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Mycoplasma hyopneumoniae (M. hyopneumoniae) is a significant porcine respiratory disease complex pathogen, prompting many swine farms and production systems to pursue M. hyopneumoniae elimination strategies. Antibody testing is cost-effective in demonstrating sustained freedom from M. hyopneumoniae, often replacing PCR testing on deep tracheal swabs. The process typically involves testing a subpopulation of the herd using an M. hyopneumoniae screening antibody ELISA, with non-negative results further assessed through confirmatory testing, such as PCR. Recently, a commercial (Biochek) fluorescent microsphere immunoassay (FMIA) for detecting M. hyopneumoniae antibodies has been introduced as an alternative to ELISA. Its performance was compared to three commercial ELISAs (Idexx, Hipra, and Biochek) using experimental serum samples from pigs inoculated with M. hyopneumoniae, M. hyorhinis, M. hyosynoviae, M. flocculare, or mock-inoculated with Friis medium. FMIA consistently detected M. hyopneumoniae at earlier time points than the ELISAs, although two false-positive results were encountered using the manufacturer's recommended cutoff. ROC analysis allowed for the evaluation of various cutoffs depending on testing objectives. Poisson regression of misclassification error counts detected no difference in the Biovet FMIA and Hipra ELISA but significantly fewer misclassification errors than Idexx and Biocheck ELISAs. This study showed FMIA as a suitable alternative to traditional ELISAs for screening purposes due to its superior antibody detection rate at early stages. Alternatively, adopting a more stringent cutoff to improve diagnostic specificity could position the FMIA as a viable confirmatory test option. Overall, FMIA is an optimal choice for M. hyopneumoniae antibody surveillance testing, offering versatility in testing strategies (e.g., triplex FMIA M. hyopneumoniae/PRRSV types 1 and 2) and contributing to improved diagnostic capabilities in porcine health management.

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The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington's disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice prior to phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further confirmed with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.

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Since the passage of the 2018 Agriculture Improvement Act (2018 Farm Bill), the number of products containing cannabis-derived compounds available to consumers have rapidly increased. Potential effects on liver function as a result from consumption of products containing cannabidiol (CBD), including hemp extracts, have been observed but the mechanisms for the effects are not fully understood. In this study, hepatocytes derived from human induced pluripotent stem cells (iPSCs) were used to evaluate potential hepatic effects of CBD and hemp extract at exposure concentrations ranging from 0.1 to 30 µM. Despite that a significant reduction in cell viability occurred only in the 30 µM group for both CBD and hemp extract, significant changes to cytochrome P450 activity, mitochondrial membrane potential, and lipid accumulation occurred within the concentration range of 0.1-3 µM for both CBD and hemp extract. Albumin and urea production, caspase 3/7 activity, and intracellular glutathione were significantly affected within the concentration range of 3-30 µM by CBD or hemp extract. These findings indicate that CBD and hemp extract can alter hepatic function and metabolism. The current study contributes data to help inform the evaluation of potential hepatotoxic effects of products containing cannabis-derived compounds.

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BACKGROUND: We aimed to derive a clinical decision rule to identify transient ischemic attack (TIA)/minor stroke patients most likely to benefit from echocardiography. METHODS: This multicentre prospective cohort study enrolled adults diagnosed with TIA/minor stroke in the emergency department who underwent a echocardiogram within 90 days, from 13 Canadian academic emergency departments from October 2006 to May 2017. Our outcome was clinically significant echocardiogram findings. RESULTS: In 7,149 eligible patients, a clinically significant finding was found in 556 (7.8%). There were a further 2,421 (33.9%) with a potentially significant finding. History of heart failure (adjusted odds ratio [OR] 3.9) or coronary artery disease (OR 2.7) were the factors most strongly associated with clinically significant echocardiogram findings, while young age, male sex, valvular heart disease and infarct (any age) on neuroimaging were modestly associated (OR between 1.3 and 1.9). The model combining these predictors into a score (range 0 to 15), had a C-statistic of 0.67 (95%CI 0.65-0.70). A cut point of 6 points or more classified 6.6% of cases as high likelihood, defined as >15% for clinically significant echocardiogram findings. CONCLUSION: Echocardiography is a very useful test in the investigations of TIA/minor stroke patients. We identified high risk clinical features, combined to create a clinical decision rule, to identify which TIA/minor stroke patients are likely to have clinically significant echocardiogram findings requiring an immediate change in management. These patients should have echocardiography prioritized while others may continue to have echocardiography conducted in a less urgent fashion.

