suggest that patients with portal hypertension and co-existing pulmonary hypertension are at a greater risk for hospitalization and incur higher mean annual total costs than portal hypertension patients without pulmonary hypertension.

Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire: feasibility of utilizing one-day versus seven-day symptom reporting.

Patient-reported outcomes are important measures to include in pulmonary arterial hypertension clinical trials but are not widely utilized in clinical practice. Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT) is the only pulmonary arterial hypertension-specific patient-reported outcomes instrument developed and validated in accordance with the US Food and Drug Administration guidance on patient-reported outcomes development. The PAH-SYMPACT tool measures pulmonary arterial hypertension-related symptoms and impact of pulmonary arterial hypertension on daily life. Symptoms are reported each day for seven consecutive days, and the impact of pulmonary arterial hypertension over one week is recalled and reported on day 7; however, daily symptom reporting may overburden patients and healthcare resources, limiting the practicality of PAH-SYMPACT outside of clinical trials. To determine the practicability of an abridged version of PAH-SYMPACT for which all reporting is completed on one day, symptom data from the SYMPHONY trial (NCT01841762; PAH-SYMPACT validation study) were retrospectively analyzed to assess whether symptoms reported on each day correlated with the weekly average and whether one-day symptom scores were sensitive to disease severity. Correlation coefficients comparing the weekly average and individual day symptom scores were mostly high or very high regardless of the day they were measured. Findings were similar when using either Spearman's rank correlation or weighted kappa method. One-day symptom scores differentiated well between World Health Organization functional classes II and III/IV pulmonary arterial hypertension and were sensitive to change in disease severity as measured by the Patient Global Assessment of Disease Severity. These data suggest that the one-day PAH-SYMPACT is feasible and appropriate for routine implementation in clinical practice.

Stress Reactivity as a Pathway from Attentional Control Deficits in Everyday Life to Depressive Symptoms in Adolescent Girls.

The goal of this research was to expand theoretical models of adolescent depression to determine whether individual differences in cognitive processing-specifically attentional control deficits-help to explain increased risk for depression during adolescence. We also examined whether this pathway was stronger in girls than in boys. A longitudinal design was used to examine whether poor attentional control in everyday life (i.e., difficulties shifting between ideas, tasks, and activities) contributes to depression over time by fostering higher levels of stress reactivity. Youth (298 boys, 338 girls) completed questionnaires assessing stress reactivity (6th and 7th grades) and depressive symptoms (6th, 7th and, 8th grades); teachers completed the shifting subscale of the Behavior Rating Scale of Executive Function (Gioia et al. 2000a) to assess attentional control (6th and 7th grades). Structural equation modeling analyses provided support for the predicted pathway in girls but not boys, yielding a significant indirect effect from 6th grade shifting deficits to 8th grade depressive symptoms via 7th grade stress reactivity. These results suggest that attentional control deficits in early adolescence heighten girls' sensitivity to stress and consequent depressive symptoms, providing a critical direction for efforts to decrease adolescent girls' risk for depression.

Emotional Clarity as a Mechanism Linking Emotional Neglect and Depressive Symptoms during Early Adolescence.

The present study examined whether emotional abuse and neglect differentially predicted decreases in emotional clarity, and whether emotional clarity, in turn, predicted increases in depressive symptoms. Participants included 204 early adolescents (52% African-American; 54% female; Mean age= 12.85 years) who completed four assessments with measures of depressive symptoms, emotional clarity, and emotional abuse and neglect. Hierarchical linear regressions indicated that emotional neglect significantly predicted decreases in emotional clarity, whereas emotional abuse did not. Further, mediational analyses revealed that decreases in emotional clarity mediated the relationship between emotional neglect and increases in depressive symptoms. The current study suggests that emotional neglect (more so than emotional abuse) may hinder an individual's ability to identify his or her own emotions, which may increase the risk of depressive symptoms during adolescence. These findings have significant implications for the development of intervention and prevention programs for depression.

Social Media and Total Joint Arthroplasty: An Analysis of Patient Utilization on Instagram.

