Evaluation of Tricyclic Antidepressant Deprescribing in the Treatment of Diabetic Peripheral Neuropathy within Federally Qualified Health Centers.

BACKGROUND: Tricyclic antidepressants (TCAs) are a treatment option for diabetic peripheral neuropathy (DPN). Existing evidence demonstrates the prolonged use of TCA therapy increases the risk of cognitive decline and dementia, likely due to the anticholinergic effects of these medications. The anticholinergic activity is thought to contribute significantly to the observed increase in cognitive decline and dementia risks associated with long-term TCA use. There is little information available to describe the usage patterns of TCAs in DPN, particularly within underserved populations who receive care at Federally Qualified Health Centers (FQHCs). OBJECTIVES: The objective of this study was to characterize: 1) prescribing patterns of TCAs as a treatment for DPN and 2) evidence of deprescribing attempts in a FQHC population. METHODS: A retrospective chart review of electronic medical record (EMR) data for patients at two different FQHCs was performed. A convenience sample of 100 adults ≥ 18 years of age was stratified into two age groups, 18-55 years, and 55+ years. All patients had a diagnosis of Type 1 or Type 2 diabetes mellitus and had been prescribed TCAs in the previous four years and had a visit with a primary care provider (PCP) in the past 12 months. RESULTS: The study population was comprised of 100 individuals. Seventy-four of 100 were persistent users of TCAs at the time of data collection, and the mean duration of utilization was 54.8 months. In total, 104 TCAs were prescribed across 100 individual patients. Of all 104 prescribed TCAs, 66 (63%) were prescribed at a rate that exceeded thresholds associated with a higher risk of dementia. Black older adults prescribed TCAs were more likely to exceed this dose threshold. CONCLUSION: 65% of patients used TCAs with a strength, frequency, and duration that exceeded risk thresholds for dementia in an older adult population. Interventions preventing use of or deprescribing TCAs in patients with DPN should be conducted for the potential benefits of preventing or delaying cognitive impairment and promoting equitable care.

Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions.

Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.

Development of small molecule inhibitors of natural killer group 2D receptor (NKG2D).

Natural killer group 2D (NKG2D) is a homodimeric activating immunoreceptor whose function is to detect and eliminate compromised cells upon binding to the NKG2D ligands (NKG2DL) major histocompatibility complex (MHC) molecules class I-related chain A (MICA) and B (MICB) and UL16 binding proteins (ULBP1-6). While typically present at low levels in healthy cells and tissue, NKG2DL expression can be induced by viral infection, cellular stress or transformation. Aberrant activity along the NKG2D/NKG2DL axis has been associated with autoimmune diseases due to the increased expression of NKG2D ligands in human disease tissue, making NKG2D inhibitors an attractive target for immunomodulation. Herein we describe the discovery and optimization of small molecule PPI (protein-protein interaction) inhibitors of NKG2D/NKG2DL. Rapid SAR was guided by structure-based drug design and accomplished by iterative singleton and parallel medicinal chemistry synthesis. These efforts resulted in the identification of several potent analogs (14, 21, 30, 45) with functional activity and improved LLE.

Impact of nicotine and cotinine on macrophage inflammatory plasticity via vesicular modifications in gastrointestinal bacteria.

OBJECTIVES: This study aimed to elucidate mechanistic explanation(s) for compositional changes to enteric microbiota by determining the impacts of continuous nicotine/cotinine exposure on representative gastrointestinal bacteria and how these alterations impact innate immune cell plasticity. METHODS: In vitro cultures of the gastrointestinal bacteria (Bacteroides fragilis 25285, Prevotella bryantii B14, and Acetoanaerobium sticklandii SR) were continuously exposed to nicotine or cotinine. Supernatant samples were collected for fermentation acid analysis. Vesicles were collected and analyzed for physiological changes in number, size, and total protein cargo. Cultured macrophages were stimulated to a tolerogenic phenotype, exposed to control or altered (nicotine or cotinine - exposed) vesicles, and inflammatory plasticity assessed via inflammatory cytokine production. RESULTS: Nicotine/cotinine exposure differentially affected metabolism of all bacteria tested in a Gram (nicotine) and concentration-dependent (cotinine) manner. Physiological studies demonstrated changes in vesiculation number and protein cargo following nicotine/cotinine exposures. Continuous exposure to 1 µM nicotine and 10 µM cotinine concentrations reduced total protein cargo of Gram (-) - 25285 and B14 vesicles, while cotinine generally increased total protein in Gram (+) - SR vesicles. We found that theses physiological changes to the vesicles of 25285 and SR formed under nicotine and cotinine, respectively, challenged the plasticity of tolerogenic macrophages. Tolerogenic macrophages exposed to vesicles from 1 µM nicotine, and 5 or 10 µΜ cotinine cultures produced significantly less IL-12p70, TNFα, or KC/GRO, regardless of macrophage exposure to nicotine/cotinine. CONCLUSIONS: Nicotine/cotinine exposure differentially alters bacterial metabolism and vesicle physiology, ultimately impacting the inflammatory response of tolerogenic macrophages.