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BACKGROUND AND AIM: Epicardial adipose tissue (EAT) plays a role in coronary artery disease (CAD). EAT has regional distribution throughout the heart and each location may have a different genetic profile and function. Glucagon like peptide-1 receptor analogs (GLP-1RAs) reduce cardiovascular risk. However, the short-term effects of GLP-1RA on microRNA (miRNA) profile of each EAT location is unknown. Objective was to evaluate if EAT miRNAs were different between coronary (CORO-EAT), left atrial EAT (LA-EAT) and subcutaneous fat (SAT), and liraglutide can modulate EAT miRNAs expression. METHODS AND RESULTS: This was a 12-week randomized, double-blind, placebo-controlled study in 38 patients with type 2 diabetes (T2DM) and coronary artery disease (CAD) who were started on either liraglutide or placebo for a minimum of 4 up to 12 weeks prior to coronary artery by-pass grafting (CABG). Fat samples were collected during CABG. miR16, miR155 and miR181a were significantly higher in CORO-EAT and in LA-EAT than SAT (p < 0.01 and p < 0.05) in overall patients. miR16 and miR181-a were significantly higher in CORO-EAT than SAT (p < 0.01), and miR155 and miR181a were higher in LA-EAT than SAT (p < 0.05) in the liraglutide group. Liraglutide-treated patients had better intra-op glucose control than placebo (146 ± 21 vs 160 ± 21 mg/dl, p < 0.01). CONCLUSIONS: Our study shows that CORO- and LA-miRNAs profiles were significantly different than SAT miRNAs in overall patients and miRNAs were significantly higher in CORO-EAT and LA-EAT than SAT in the liraglutide group. Pre-op liraglutide was also associated with better intra operative glucose control than placebo independently of weight loss.

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BACKGROUND: Robot-assisted techniques are increasingly integrated into the field of spine surgery, with the potential benefits of increased accuracy and reduced radiation exposure. The objective of this study was to describe the technique of minimally invasive robot-assisted direct pars repair with 2 case illustrations. OBSERVATIONS: An 18-year-old male and a 42-year-old male, both with bilateral L5 spondylolysis, underwent successful minimally invasive L5 direct pars repairs with robotic assistance after conservative measures failed, and their cases are presented herein. LESSONS: A robot-assisted direct pars repair is a safe and effective technique for treating bilateral lumbar spondylolysis. The integration of robot-assisted techniques in spine surgery has the potential to improve outcomes, decrease surgical time, and reduce the amount of radiation exposure to operating room staff. https://thejns.org/doi/10.3171/CASE2415.

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Most gene functions have been discovered through phenotypic observations under loss of function experiments that lack temporal control. However, cell signaling relies on limited transcriptional effectors, having to be re-used temporally and spatially within the organism. Despite that, the dynamic nature of signaling pathways have been overlooked due to the difficulty on their assessment, resulting in important bottlenecks. Here, we have utilized the rapid and synchronized developmental transitions occurring within the zebrafish embryo, in conjunction with custom NF-kB reporter embryos driving destabilized fluorophores that report signaling dynamics in real time. We reveal that NF-kB signaling works as a clock that controls the developmental progression of hematopoietic stem and progenitor cells (HSPCs) by two p65 activity waves that inhibit cell cycle. Temporal disruption of each wave results in contrasting phenotypic outcomes: loss of HSPCs due to impaired specification versus proliferative expansion and failure to delaminate from their niche. We also show functional conservation during human hematopoietic development using iPSC models. Our work identifies p65 as a previously unrecognized contributor to cell cycle regulation, revealing why and when pro-inflammatory signaling is required during HSPC development. It highlights the importance of considering and leveraging cell signaling as a temporally dynamic entity.

