Evolution of More Aggressive LDL-Cholesterol Targets and Therapies for Cardiovascular Disease Prevention.

Over the last half-century, discussions on the exact targets for low-density lipoprotein cholesterol (LDL-C) reduction have evolved towards a more aggressive approach with lower LDL-C targets, particularly for high-risk patients with pre-existing atherosclerotic cardiovascular disease (ASCVD). A wealth of cardiovascular outcome trials have shown the efficacy of statin therapy in general, as well as the incremental impact of high-intensity statin therapy in particular. More recent trials have further demonstrated the impact of non-statin therapies, including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and, most recently, bempedoic acid, on reducing ASCVD outcomes. The availability of these and other newer therapies has prompted clinicians to strive for lower LDL-C targets to address residual ASCVD risk after statin therapy. This paper will provide an overview of the historical trends in lipid management and therapeutics and review the current state of evidence for lower LDL-C targets in clinical guidelines and recommendations.

Shortened Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Contemporary Clinical Review.

Percutaneous coronary intervention with stent implantation is an integral aspect of minimally interventional cardiac procedures. The technology and techniques behind stent design and implantation have evolved rapidly over several decades. However, continued discourse remains around optimal peri- and post-interventional management with dual antiplatelet therapy to minimise both major cardiovascular or cerebrovascular events and iatrogenic bleeding risk. Standard guidelines around dual antiplatelet therapy historically recommended long-term dual antiplatelet therapy for 12 months (with consideration for >12 months in certain patients); however, emerging data and generational improvements in the safety of drug-eluting stents have ushered in a new era of short-term therapy to reduce the incidence of major bleeding events. This case review will provide an overview of the current state of guidelines around duration of dual antiplatelet therapy and examine recent updates and continued gaps in existing research.

Nonsteroidal anti-inflammatory drugs in end-stage kidney disease: dangerous or underutilized?

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a popular class of analgesic and anti-inflammatory medications, but their use is often avoided in end-stage kidney disease (ESKD) patients due to their reputation for nephrotoxic side effects. This removes a useful agent from the analgesic arsenal, even as ESKD patients suffer from proportionally more severe chronic pain than the general population as well as from a large reliance on opioid medications. Areas Covered: This paper reviews the current literature to comprehensively define the pharmacologic mechanisms and adverse effects of NSAIDs and reassesses the viability of their use in ESKD patients. Expert opinion: The evidence directly examining the impact of NSAIDs on long-term outcomes in ESKD is limited. Further study quantifying the risk of NSAID use - especially in dialysis-dependent patients - is warranted. Given the difficulty in achieving adequate pain control in ESKD patients, limited use of NSAIDs in these patients may yet be justified.

Wide pulse pressure: A clinical review.

Pulse pressure naturally increases over time as individuals' age due to arteriosclerosis and diffuse vascular stiffening. However, the differential for widened pulse pressure is broad and includes causes of hyperdynamic circulation and high-output heart failure, such as aortic regurgitation and hyperthyroidism. In the absence of an underlying cause, wide pulse pressure is a sign of deteriorating cardiovascular health and carries increased risk for mortality, disease progression, and adverse clinical outcomes in chronic diseases including cardiovascular disease and chronic kidney disease. Current emphasis of antihypertensive treatment on systolic and diastolic blood pressure does not always address pulse pressure, thus subjecting many patients to an independent risk factor for poor outcomes. Pulse pressure control is more successfully achieved with thiazide diuretics and long-acting nitrates when compared to other antihypertensive agents, but further research is needed to quantify the additional benefits of pulse pressure control over conventional blood pressure therapy. This case review provides an overview of the pathogenesis, pathologic causes, and treatment of widened pulse pressure and evaluates current evidence for pulse pressure as a predictor of clinical outcomes.

Refractive Outcomes for Cataract Surgery With Toric Intraocular Lenses at a Veterans Affairs Medical Center.