The Impact of the Cold Pressor Test on Inter-arm Differences in Blood Pressure.

A large inter-arm difference (IAD+; ≥10mmHg between arms at rest) in blood pressure (BP) at rest is linked to cardiovascular risk, and exercise can change this difference. As mechanisms for IAD are elusive, unique physiological stimuli may provide insight towards a better understanding of this phenomenon. The cold pressor test (CPT) has a potent effect on BP and acts primarily through sympathetic nervous system (SNS) stimulation, though the effects of SNS stimulation on IAD are unknown. Therefore, the purpose of the present study was to examine the effects of the CPT on IAD. BP was monitored simultaneously using two automated, auscultatory monitors (SunTech Tango) and a non-invasive hemodynamic device (Physioflow). Participants completed a CPT test, including a 15-minute rest, three pre-test BP measurements (averaged), and a three-minute water immersion (3°C; measurements at 30-sec and 2-min). Descriptive statistics were calculated, and a repeated measures ANOVA test used to compare both the absolute and relative IAD responses. The CPT induced an average absolute increase in IAD of 4.0 mmHg at 30-sec and 6.7mmHg at 2-min across all participants (P<0.05). Differences in both the absolute and relative IAD responses to the CPT were noted between IAD- and IAD+ individuals (P<0.05). Despite a consistent HR response to the CPT between groups, stroke volume was lower in IAD+ participants at 30-sec and 2-min. Sympathetic stimulation via the CPT induced changes in both the inter-arm difference in blood pressure and hemodynamics in young, apparently-healthy individuals.

Pharmacist-led hormonal contraceptive prescribing service in a Federally Qualified Health Center: Initial implementation outcomes.

BACKGROUND: The United States has a higher rate of unintended pregnancy than many other developed countries, and Indiana's unintended pregnancy rate is above the national average. Unintended pregnancy rates are highest among low-income women. Federally Qualified Health Centers (FQHC) provide care for the underserved and uninsured patient population. OBJECTIVE: To determine the acceptability, adoption, appropriateness, and feasibility of a pharmacist-led hormonal contraception prescribing service within a FQHC through a collaborative drug therapy management protocol. METHODS: An explanatory mixed methods analysis included surveys followed by semistructured interviews. A survey was created and distributed to all patients who received the service and all providers (physicians and nurse practitioners) employed at the FQHC during service implementation. Semistructured interviews were conducted with a subset of patients and providers. RESULTS: A total of 11 patients and 8 providers completed the survey between January 1, 2022 and June 10, 2022. Of these participants, 4 patients and 4 providers completed an interview between May 1, 2022 and June 30, 2022. Both patients and providers perceived the service as acceptable and appropriate, and providers perceived implementation of the service within clinic as feasible. Ten patients received a prescription from the pharmacist; 1 patient was referred to a provider as the pharmacist was unable to prescribe the medication requested. CONCLUSION: Implementation of pharmacist prescribed hormonal contraception was perceived as acceptable, appropriate, and feasible by patients and providers. Pharmacists are perceived by patients and providers as an additional resource for hormonal contraception prescribing within a FQHC due to their clinical knowledge, efficiency, and attention paid to patients' concerns.

Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Dendritic Cell Membrane-Derived Nanovesicles for Targeted T Cell Activation.

T cells play an integral role in the generation of an effective immune response and are responsible for clearing foreign microbes that have bypassed innate immune system defenses and possess cognate antigens. The immune response can be directed toward a desired target through the selective priming and activation of T cells. Due to their ability to activate a T cell response, dendritic cells and endogenous vesicles from dendritic cells are being developed for cancer immunotherapy treatment. However, current platforms, such as exosomes and synthetic nanoparticles, are limited by their production methods and application constraints. Here, we engineer nanovesicles derived from dendritic cell membranes with similar properties as dendritic cell exosomes via nitrogen cavitation. These cell-derived nanovesicles are capable of activating antigen-specific T cells through direct and indirect mechanisms. Additionally, these nanovesicles can be produced in large yields, overcoming production constraints that limit clinical application of alternative immunomodulatory vesicle or nanoparticle-based methods. Thus, dendritic cell-derived nanovesicles generated by nitrogen cavitation show potential as an immunotherapy platform to stimulate and direct T cell response.