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BACKGROUND AND OBJECTIVES: Venous air embolism (VAE) can cause significant morbidity and mortality. Prevention and management of VAE include cessation of air entrainment, positioning changes, and hemodynamic support. The degree to which position change and cardiac output (CO) moderate resolution of intracardiac air has not been rigorously studied using contemporary transesophageal echocardiography (TEE). METHODS: This observational cohort-type study aimed to identify the effect of supine vs sitting positioning on the movement and resolution of intracardiac air. In 20 patients undergoing seated neurosurgery, central venous air aspiration catheters were placed through the median basilic vein. TEE was used to estimate the time required for clearance of agitated microbubbles from the right atrium and ventricle in both the supine and sitting position. Estimates of CO were also obtained echocardiographically in each position. RESULTS: Average clearance time was faster in the sitting vs the supine position with no significant difference in CO. A negative correlation between CO and right atrial clearance time across all patients was demonstrated with a Pearson coefficient of -0.4 (95% CI -0.07, -0.65) with P = .02. CONCLUSION: During VAE, both patient position and CO can significantly affect how bubbles move through intracardiac chambers. However, augmenting CO during VAE may be clinically more feasible, efficient, and productive than changing positioning-especially during crises unless the changing in position is intended to halt the entrainment of air. Further TEE studies of intravascular air movement affected by other position changes (lateral, reverse Trendelenburg) and vasopressors should be considered.

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BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospective data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illnesses, identify factors associated with the risk of PACS, and explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Participants with COVID-19 had significantly more severe illness compared to those with non-COVID-19 respiratory illnesses (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 experienced more severe and longer-lasting symptoms than those with non-COVID-19 respiratory illnesses, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19. FUNDING: Bill & Melinda Gates Foundation [INV-017302] and others (see Acknowledgements).

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Environmental influences on brain structure and function during early development have been well-characterized, but whether early environments are associated with the pace of brain development is not clear. In pre-registered analyses, we use flexible non-linear models to test the theory that prenatal disadvantage is associated with differences in trajectories of intrinsic brain network development from birth to three years (n = 261). Prenatal disadvantage was assessed using a latent factor of socioeconomic disadvantage that included measures of mother's income-to-needs ratio, educational attainment, area deprivation index, insurance status, and nutrition. We find that prenatal disadvantage is associated with developmental increases in cortical network segregation, with neonates and toddlers with greater exposure to prenatal disadvantage showing a steeper increase in cortical network segregation with age, consistent with accelerated network development. Associations between prenatal disadvantage and cortical network segregation occur at the local scale and conform to a sensorimotor-association hierarchy of cortical organization. Disadvantage-associated differences in cortical network segregation are associated with language abilities at two years, such that lower segregation is associated with improved language abilities. These results shed light on associations between the early environment and trajectories of cortical development.

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The experience of itch and its associated chronic conditions (i.e., atopic dermatitis) form a significant burden of disease. Knowledge of how the brain processes itch, that might occur uniquely for chronic itch populations, could be used to guide more effective psychotherapeutic interventions for these groups. To build the evidence base for such approaches, we conducted a series of coordinates-based fMRI analyses, to identify the shared neural mechanisms for itch across the published literature. Upon so doing, we identified a core "itch network" that spans the Basal Ganglia/Thalamus, Claustrum and Insula. Additionally, we found evidence that the Paracentral Lobule and Medial Frontal Gyrus, regions associated with cognitive control and response inhibition, deactivate during itch. Interestingly, a separate analysis for chronic itch populations identified significant recruitment of the Left Paracentral Lobule, potentially suggesting the recruitment of cognitive control mechanisms to resist the urge to scratch. We position these results in light of further integrative studies that could use neuroimaging alongside clinical studies, to explore how transdiagnostic psychological approaches-such as mindfulness and compassion training-might help to improve quality of life for individuals who experience chronic itch.