Background: Refractive outcomes for cataract surgery with toric intraocular lenses (IOLs) are not well described in a teaching hospital setting. This study investigated the refractive outcomes of cataract surgery with toric IOLs at an academic-affiliated Veterans Affairs Medical Center (VAMC) and compared the accuracy of 2 biometric formulae for toric IOL power calculation. Methods: A retrospective chart review of patients who received cataract surgery with toric IOLs from November 2013 to May 2018 was conducted. The Holladay 2 and Barrett toric IOL formulae were used to predict the postoperative refraction for each cataract surgery. The main outcome measures were best-corrected visual acuity (BCVA) and the difference in cylinder between the preoperative and postoperative manifest refractions. The accuracy of each biometric formula was also assessed using 2-tailed t tests of the mean absolute error, and subgroup analyses were conducted for short, medium, and long eyes. Results: Of 325 charts reviewed, 283 patients met the inclusion criteria; 87% (248/283) of these surgeries were performed by resident surgeons. The median postoperative BCVA was 20/20, and 92% of patients had a postoperative BCVA of 20/25 or better. There was no statistically significant difference in mean absolute error between the 2 formulae for the entire axial length range (P = .21), as well as the short (P = .94), medium (P = .49), and long axial length (P = .08) groups. Conclusions: To our knowledge, this is the largest study that compared the performance of the Barrett toric and Holladay 2 formulae and the first that made the comparison in a teaching hospital setting. This study suggests that the 2 formulae have similar refractive outcomes across all axial lengths.

Augmented reality in medical education: a systematic review.

INTRODUCTION: The field of augmented reality (AR) is rapidly growing with many new potential applications in medical education. This systematic review investigated the current state of augmented reality applications (ARAs) and developed an analytical model to guide future research in assessing ARAs as teaching tools in medical education. METHODS: A literature search was conducted using PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar. This review followed PRISMA guidelines and included publications from January 1, 2000 to June 18, 2018. Inclusion criteria were experimental studies evaluating ARAs implemented in healthcare education published in English. Our review evaluated study quality and determined whether studies assessed ARA validity using criteria established by the GRADE Working Group and Gallagher et al., respectively. These findings were used to formulate an analytical model to assess the readiness of ARAs for implementation in medical education. RESULTS: We identified 100,807 articles in the initial literature search; 36 met inclusion criteria for final review and were categorized into three categories: Surgery (23), Anatomy (9), and Other (4). The overall quality of the studies was poor and no ARA was tested for all five stages of validity. Our analytical model evaluates the importance of research quality, application content, outcomes, and feasibility of an ARA to gauge its readiness for implementation. CONCLUSION: While AR technology is growing at a rapid rate, the current quality and breadth of AR research in medical training is insufficient to recommend the adoption into educational curricula. We hope our analytical model will help standardize AR assessment methods and define the role of AR technology in medical education.

CONTEXTE: Le domaine de la réalité augmentée (RA) est en pleine émergence et dispose de plusieurs nouvelles applications potentielles en éducation médicale. Cette revue systématique a évalué l'état actuel des applications de réalité augmentée (ARA) afin d'et élaboré un modèle analytique pour orienter les futures recherches sur l'évaluation des ARA comme outils pédagogiques en éducationmédicale. MÉTHODES: Une recherche documentaire a été menée à l'aide de PubMed, Web of Science, Cochrane Library et Google Scholar. Cette revue a suivi les directives de la méthode PRISMA et contenait les publications du 1er janvier 2000 au 18 juin 2018. Les études étaient retenues si elles avaient un devis expérimental et qu'elles avaient été publiées en anglais et qu'elles évaluaient des ARA mises en place dans l'enseignement des soins de santé. Notre revuea évalué la qualité des études et déterminé si les études ont pu évaluer la validité des ARA en utilisant les critères établis par le GRADE Working Group et Gallagher et coll., respectivement. À partir de ces conclusions, nous avons formulé un modèle analytique afin d'évaluer si les ARA peuvent être mises en place dans la formation médicale. RÉSULTATS: Nous avons trouvé 100 807 articles lors de la recherche documentaire initiale; 36 ont satisfait aux critères d'inclusion pour l'examen final et ont été classés dans trois catégories : chirurgie (23), anatomie (9) et autre (4). La qualité globaledes études était de mauvaise et aucune ARA n'a été testée pour toutes les cinq étapes de validité. Notre modèle analytique évalue l'importance de la qualité des recherches, du contenu des applications, des résultats, et de la faisabilité d'une ARA pour déterminer si elle est prête à être mise en place. CONCLUSION: Bien que la technologie de la RA progresse rapidement, la qualité et l'étendue actuelles de la recherche sur la RA en éducationmédicale sont insuffisantes pour recommander son adoption dans le cursus de formation. Nous espérons que notre modèle analytique aidera à uniformiserles méthodes d'évaluations de la RA et à déterminer le rôle de la technologie liée à la RA en éducation médicale.