Structural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel.

Mechanosensitive channels of small conductance, found in many living organisms, open under elevated membrane tension and thus play crucial roles in biological response to mechanical stress. Amongst these channels, MscK is unique in that its activation also requires external potassium ions. To better understand this dual gating mechanism by force and ligand, we elucidate distinct structures of MscK along the gating cycle using cryo-electron microscopy. The heptameric channel comprises three layers: a cytoplasmic domain, a periplasmic gating ring, and a markedly curved transmembrane domain that flattens and expands upon channel opening, which is accompanied by dilation of the periplasmic ring. Furthermore, our results support a potentially unifying mechanotransduction mechanism in ion channels depicted as flattening and expansion of the transmembrane domain.

A genotyping-in-thousands by sequencing panel to inform invasive deer management using noninvasive fecal and hair samples.

Studies in ecology, evolution, and conservation often rely on noninvasive samples, making it challenging to generate large amounts of high-quality genetic data for many elusive and at-risk species. We developed and optimized a Genotyping-in-Thousands by sequencing (GT-seq) panel using noninvasive samples to inform the management of invasive Sitka black-tailed deer (Odocoileus hemionus sitkensis) in Haida Gwaii (Canada). We validated our panel using paired high-quality tissue and noninvasive fecal and hair samples to simultaneously distinguish individuals, identify sex, and reconstruct kinship among deer sampled across the archipelago, then provided a proof-of-concept application using field-collected feces on SGang Gwaay, an island of high ecological and cultural value. Genotyping success across 244 loci was high (90.3%) and comparable to that of high-quality tissue samples genotyped using restriction-site associated DNA sequencing (92.4%), while genotyping discordance between paired high-quality tissue and noninvasive samples was low (0.50%). The panel will be used to inform future invasive species operations in Haida Gwaii by providing individual and population information to inform management. More broadly, our GT-seq workflow that includes quality control analyses for targeted SNP selection and a modified protocol may be of wider utility for other studies and systems where noninvasive genetic sampling is employed.

Outcomes After Hamstring ACL Reconstruction With Suture Tape Reinforcement in Adolescent Athletes.

Background: Previous studies have suggested that suture tape-reinforced anterior cruciate ligament (ACL) grafts may have higher ultimate failure loads without stress-shielding. In patients at high risk for graft failure, such as adolescents, the addition of suture tape could have beneficial outcomes. Hypothesis: Suture tape reinforcement (STR) of ACL grafts in adolescent patients would lead to fewer graft ruptures during early recovery, without hindering subjective outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review was performed on adolescent patients with a minimum 2-year follow-up after hamstring tendon autograft ACL reconstruction; enrolled were patients from both before (n = 40) and after (n = 40) a shift in surgical technique that added STR. Both the no-STR and the STR cohorts were contacted yearly to obtain patient-reported outcome data for visual analog scale (VAS; range, 0-10) for pain score, Single Assessment Numeric Evaluation, Lysholm score, Tegner activity score, patient satisfaction score (range, 0-100), and return to previous level of sport (yes/no). The cohorts were then matched based on follow-up duration, excluding those with follow-up of <2 years and >3 years to maintain consistency in duration of follow-up. Graft failure was defined as either graft rupture or recurrent instability symptoms, and failures occurring from index procedure to the 3-year mark were recorded for calculations of failure rate. Results: There were no differences between cohorts in mean age [STR, 15.7 years (range, 9.5-18.7 years); no STR, 14.9 years (range, 9.3-18.8 years)], follow-up duration, laterality, or graft size. While not statistically significant, 2 (5%) patients in the STR cohort experienced graft rupture compared with 7 (17.5%) patients in the no-STR cohort. The Tegner score was significantly higher in the STR cohort (P = .017); no between-group differences were seen on the other outcome scores. A subanalysis of the STR cohort comparing small-diameter grafts (<8 mm) with grafts ≥8 mm also demonstrated no difference in outcome measures, with 1 graft failure in each cohort. Conclusion: Study outcomes indicated that patients treated with ACL reconstruction and STR experienced a significant improvement in Tegner scores while at the same time maintaining the other subjective outcomes.

Population genomics of Sitka black-tailed deer supports invasive species management and ecological restoration on islands.