BACKGROUND: The purpose of this study was to analyze the nature of shared content of total joint arthroplasty patients on Instagram. Specifically, we evaluated social media posts for: (1) perspective and timing; (2) tone; (3) focus (activities of daily living [ADLs], rehabilitation, return-to-work); and (4) the comparison between hip and knee arthroplasties. METHODS: A search of the public Instagram domain was performed over a 6-month period. Total hip and knee arthroplasties (THA and TKA) were selected for the analysis using the following terms: "#totalhipreplacement," "#totalkneereplacement," and associated terms. 1287 individual public posts of human subjects were shared during the period. A categorical scoring system was utilized for media format (photo or video), time (preoperative, perioperative, or postoperative) period, tone (positive or negative), return-to-work, ADLs, rehabilitation, surgical site, radiograph image, satisfaction, and dissatisfaction. RESULTS: Ninety-one percent of the posts were shared during the postoperative period. Ninety-three percent of posts had a positive tone. Thirty-four percent of posts focused on both ADLs and 33.8% on rehabilitation. TKA patients shared more about their surgical site (14.5% vs 3.3%, P < .001) and rehabilitation (58.9% vs 8.8%, P < .001) than THA patients, whereas THA patients shared more about ADLs than TKA patients (60.5% vs 7.6%, P < .001). CONCLUSION: When sharing their experience on Instagram, arthroplasty patients did so with a positive tone, starting a week after surgery. TKA posts focused more on rehabilitation and wound healing than THA patients, whereas THA patients shared more posts on ADLs. The analysis of social media posts provides insight into what matters to patients after total joint arthroplasty.

Nitric oxide differentially affects proteasome activator 28 after arterial injury in type 1 and type 2 diabetic rats.

BACKGROUND: Diabetic patients display aggressive restenosis after vascular interventions, likely because of proproliferative influences of hyperglycemia and hyperinsulinemia. We have shown that nitric oxide (NO) inhibits neointimal hyperplasia in type 2, but not in type 1, diabetic rats. Here, we examined proteasome activator 28 (PA28) after arterial injury in different diabetic environments, with or without NO. We hypothesize that NO differentially affects PA28 levels based on metabolic environment. MATERIALS AND METHODS: Vascular smooth muscle cell (VSMC) lysates from male, nondiabetic Lean Zucker (LZ) and Zucker Diabetic Fatty (ZDF) rats were assayed for 26S proteasome activity with or without PA28 and S-nitroso-N-acetylpenicillamine. LZ and ZDF VSMCs were treated with (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate for 24 h. Balloon-injured carotid arteries from LZ, streptozotocin-injected LZ (STZ, type 1), and ZDF (type 2) rats treated with disodium 1-[2-(carboxylato)pyrrolidin-1-iyl]diazen-1-ium-1,2-diolate were harvested at 3 or 14 d. PA28α was assessed by Western blotting and immunofluorescent staining. RESULTS: S-nitroso-N-acetylpenicillamine reversed PA28-stimulated increases in 26S proteasome activity in LZ and ZDF VSMCs. Increased (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate lowered PA28α in LZ VSMCs but increased PA28α in ZDF VSMCs. At 3 d after injury, disodium 1-[2-(carboxylato)pyrrolidin-1-iyl]diazen-1-ium-1,2-diolate potentiated injury-induced PA28α decreases in LZ, STZ, and ZDF rats, suggesting VSMCs, depleted at this early time point, are major sources of PA28α. At 14 d after injury, total PA28α staining returned to baseline. However, although intimal and medial PA28α staining increased in injured STZ rats, adventitial PA28α staining increased in injured ZDF rats. CONCLUSIONS: PA28 dysregulation may explain the differential ability of NO to inhibit neointimal hyperplasia in type 1 versus type 2 diabetes.

Respiratory sinus arrhythmia as a predictor of eating disorder symptoms in college students: Moderation by responses to stress and parent psychological control.