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INTRODUCTION: Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies. METHODS: In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3-12 mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed. RESULTS: The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19% [96/505] vs. 8% [8/101]) and increased with vesatolimod dose and exposure. Most flu-like AEIs with vesatolimod were grade 1 or 2 severity (55% [53 of 96] grade 1; 35% [34 of 96] grade 2) with onset primarily after the first and second dose. Occurrence of flu-like AEIs after doses 1-3 was predictive of reoccurrence after later doses. Dose-dependent elevations of pharmacodynamic biomarkers (interferon-stimulated gene 15, 2'-5'-oligoadenylate synthetase 1, myxovirus resistance-1, interferon-α, interleukin-1 receptor antagonist, interferon-γ-induced protein 10, interferon-inducible T-cell-α chemoattractant) observed in participants with flu-like AEIs suggest a link with vesatolimod mechanism of action. CONCLUSIONS: Flu-like AEIs associated with vesatolimod administration were typically mild but increased with exposure, which may be predicted by the response to initial doses. The data suggest that adaptive clinical monitoring could help maximize pharmacodynamic responses and balance adverse events in future clinical trials of vesatolimod.

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Emerging evidence implicates common genetic variation - aggregated into polygenic scores (PGS) - in the onset and phenotypic presentation of rare diseases. Here, we comprehensively map individual polygenic liability for 1102 open-source PGS in a cohort of 3059 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. Using this resource, we demonstrate increased polygenic liability in probands with an inherited candidate disease variant (VUS) compared to unaffected carrier parents. Further, we show an enrichment for large-effect rare variants in putative core PGS genes for associated complex traits. Overall, our study supports and expands on previous findings of complex trait associations in rare diseases, implicates polygenic liability as a potential mechanism underlying variable penetrance of candidate causal variants, and provides a framework for identifying novel candidate rare disease genes.

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Introduction: COVID-19 hospitalization rates among unvaccinated children are double of that of vaccinated children, and this difference is greater among racial and ethnic minority children. Vaccination rates among children remain suboptimal. Few studies have characterized barriers to COVID-19 vaccination among historically marginalized communities. Methods: From January 2022 to May 2022, parents and guardians of children aged 12 months to 18 years presenting for pediatric care at a hospital-based primary care clinic were surveyed about perceptions of COVID-19 vaccines, intentions to vaccinate their child, and trusted sources of information. Results: A total of 113 parents/guardians participated, with 92% self-identifying with a historically marginalized racial/ethnic group. A total of 54% of respondents either did not plan to vaccinate their child against COVID-19 or were unsure. The obstacles to vaccination most frequently cited were related to (1) unknown side effects, (2) the rapid development of the vaccine, and (3) unsafe ingredients. Worries about being used as experimental subjects and potential impacts on fertility were also reported. Parents who planned to vaccinate their child reported higher rates of trust in doctors, local clinics, hospitals, and health departments. Conclusions: High rates of COVID-19 vaccination hesitancy exist among parents/guardians from historically marginalized groups. Barriers to vaccination were frequently related to side effects, whereas a high level of trust in healthcare providers as sources of information may be a facilitator. Strategies to improve health outcomes and boost vaccination rates should focus on equipping pediatric healthcare providers with the knowledge and skills necessary to address these known barriers to COVID-19 vaccination.