Invasive mammals represent a critical threat to island biodiversity; eradications can result in ecological restoration yet may fail in the absence of key population parameters. Over-browsing by invasive Sitka black-tailed deer (Odocoileus hemionus sitkensis) is causing severe ecological and cultural impacts across the Haida Gwaii archipelago (Canada). Previous eradication attempts demonstrate forest regeneration upon deer removal, but reinvasion reverses conservation gains. Here we use restriction-site associated DNA sequencing (12,947 SNPs) to investigate connectivity and gene flow of invasive deer (n = 181) across 15 islands, revealing little structure throughout Haida Gwaii and identifying the large, central island of Moresby (>2600 km2) as the greatest source of migrants. As a result, the archipelago itself should be considered the primary eradication unit, with the exception of geographically isolated islands like SGang Gwaay. Thus, limiting eradications to isolated islands combined with controlled culling and enhanced biosecurity may be the most effective strategies for achieving ecological restoration goals.

Neuron-Derived Extracellular Vesicles Modulate Microglia Activation and Function.

Microglia act as the immune cells of the central nervous system (CNS). They play an important role in maintaining brain homeostasis but also in mediating neuroimmune responses to insult. The interactions between neurons and microglia represent a key process for neuroimmune regulation and subsequent effects on CNS integrity. However, the molecular mechanisms of neuron-glia communication in regulating microglia function are not fully understood. One recently described means of this intercellular communication is via nano-sized extracellular vesicles (EVs) that transfer a large diversity of molecules between neurons and microglia, such as proteins, lipids, and nucleic acids. To determine the effects of neuron-derived EVs (NDEVs) on microglia, NDEVs were isolated from the culture supernatant of rat cortical neurons. When NDEVs were added to primary cultured rat microglia, we found significantly improved microglia viability via inhibition of apoptosis. Additionally, application of NDEVs to cultured microglia also inhibited the expression of activation surface markers on microglia. Furthermore, NDEVs reduced the LPS-induced proinflammatory response in microglia according to reduced gene expression of proinflammatory cytokines (TNF-α, IL-6, MCP-1) and iNOS, but increased expression of the anti-inflammatory cytokine, IL-10. These findings support that neurons critically regulate microglia activity and control inflammation via EV-mediated neuron-glia communication. (Supported by R21AA025563 and R01AA025591).

Magnitude and significance of interarm blood pressure differences in children and adolescents.

BACKGROUND: An interarm difference (IAD) in blood pressure (BP) of 10 mmHg or more is a potential cardiovascular risk factor in adults, given its association with cardiovascular events/mortality. In children and adolescents, accurate BP assessment is critical for identifying risk of end organ damage. However, IAD has not been systematically studied in paediatric patients; if present and of significant magnitude, measuring BP in only one arm could lead to misclassification of hypertensive status. METHOD: In 95 children/adolescents with a normal aorta (including 15 with a history of tetralogy of Fallot) aged 7-18 years attending the Royal Children's Hospital, Melbourne, we aimed to determine the magnitude of IAD, frequency of IAD of at least 10 mmHg, difference in BP classification between arms, and influence of repeat measures on IAD in a single visit. After 5 min rest, simultaneous bilateral BP was measured in triplicate with an automated device. RESULTS: Absolute systolic IAD was 5.0 mmHg (median, interquartile range 2-8 mmHg) and was 10 mmHg or more in 14%, with no change on repeat measures. In patients with a history of aortic surgery, IAD of 10 mmHg or more occurred in 27% (transposition of the great arteries, n = 15) and 75% (aortic coarctation, n = 8). Differences in BP classification, based on initial left vs. right arm measures, occurred in 25% (normal aorta) and 40%/63% (aortic surgery), or 17% and 33%/50%, respectively if second and third measurements were averaged. CONCLUSION: Substantial interarm BP differences were common, even in apparently healthy children and adolescents: evaluation of IAD may, therefore, be important for BP classification in the paediatric setting.

Discovery of small molecule positive allosteric modulators of the secretin receptor.

The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a high-throughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs. Here we outline a comprehensive study comprising a structure-activity series based on commercially available analogs of the three hit scaffold sets A (2-sulfonyl pyrimidines), B (2-mercapto pyrimidines) and C (2-amino pyrimidines), which revealed determinants of activity, cooperativity and specificity. Structural optimization of original hits resulted in analog B2, which substantially enhances signaling of truncated secretin peptides and prolongs residence time of labeled secretin up to 13-fold in a dose-dependent manner. Furthermore, we found that investigated compounds display structural similarity to positive allosteric modulators (PAMs) active at the glucagon-like peptide-1 receptor (GLP-1R), and we were able to confirm cross-recognition of that receptor by a subset of analogs. Studies using SCTR and GLP-1R mutants revealed that scaffold A, but not B and C, likely acts via two distinct mechanisms, one of which constitutes covalent modification of Cys-347GLP-1R known from GLP-1R-selective modulators. The scaffolds identified in this study might not only serve as novel pharmacologic tools to decipher SCTR- or GLP-1R-specific signaling pathways, but also as structural leads to elucidate allosteric binding sites facilitating the future development of orally available therapeutic approaches targeting these receptors.