This longitudinal study examined the prospective contribution of respiratory sinus arrhythmia (RSA), a key physiological indicator of self-regulation, to eating disorder symptoms in college students, and whether this link was moderated by maladaptive responses to stress and parent psychological control. At Wave 1, college students' RSA was measured at rest. At Waves 1 and 2 (six-month follow-up), students reported on their eating disorder symptoms, coping and involuntary responses to stress, and perceptions of their parents' use of psychological control. Significant three-way interactions indicated that the link between RSA and subsequent eating disorder symptoms was contingent on responses to stress and parent psychological control. In the context of maladaptive responses to stress and high psychological control, RSA predicted increased eating disorder symptoms over time. In the absence of parent psychological control, high RSA was beneficial in most cases, even when individuals reported maladaptive responses to stress. This study presents novel evidence that high RSA contributes to risk for or resilience to eating disorder symptoms over time. RSA can be protective against eating disorder symptoms, but in some contexts, the self-regulation resources that high RSA provides may be inappropriately applied to eating cognitions and behaviors. This research highlights the importance of examining physiological functioning conjointly with other risk factors as precursors to eating disorder symptoms over time.

Establishment of a rat and guinea pig aortic interposition graft model reveals model-specific patterns of intimal hyperplasia.

OBJECTIVE: Although the aortic interposition bypass model has been widely used to evaluate biomaterials for bypass grafting, there is no comprehensive description of the procedure or of the distribution of intimal hyperplasia that results. The objectives of this study were to (1) review and summarize approaches of aortic interposition grafting in animal models, (2) determine the pertinent anatomy for this procedure, (3) validate this model in the rat and guinea pig, and (4) compare the distribution of intimal hyperplasia that develops in each species. METHODS: A literature search was performed in PubMed from 1980 to the present to analyze the use of anesthesia, anticoagulation, antiplatelet agents, graft material, suture, and anastomotic techniques. Using 10-week-old male Sprague-Dawley rats and Hartley guinea pigs, we established pertinent aortic anatomy, developed comparable models, and assessed complications for each model. At 30 days, the graft and associated aorta were explanted, intimal formation was assessed morphometrically, and cellularity was assessed via nuclear counting. RESULTS: We reviewed 30 articles and summarized the pertinent procedural findings. Upon establishing both animal models, key anatomic differences between the species that affect this model were noted. Guinea pigs have a much larger cecum, increased retroperitoneal fat, and lack the iliolumbar vessels compared with the rat. Surgical outcomes for the rat model included a 53% technical success rate and a 32% technical error rate. Surgical outcomes for the guinea pig model included a 69% technical success rate and a 31% technical error rate. These two species demonstrated unique distribution of intimal hyperplasia at 30 days. Intimal hyperplasia in the rat model was greatest at two areas, the proximal graft (5400 µm2; P < .001) and distal graft (2800 µm2; P < .04), whereas the guinea pig model developed similar intimal hyperplasia throughout the graft (4500-5100 µm2; P < .01). CONCLUSIONS: In this report, we summarize the literature on the aortic interposition graft model, present a detailed description of the anatomy and aortic interposition graft procedure in the rat and guinea pig, and describe a unique distribution of intimal formation that results in both species. This information will be helpful when designing studies to evaluate novel graft materials in the future.

Microparticle levels after arterial injury and NO therapy in diabetes.

BACKGROUND: Little is known about how arterial injury, nitric oxide (NO), or the diabetic milieu impact microparticle (MP) levels in the vasculature. We hypothesized that MP levels would increase following local arterial injury, and that NO would modify MP levels differently based on the metabolic environment. MATERIALS AND METHODS: Type 1 diabetes was induced in male Lean Zucker (LZ) rats with streptozotocin, and type 2 diabetes was induced in male Zucker diabetic fatty rats through diet. Lean Zucker rats served as nondiabetic controls. The rat carotid balloon injury was performed ± NO (n > 4/group). Blood was obtained at intervals from baseline to 14 d after injury and analyzed for platelet MP (PMP), leukocyte MP (LMP), and endothelial MP (EMP) using fluorescence-activated cell sorting (FACS) analysis. RESULTS: At baseline, type 1 diabetic rats had the highest EMP levels (P < 0.05). After arterial injury, type 1 and type 2 diabetic rats had a transient increase in EMP levels (P < 0.05) before decreasing below baseline levels. Both LMP and PMP levels generally declined after injury in all three animal models but were the lowest in both type 1 and type 2 diabetic rats. NO therapy had little impact on MP levels in nondiabetic and type 1 diabetic rats after injury. Conversely, NO caused a dramatic increase in EMP, LMP, and PMP levels in type 2 diabetic animals at early time points after injury (P < 0.05). CONCLUSIONS: These data demonstrate that the diabetic milieu impacts MP levels at baseline, after arterial injury and with NO treatment.

Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury.

AIMS: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. RESULTS: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. INNOVATION: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. CONCLUSION: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases.

Long-term effect of PROLI/NO on cellular proliferation and phenotype after arterial injury.

Vascular interventions are associated with high failure rates from restenosis secondary to negative remodeling and neointimal hyperplasia. Periadventitial delivery of nitric oxide (NO) inhibits neointimal hyperplasia, preserving lumen patency. With the development of new localized delivery vehicles, NO-based therapies remain a promising therapeutic avenue for the prevention of restenosis. While the time course of events during neointimal development has been well established, a full characterization of the impact of NO donors on the cells that comprise the arterial wall has not been performed. Thus, the aim of our study was to perform a detailed assessment of proliferation, cellularity, inflammation, and phenotypic cellular modulation in injured arteries treated with the short-lived NO donor, PROLI/NO. PROLI/NO provided durable inhibition of neointimal hyperplasia for 6 months after arterial injury. PROLI/NO inhibited proliferation and cellularity in the media and intima at all of the time points studied. However, PROLI/NO caused an increase in adventitial proliferation at 2 weeks, resulting in increased cellularity at 2 and 8 weeks compared to injury alone. PROLI/NO promoted local protein S-nitrosation and increased local tyrosine nitration, without measurable systemic effects. PROLI/NO predominantly inhibited contractile smooth muscle cells in the intima and media, and had little to no effect on vascular smooth muscle cells or myofibroblasts in the adventitia. Finally, PROLI/NO caused a delayed and decreased leukocyte infiltration response after injury. Our results show that a short-lived NO donor exerts durable effects on proliferation, phenotype modulation, and inflammation that result in long-term inhibition of neointimal hyperplasia.

Deficits in Emotional Clarity and Vulnerability to Peer Victimization and Internalizing Symptoms Among Early Adolescents.

Peer victimization is a significant risk factor for a range of negative outcomes during adolescence, including depression and anxiety. Recent research has evaluated individual characteristics that heighten the risk of experiencing peer victimization. However, the role of emotional clarity, or the ability to understand one's emotions, in being the target of peer victimization remains unclear. Thus, the present study evaluated whether deficits in emotional clarity increased the risk of experiencing peer victimization, particularly among adolescent girls, which, in turn, contributed to prospective levels of depressive and anxiety symptoms. In the present study, 355 early adolescents (ages 12-13; 53% female; 51% African American) who were part of the Adolescent Cognition and Emotion project completed measures of emotional clarity, depressive symptoms, and anxiety symptoms at baseline, and measures of peer victimization, depressive symptoms, and anxiety symptoms at follow-up. Moderation analyses indicated that deficits in emotional clarity predicted greater peer victimization among adolescent girls, but not adolescent boys. Moderated mediation analyses revealed that deficits in emotional clarity contributed to relational peer victimization, which, in turn, predicted prospective levels of depressive and anxiety symptoms among adolescent girls, but not boys. These findings indicate that deficits in emotional clarity represent a significant risk factor for adolescent girls to experience relational peer victimization, which, in turn, contributed to prospective levels of internalizing symptoms. Thus, prevention programs should target deficits in emotional clarity to prevent peer victimization and subsequent internalizing symptoms among adolescent girls.

The cyclical nature of depressed mood and future risk: Depression, rumination, and deficits in emotional clarity in adolescent girls.

