Nearly All Peer-to-Peer Reviews for CT and MRI Prior Authorization Denials for Orthopedic Specialists Are Approved.

In the event of prior authorization denial, physicians may request peer-to-peer review, which may delay treatment and increase administrative burden. The purpose of this study was to quantify the approval rate of peer-to-peer review and evaluate its efficiency in the context of advanced imaging use in an orthopedic practice. Patients at a single outpatient orthopedic clinic initially receiving an insurance denial for computed tomography or magnetic resonance imaging requiring peer-to-peer review from March to December 2022 were prospectively enrolled. Characteristics of the request, peer-to-peer review, and the reviewer and dates in the process were collected. If the study was approved after peer-to-peer review, the date of the imaging study and brief results were recorded. A total of 62 denials were included. One denial was approved prior to peer-to-peer review. Fifty-eight (of 61, 95.1%) reviews were approved, of which 51 (of 58, 87.9%) studies were completed by patients. Reviewers were always physicians (61 of 61, 100%), but of those whose specialty was known, none were orthopedic surgeons. Forty-four of 61 (72.1%) reviewers reported reviewing clinical notes in advance. The median number of days from visit to peer-to-peer review was 9.0 (interquartile range, 7.0-13.25). The median number of days from visit to imaging center appointment was 13.5 (interquartile range, 9.0-20.75) for approved studies. Of the 51 approved studies completed by patients, the results of 38 (74.5%) confirmed the suspected diagnosis. In an orthopedic specialty practice, almost all peer-to-peer reviews were approved, with the majority of the completed studies confirming the suspected diagnosis. Thus, patient care was delayed. Reform is crucial to improve the efficiency of the review process, especially in light of additional administrative and financial burden. [Orthopedics. 202x;4x(x):xx-xx.].

A critical appraisal of Evicore's guidelines for advanced diagnostic imaging of the spine for lower extremity pain with neurological features.

Background: This analysis aims to evaluate the methodological quality of Evicore's spinal imaging guidelines for lower extremity pain with neurological features with or without lower back pain by leveraging the AGREE II tool. The AGREE II tool provides a framework to assess guideline development. It is well validated and has been used to evaluate many other guidelines previously. Methods: Five appraisers used the AGREE II appraisal tool to conduct a comprehensive review of Evicore's spinal imaging guidelines for lower extremity pain with neurological features. Appraisers provided an overall assessment of the guidelines as well as specific scores pertaining to domains including scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability, and editorial independence. Results: Appraisers assigned numerical grades of 2, 2, 2, 3 and 4 (out of 7 total points, with 7 being the highest) for overall quality of the guidelines. Three appraisers recommended use of the guideline with modifications and two appraisers did not recommend the guideline. The AGREE II ratings had good reliability across the different raters [intraclass correlation coefficient (ICC) =0.881, 95% confidence interval (CI): 0.77, 0.94]. Conclusions: Evicore's guidelines would greatly benefit from increased identification and diversification of guideline development parties and stakeholders, increased rigor of development including a more robust discussion of the body of evidence and its strengths and limitations, and incorporation of more explicit suggestions for implementation of guideline recommendations by healthcare providers.

Evaluating the Academic Influence of Orthopedic Surgeons in Spinal Literature Through Relative Citation Ratio.