Development of a Testing Funnel for Identification of Small-Molecule Modulators Targeting Secretin Receptors.

The secretin receptor (SCTR), a prototypical class B G protein-coupled receptor (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of its endogenous peptide ligand secretin. SCTRs can be found in a variety of tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, and brain. Beyond that, modulation of SCTR-mediated signaling has therapeutic potential for the treatment of multiple diseases, such as heart failure, obesity, and diabetes. However, no ligands other than secretin and its peptide analogs have been described to regulate SCTRs, probably due to inherent challenges in family B GPCR drug discovery. Here we report creation of a testing funnel that allowed targeted detection of SCTR small-molecule activators. Pursuing the strategy to identify positive allosteric modulators (PAMs), we established a unique primary screening assay employing a mixture of three orthosteric stimulators that was compared in a screening campaign testing 12,000 small-molecule compounds. Beyond that, we developed a comprehensive set of secondary assays, such as a radiolabel-free target engagement assay and a NanoBiT (NanoLuc Binary Technology)-based approach to detect ß-arrestin-2 recruitment, all feasible in a high-throughput environment as well as capable of profiling ligands and hits regarding their effect on binding and receptor function. This combination of methods enabled the discovery of five promising scaffolds, four of which have been validated and further characterized with respect to their allosteric activities. We propose that our results may serve as starting points for developing the first in vivo active small molecules targeting SCTRs.

Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793.

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.

Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans.

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO2 inhalation challenge to induce panic symptoms. In the rat CO2 model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P < 0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO2 exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

Sex differences in the association between PTSD symptoms with cardiac autonomic function and subclinical atherosclerotic risk.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a public health concern that may elevate the risk for cardiovascular disease (CVD). There are established sex differences in both PTSD risk and CVD risk. PURPOSE: To examine sex-specific associations between subclinical PTSD symptom severity and subclinical CVD risk in young men and women. METHODS: A total of 61 young adults (women: n = 29, mean age: 26 ± 7 years) completed the post-traumatic stress disorder civilian checklist (PCL) and the Center for Epidemiologic Studies Depression Scale (CES-D). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV). Peripheral vasomotor function was measured as flow-mediated slowing (FMS) of carotid-radial PWV following 5-min forearm occlusion. Heart rate variability was used to assess sympathovagal balance as LF/HF ratio. RESULTS: PCL score was positively correlated with CES-D score (r = 0.79, p < .001), cfPWV (r = 0.33, p = .03) and LF/HF ratio (r = 0.42, p = .009) in men. PCL score was positively correlated to CES-D score (r = 0.80, p < .001) in women, but was inversely correlated to cfPWV (r = -0.38, p = .02) and LF/HF ratio (r = -0.34, p = .04). PCL score was also inversely associated with FMS in women (r = -0.49, p = .01). CONCLUSION: There are sex differences in the association of PTSD symptoms and subclinical atherosclerosis. In men, increased PTSD symptoms may increase CVD risk by increasing sympathovagal balance and aortic stiffness. In women, increased PTSD symptoms may increase CVD risk via reducing vasomotor function.

Inequalities in Pediatric Fracture Care Timeline Based on Insurance Type.

INTRODUCTION: Socioeconomic and insurance status are often linked with limited access to health care. Despite several government-funded projects aimed at curtailing these barriers, pediatric orthopaedic patients continue to experience delays in receiving timely care for fracture treatments. This delay has been well-identified within the orthopaedic literature but, to our knowledge, has never been characterized based on timeline. Thus, the goal of this study is to evaluate the role of ethnicity, socioeconomic status, and insurance type on the timeline of pediatric patients to obtain orthopaedic care within our community. METHODS: Pediatric patients presenting to our clinic for the treatment of one of 21 most common fractures were included. Patient demographics and the timeline of patient care were collected by retrospective chart review. RESULTS: Government-funded insurance accounted for 60.6% of the 413 patients. These patients experienced significant (P < 0.001) delays in access to care when compared with commercial insurance patients; the time between injury and referral as well as the overall time from injury to orthopaedic evaluation was 2.8 and twofold greater at 4.4 days and 9.2 days, respectively. A strong correlation was established between income levels and insurance type. DISCUSSION: Pediatric patients with a lower socioeconomic status are more likely to rely on government-funded insurance and experience delays in fracture evaluation.