Accuracy of biometric formulae for intraocular lens power calculation in a teaching hospital.

AIM: To evaluate the accuracy of three commonly used biometric formulae across different axial lengths (ALs) at one United States Veterans Affairs teaching hospital. METHODS: A retrospective chart review was conducted from November 2013 to May 2018. One eye of each patient who underwent cataract surgery with a monofocal intraocular lens (IOL) was included. The range of postoperative follow-up period was from 3wk to 4mo. The Holladay 2, Barrett Universal II, and Hill-Radial Basis Function (Hill-RBF) formulae were used to predict the postoperative refraction for all cataract surgeries. For each formula, we calculated the prediction errors [including mean absolute prediction error (MAE)] and the percentage of eyes within ±0.25 diopter (D) and ±0.5 D of predicted refraction. We performed subgroup analyses for short (AL<22.0 mm), medium (AL 22.0-25.0 mm), and long eyes (AL>25.0 mm). RESULTS: A total of 1131 patients were screened, and 909 met the inclusion criteria. Resident ophthalmologists were the primary surgeons in 710 (78.1%) cases. We found no statistically significant difference in predictive accuracy among the three formulae over the entire AL range or in the short, medium, and long eye subgroups. Across the entire AL range, the Hill-RBF formula resulted in the lowest MAE (0.384 D) and the highest percentage of eyes with postoperative refraction within ±0.25 D (42.7%) and ±0.5 D (75.5%) of predicted. All three formulae had the highest MAEs (>0.5 D) and lowest percentage within ±0.5 D of predicted refraction (<55%) in short eyes. CONCLUSION: In cataract surgery patients at our teaching hospital, three commonly used biometric formulae demonstrate similar refractive accuracy across all ALs. Short eyes pose the greatest challenge to predicting postoperative refractive error.

Example-Based Learning as a Guide for Revising a Peer-Reviewed Manuscript.

Publishing medical research is an increasingly competitive process for junior researchers. One critical step is revising a manuscript with editorial team feedback. This article's purpose is to utilize a novel example-based learning approach to provide trainees and junior faculty with ten steps on how to successfully navigate the manuscript peer-review process. To this end, each step in the proposed guide is correlated with the authors' most recent publication experience, with key manuscript and editor response letter versions made available through an open-access digital repository.

Epitope-Specific Evolution of Human B Cell Responses to Borrelia burgdorferi VlsE Protein from Early to Late Stages of Lyme Disease.

Most immunogenic proteins of Borrelia burgdorferi, the causative agent of Lyme disease, are known or expected to contain multiple B cell epitopes. However, the kinetics of the development of human B cell responses toward the various epitopes of individual proteins during the course of Lyme disease has not been examined. Using the highly immunogenic VlsE as a model Ag, we investigated the evolution of humoral immune responses toward its immunodominant sequences in 90 patients with a range of early to late manifestations of Lyme disease. The results demonstrate the existence of asynchronous, independently developing, Ab responses against the two major immunogenic regions of the VlsE molecule in the human host. Despite their strong immunogenicity, the target epitopes were inaccessible to Abs on intact spirochetes, suggesting a lack of direct immunoprotective effect. These observations document the association of immune reactivity toward specific VlsE sequences with different phases of Lyme disease, demonstrating the potential use of detailed epitope mapping of Ags for staging of the infection, and offer insights regarding the pathogen's possible immune evasion mechanisms.