INTRODUCTION:  The innovative iCite tool applies the relative citation ratio (RCR) to gauge the time and field-adjusted scientific influence of a publication. This study examines scholarly effects on spine surgery to distinguish the impact made by orthopedic surgeons, neurosurgeons, and several other specialists. MATERIALS AND METHODS:  From 2013 to 2017, 100 of the highest RCR-rated articles were gathered for each of the following terms: cervical disc herniation (CDH), lumbar disc herniation (LDH), lumbar spinal stenosis (LSS), neurogenic claudication (NC), radiculopathy (RAD), and sciatica (SC). The first, second, and last authors were queried for background and academic qualifications and placed into the following specialty categories: orthopedic surgery, neurosurgery, pain management, medicine, and others. To provide an alternative degree of influence, the Scopus database was employed to classify the h-index associated with each author. RESULTS:  Across the six search terms, there were 526 orthopedic surgeons among 1,730 authors (30.4%), with the highest representation in LSS (118/290, 40.7%), and the lowest in SC (45/286, 15.7%). Orthopedics was the most influential specialty across all six research terms by median RCR (p = 0.012). Compared to their neurosurgical counterparts, orthopedic authors had a greater influence in CDH (3.93 vs. 2.63, p = 0.0492), LDH (5.10 vs. 4.99, p = 1.0000), NC (2.16 vs. 1.40, p = 0.2370), and SC (3.35 vs. 3.04, p = 0.5285), but had a lower influence in LSS (5.13 vs. 5.32, p = 0.7736) and RAD (5.03 vs. 6.05, p = 0.3938). CONCLUSION:  Orthopedic surgeons lead other specialties when determining scholarly influence through RCR across six of the pre-designated research domains within spine surgery. For orthopedics, a modest influence in LSS and RAD may suggest potential areas of future focus. The use of bibliometrics to analyze available literature enables us to identify other specialties that have contributed to our field and promote interdisciplinary collaboration.

The Influence of Orthopedic Journals in Knee Arthritis Treatment Research: Evaluation Using Relative Citation Ratio.

Introduction The iCite database, developed by the National Institute of Health (NIH), utilizes a bibliometric known as the relative citation ratio (RCR) to gauge scholarly impact. The goal of this study was to use the RCR to evaluate the influence of orthopedic journals in regard to knee arthritis treatment literature, as no such studies exist to date. Materials and methods The 100 highest RCR-rated articles published between 2007 and 2017 were obtained in the following categories: physical therapy (PT), viscosupplementation (VS), nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid injection (CSI), results of total knee arthroplasty (TKA), platelet-rich plasma (PRP), and meniscectomy (MS). Journals were categorized with respect to the following specialties: general orthopedics (GO), orthopedic subspecialty (OSS), nonsurgical musculoskeletal (NSMSK), general medicine (GM), and basic science/nonclinical (BS/NC). Results Across the seven domains, GO journals held the highest median RCR, while OSS ranked fourth (RCR, 6.60 versus 3.95; p=0.0027). GO journals were considered the most influential specialty in CSI (RCR, 2.99), while OSS journals held the highest median RCR in PRP (RCR, 4.10). OSS and GO journals ranked third (RCR, 4.79) and fourth (RCR, 4.21), respectively, in NSAIDs, lagging behind NSMSK and GM journals. Conclusions Bibliometric tools, such as the RCR, can inform the orthopedic field of current and future research trends and help guide further research efforts. Currently, publications in GO journals hold a strong influence in CSI but less so in PT and NSAIDs. The use of bibliometrics allows the identification of highly influential non-orthopedic articles and journals to read while identifying influential non-orthopedic researchers to promote interdisciplinary collaboration.

Factors Associated With Repeat Emergency Department Visits for Low Back Pain.

Background Low back pain represents 2-3% of Emergency Department (ED) visits. In this study, we aimed to identify patient and treatment-related variables that contributed to repeat visits to the ED for low back pain within a 12-month period. Methodology We conducted a retrospective review of adult patients presenting to the ED of one hospital over a two-year period with the primary diagnosis of low back pain. The primary outcome included return to the ED within 12 months with the same complaint, and the secondary outcome included return to the ED within 30 days or six months. Results A total of 793 patients met the inclusion criteria. The rate of return to the ED with the same complaint within 30 days, six months, and 12 months of the first visit was 7%, 11%, and 14%, respectively. Patients who received opioids at discharge were more likely to return within 12 months (68% vs. 55%; p = 0.0075) and six months (68% vs. 56%; p = 0.0184) compared to those who did not receive opioids at discharge. Undergoing an X-ray decreased the odds of a 30-day return visit by 70% (p = 0.0067), and by 59% within 12 months (p = 0.0032). Receiving opioids at discharge also doubled the odds of return within 12 months (odds ratio = 2.030, p = 0.0183), while receiving nonsteroidal anti-inflammatory drugs (NSAIDs) reduced the odds by 60% (p = 0.0028). Conclusions Patients who received opioids at discharge were more likely to have a return visit for low back pain within six and 12 months. Patients who underwent X-rays at the index visit and were prescribed NSAIDs at discharge were less likely to return to the ED for low back pain.