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INTRODUCTION: Optimal management of retroversion in anatomic total shoulder arthroplasty (aTSA) remains controversial and limited attention has been directed to the impact of glenoid inclination. Prior biomechanical study suggest that residual glenoid inclination generates shear stresses that may lead to early glenoid loosening. Combined biplanar glenoid deformities may complicate anatomic glenoid reconstruction and affect outcomes. The goal of this matched-cohort analysis was to assess the relationship between biplanar deformities and mid-term radiographic loosening in aTSA. METHODS: The study cohort was identified via an institutional repository of 337 preoperative CT scans from 2010-2017. Glenoid retroversion, inclination, and humeral head subluxation were assessed via 3D-planning software. Patients with retroversion ≥ 20˚ and inclination ≥ 10˚ who underwent aTSA with eccentric reaming and non-augmented components were matched by age, sex, retroversion, and Walch classification to patients with retroversion ≥ 20˚ only. Primary outcome was glenoid component Lazarus radiolucency score. RESULTS: Twenty-eight study subjects were matched to 28 controls with retroversion only. No difference in age (61.3 vs. 63.6 years, p=0.26), sex (19 [68%] vs. 19 [68%] male, p=1.0), or follow-up (6.1 vs. 6.4 years, p=0.59). Biplanar deformities had greater inclination (14.5˚ versus 5.3˚, p<0.001), retroversion (30.0˚ versus 25.6˚, p=0.01) and humeral subluxation (86.3% versus 82.1%, p=0.03). Biplanar patients had greater postoperative implant superior inclination (5.9 [4.6] vs. 3.0 [3.6] degrees, p=0.01) but similar rate of complete seating 24 [86%] vs. 24 [86%] p=1.0). At final follow-up, biplanar subjects had higher Lazarus radiolucent scores (2.4 [1.7] vs. 1.6 [1.1], p=0.03) and higher proportion of patients with glenoid radiolucency (19 [68%] vs. 11 [39%], p=0.03). No difference in complete component seating (86% versus 86%, p=0.47) or initial radiolucency grade (0.21 versus 0.29, p=0.55) on immediate postop radiographs. Biplanar patients demonstrated a greater amount of posterior subluxation at immediate postop(3.5% [1.3%] versus 1.8% [0.6%]; p=0.03) and final follow-up (7.6% [2.8%] versus 4.0% [1.8%]; p=0.04). At final radiographic follow-up, biplanar subjects had higher Lazarus radiolucent scores (2.4 [1.7] vs. 1.6 [1.1], p=0.03; ICC=0.82). Bivariate regression analysis demonstrated biplanar deformity was the only significant predictor (OR 3.3, p=0.04) of glenoid radiolucency. CONCLUSION: Biplanar glenoid deformity resulted in time-zero glenoid implant superior inclination and increased mid-term radiographic loosening and posterior subluxation. Attention to glenoid inclination is important for successful anatomical glenoid reconstruction. Future research is warranted to understand the long-term implications of these findings and impact of utilizing augmented implants or reverse shoulder arthroplasty to manage biplanar deformities.

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INTRODUCTION: Vascular smooth muscle cells are important in intimal hyperplasia. Thrombospondin-1 is a matricellular protein involved in the vascular injury response. Statins are cholesterol lowering drugs that have beneficial cardiovascular effects. Statis have been shown to inhibit smooth muscle migration through the mevalonate pathway. This effect is thought to be mediated by small G protein Ras and Rho turnover which requires many hours. While many patients undergoing treatment for vascular disease are on statins, many are not. Thus immediate pretreatment with statins before surgery may be beneficial. We hypothesized that statins have effects independent of the mevalonate pathway and thus have an immediate effect. METHODS: Human vascular smooth muscle cells were pretreated for 20 h (long-term) or 20 min (short-term) with fluvastatin, or mevalonolactone plus fluvastatin. Thrombospondin-1-induced migration, activation of p42/p44 extracellular signal-regulated kinase, c-Src, focal adhesion kinase and PI3 kinase was determined. The effect of fluvastatin on thrombospondin-1-induced expression of THBS1, FOS, HAS2 and TGFB2 was examined. RESULTS: Both treatments inhibited thrombospondin-1-induced chemotaxis back to the control group. Mevalonolactone reversed the long-term statin effect by increasing migration but had no effect on the short-term statin response. p42/p44 extracellular signal-regulated kinase was activated by thrombospondin-1 and both treatments augmented activation. Neither treatment affected c-Src activity, but both inhibited focal adhesion kinase and PI3 kinase activity. Only long-term statin treatment inhibited THBS1 expression while both treatments inhibited FOS and TGFB2 expression. Neither treatment affected HAS2. FOS knockdown inhibited thrombospondin-1-induced HAS2 but not TGFß2 gene expression. CONCLUSION: Long-term fluvastatin inhibited thrombospondin-1-induced chemotaxis through the mevalonate pathway while short-term fluvastatin inhibited chemotaxis through an alternate mechanism. Short-term stains have immediate effects independent of the mevalonate pathway. Acute local treatment with statins followed by longer term therapy may limit the vascular response to injury.