Association of immune response to endothelial cell growth factor with early disseminated and late manifestations of Lyme disease but not posttreatment Lyme disease syndrome.

Endothelial cell growth factor has been recently proposed as a potential autoantigen in manifestations of Lyme disease that are thought to involve immune-mediated mechanisms. Our findings indicate that a humoral immune response to this protein is not associated with posttreatment Lyme disease syndrome.

Clinically viable magnetic poly(lactide-co-glycolide) particles for MRI-based cell tracking.

PURPOSE: To design, fabricate, characterize, and in vivo assay clinically viable magnetic particles for MRI-based cell tracking. METHODS: Poly(lactide-co-glycolide) (PLGA) encapsulated magnetic nano and microparticles were fabricated. Multiple biologically relevant experiments were performed to assess cell viability, cellular performance, and stem cell differentiation. In vivo MRI experiments were performed to separately test cell transplantation and cell migration paradigms, as well as in vivo biodegradation. RESULTS: Highly magnetic nano (∼100 nm) and microparticles (∼1-2 µm) were fabricated. Magnetic cell labeling in culture occurred rapidly achieving 3-50 pg Fe/cell at 3 h for different particles types, and >100 pg Fe/cell after 10 h, without the requirement of a transfection agent, and with no effect on cell viability. The capability of magnetically labeled mesenchymal or neural stem cells to differentiate down multiple lineages, or for magnetically labeled immune cells to release cytokines following stimulation, was uncompromised. An in vivo biodegradation study revealed that NPs degraded ∼80% over the course of 12 weeks. MRI detected as few as 10 magnetically labeled cells, transplanted into the brains of rats. Also, these particles enabled the in vivo monitoring of endogenous neural progenitor cell migration in rat brains over 2 weeks. CONCLUSION: The robust MRI properties and benign safety profile of these particles make them promising candidates for clinical translation for MRI-based cell tracking.

The effect of cryoprotection on the use of PLGA encapsulated iron oxide nanoparticles for magnetic cell labeling.

Magnetic PLGA nanoparticles are a significant advancement in the quest to translate MRI-based cell tracking to the clinic. The benefits of these types of particles are that they encapsulate large amounts of iron oxide nanocrystals within an FDA-approved polymer matrix, combining the best aspects of inert micron-sized iron oxide particles, or MPIOs, and biodegradable small particles of iron oxide, or SPIOs. Practically, PLGA nanoparticle fabrication and storage requires some form of cryoprotectant to both protect the particle during freeze drying and to promote resuspension. While this is a commonly employed procedure in the fabrication of drug loaded PLGA nanoparticles, it has yet to be investigated for magnetic particles and what effect this might have on internalization of magnetic particles. As such, in this study, magnetic PLGA nanoparticles were fabricated with various concentrations of two common cryoprotectants, dextrose and sucrose, and analyzed for their ability to magnetically label cells. It was found that cryoprotection with either sugar significantly enhanced the ability to resuspend nanoparticles without aggregation. Magnetic cell labeling was impacted by sugar concentration, with higher sugar concentrations used during freeze drying more significantly reducing magnetic cell labeling than lower concentrations. These studies suggest that cryoprotection with 1% dextrose is an optimal compromise that preserves monodispersity following resuspension and high magnetic cell labeling.

Specific chemotaxis of magnetically labeled mesenchymal stem cells: implications for MRI of glioma.