Deficits in emotional clarity, the understanding and awareness of one's own emotions and the ability to label them appropriately, are associated with increased depressive symptoms. Surprisingly, few studies have examined factors associated with reduction in emotional clarity for adolescents, such as depressed mood and ruminative response styles. The present study examined rumination as a potential mediator of the relationship between depressive symptoms and changes in emotional clarity, focusing on sex differences. Participants included 223 adolescents (51.60% female, Mean age = 12.39). Controlling for baseline levels of emotional clarity, initial depressive symptoms predicted decreases in emotional clarity. Further, rumination prospectively mediated the relationship between baseline depressive symptoms and follow-up emotional clarity for girls, but not boys. Findings suggest that depressive symptoms may increase girls' tendencies to engage in repetitive, negative thinking, which may reduce the ability to understand and label emotions, a potentially cyclical process that confers vulnerability to future depression.

Periadventitial atRA citrate-based polyester membranes reduce neointimal hyperplasia and restenosis after carotid injury in rats.

Oral all-trans retinoic acid (atRA) has been shown to reduce the formation of neointimal hyperplasia; however, the dose required was 30 times the chemotherapeutic dose, which already has reported side effects. As neointimal formation is a localized process, new approaches to localized delivery are required. This study assessed whether atRA within a citrate-based polyester, poly(1,8 octanediolcitrate) (POC), perivascular membrane would prevent neointimal hyperplasia following arterial injury. atRA-POC membranes were prepared and characterized for atRA release via high-performance liquid chromatography with mass spectrometry detection. Rat adventitial fibroblasts (AF) and vascular smooth muscle cells (VSMC) were exposed to various concentrations of atRA; proliferation, apoptosis, and necrosis were assessed in vitro. The rat carotid artery balloon injury model was used to evaluate the impact of the atRA-POC membranes on neointimal formation, cell proliferation, apoptosis, macrophage infiltration, and vascular cell adhesion molecule 1 (VCAM-1) expression in vivo. atRA-POC membranes released 12 µg of atRA over 2 wk, with 92% of the release occurring in the first week. At 24 h, atRA (200 µmol/l) inhibited [(3)H]-thymidine incorporation into AF and VSMC by 78% and 72%, respectively (*P = 0.001), with negligible apoptosis or necrosis. Histomorphometry analysis showed that atRA-POC membranes inhibited neointimal formation after balloon injury, with a 56%, 57%, and 50% decrease in the intimal area, intima-to-media area ratio, and percent stenosis, respectively (P = 0.001). atRA-POC membranes had no appreciable effect on apoptosis or proliferation at 2 wk. Regarding biocompatibility, we found a 76% decrease in macrophage infiltration in the intima layer (P < 0.003) in animals treated with atRA-POC membranes, with a coinciding 53% reduction in VCAM-1 staining (P < 0.001). In conclusion, perivascular delivery of atRA inhibited neointimal formation and restenosis. These data suggest that atRA-POC membranes may be suitable as localized therapy to inhibit neointimal hyperplasia following open cardiovascular procedures.

The prospective contribution of childhood maltreatment to low self-worth, low relationship quality, and symptomatology across adolescence: A developmental-organizational perspective.

This research investigated the prospective contribution of childhood maltreatment to low self-worth, low relationship quality, and symptoms during adolescence. Further, the stability and cross-lagged effects of these sequelae of maltreatment were examined over time. History of maltreatment during childhood was obtained, and youth (407 maltreated, 228 nonmaltreated; 376 males, 259 females) completed 2 subsequent assessments spaced approximately 2 years apart during early-mid and mid-late adolescence. As anticipated, childhood maltreatment experiences predicted low self-worth, low relationship quality, and both internalizing and externalizing symptoms in early-mid adolescence. Beyond the stability paths of each outcome variable, significant cross-lagged effects were observed among low self-worth, low relationship quality, and internalizing symptoms across adolescence. In contrast, cross-lagged effects were not observed among adolescent externalizing symptoms. These findings support a developmental-organizational model in which childhood maltreatment creates multiple vulnerabilities that evince continuity and generate mutually influencing effects across adolescence.