PURPOSE: Glioblastoma multiforme (GBM) is a lethal disease marked by infiltration of cancerous cells into the surrounding normal brain. The dire outcome of GBM patients stems in part from the limitations of current neuroimaging methods. Notably, early cancer detection methodologies are lacking, without the ability to identify aggressive, metastatic tumor cells. We propose a novel approach for tumor detection using magnetic resonance imaging (MRI) based on imaging specific tumor tropism of mesenchymal stem cells (MSCs) labeled with micron-sized iron oxide particles (MPIOs). PROCEDURES: MPIO labeled and unlabeled MSCs were compared for viability, multi-lineage differentiation, and migration, where both chemotactic and chemokinetic movement were assessed in the presence of serum-free medium, serum-containing medium, and glioma-conditioned medium. MRI was performed on agarose samples, consisting of MPIO-labeled single MSCs, to confirm the capability to detect single cells. RESULTS: We determined that MPIO-labeled MSCs exhibit specific and significant chemotactic migration towards glioma-conditioned medium in vitro. Confocal fluorescence microscopy confirmed that MPIOs are internalized and do not impact important cell processes of MSCs. Lastly, MPIO-labeled MSCs appear as single distinct, dark spots on T(2)*-weighted MRI, supporting the robustness of this contrast agent for cell tracking. CONCLUSIONS: This is the first study to show that MPIO-labeled MSCs exhibit specific tropism toward tumor-secreted factors in vitro. The potential for detecting single MPIO-labeled MSCs provides rationale for in vivo extension of this methodology to visualize GBM in animal models.

Enhanced magnetic cell labeling efficiency using -NH2 coated MPIOs.

Strategies have been developed for labeling cells with micron sized iron oxide particles (MPIOs) for in vivo visualization of cells by magnetic resonance imaging. Although this approach is well established and has a variety of applications, current protocols employ long labeling times. It has been previously demonstrated that incubation of dextran coated iron oxide nanoparticles with positively charged transfection agents, such as poly-L-lysine increases labeling efficiency. Therefore, we sought to ascertain whether preincubating MPIOs with various quantities of poly-L-lysine would similarly enhance the rate of magnetic cell labeling. This was also tested against an NH(2) functionalized, commercially available MPIO. Indeed, we demonstrate significantly increased rate of magnetic cell labeling with MPIOs previously incubated with varying amounts of poly-L-lysine, with robust intracellular labeling at 2 hours. Yet the most robust labeling was achieved with the MPIO-NH(2). Interestingly, even for particle formulations which still had negative zeta potential, enhancement of magnetic cell labeling was achieved.

On the use of micron-sized iron oxide particles (MPIOS) to label resting monocytes in bone marrow.

PURPOSE: The use of MRI to monitor immune cell infiltration into various pathologies is well established. In an effort to boost the magnetic material within immune cells, this work attempted to label resting monocytes within bone marrow, in mice, by intravenous administration of micron-sized iron oxide particles (MPIOs), similar in fashion to the administration of (U)SPIO. PROCEDURES: MPIOs were incubated with various immune cells both in culture, and in whole blood. Flow cytometry and histology were used to analyze magnetic cell labeling. Also, MPIOs were injected intravenously into mice. In vivo, high-resolution 3-D MRI was performed on mouse legs, and signal changes were quantified. Flow cytometry and histology were used to analyze magnetic cell labeling of bone marrow resident cells. RESULTS: It is demonstrated here that monocytes and neutrophils can indeed endocytose MPIOs both in cell culture and ex vivo in whole blood. However, despite rapid accumulation of MPIOs within the bone marrow following injection, MPIOs did not label monocytes or any other hematopoietic cell type in the marrow. Hypotheses are drawn to explain these results in light of recent usage of MPIOs for immune cell tracking. CONCLUSIONS: Systemic administration of various MPIO formulations showed that MPIOs arrive in bone marrow rapidly following injection and remain there for at least 7 days. Data also shows slow clearance of some particles from the tissue over this period. While MPIOs can efficiently label monocytes in culture and in whole blood ex vivo, they were not found to label bone marrow resident monocytes.