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.

The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

Stand-Alone Interbody Cage to Treat Cervical Facet Dislocation: A Case Report.

CASE: We present a 36-year-old man who sustained a traumatic C5-6 unilateral facet dislocation without neurological deficit. The patient was treated with anterior diskectomy and fusion using a stand-alone interbody cage. CONCLUSION: Current treatment of cervical facet dislocations (CFDs) in patients undergoing an anterior cervical diskectomy and fusion commonly makes use of plates with screw fixation and interbody grafts or cages to achieve spinal fusion after the diskectomy is performed. This report documents the successful treatment of a CFD with a stand-alone interbody cage.

Patient Satisfaction with Orthopedic Telemedicine Health Visits During the COVID-19 Pandemic.

Background:Telemedicine usage in orthopedic surgery has seen a dramatic increase as a result of the severe acute respiratory syndrome coronavirus 2 pandemic. The purpose of this study was to examine patient perceptions with telemedicine at a large orthopedic practice.Materials and Methods:An anonymous online survey was distributed to all patients who received a telemedicine health visit at our institution for musculoskeletal complaints from March 17 to June 1, 2020. Responses were scored on a 5-point Likert scale (strongly disagree, disagree, neutral, agree, and strongly agree, 1-5) and analyzed by average score and percent reaching top box.Results:A majority of patients (76.5%) were satisfied with their visit, and only 19.2% did not want telemedicine as a future option. Patients who presented for follow-up visits (4.11 vs. 3.94, p = 0.0053; 48% vs. 41%, p = 0.02) and utilized video (4.21 vs. 3.88, p < 0.001; 51% vs. 39%, p < 0.001) were more satisfied. Average satisfaction between older (>65 years) and younger patients was similar (4.06 vs. 4.06, p = 0.97), however, younger patients were more likely to reach top box (42% vs. 51%, p < 0.001). Confidence that the physician came to the correct diagnosis (r = 0.78, p < 0.001) and receiving the same information and care as an in-office visit (r = 0.60, p < 0.001) demonstrated the strongest correlation with satisfaction and desire for future telemedicine visits, respectively. Interestingly, 31.1% of patients would have sought treatment elsewhere had telemedicine not been an option.Conclusions:Overall, satisfaction rates are high for orthopedic patients undergoing telemedicine visits. Patients are more confident in telemedicine when presenting for a follow-up visit and with the use of video.

Preparedness for a 'no-notice' mass-casualty incident: a nuclear detonation scenario.

PURPOSE: An effective response for a mass-casualty incident requires understanding the relevant basic science and physical impact; detailed preparedness among jurisdictions; and clear, sequential response planning, including formal operational exercises, logistics, interagency, and public-private coordination, rapid activation of resilience, and continual improvement from lessons learned and new knowledge. This ConRad 2021 meeting report describes steps for civilian medical and public health response planning for a nuclear detonation; the utility of this type of planning for broader application; and extension of this planning to the international community. CONCLUSION: A nuclear detonation requires a response within minutes to what will be a large-scale disaster complicated by radiation, including some elements that are similar to a broad range of incidents. The response could be further complicated if multiple incidents occur simultaneously. Required are detailed planning, preparedness and scripting for an immediate operational response, addressing clinical manifestations of evolving radiation illness, and flexibility to adapt to a rapidly changing situation. This need translates into the use of just-in-time information; effective, credible communication; situational awareness on a global scale; and a template upon which to apply capabilities in a multi-sector response. This effort is greatly facilitated using a 'playbook' approach, the basics of which are presented.

Differences in Patient and Physician Perceptions of Urgency for Musculoskeletal Conditions During the COVID-19 Pandemic.

In 2020, the coronavirus disease 2019 (COVID-19) pandemic limited musculoskeletal care to urgent or "nonelective" office visits and procedures. No guidelines exist to inform patients or physicians what meets these criteria. The purpose of this multi-institutional study was to describe the differences in perceptions of urgency for musculoskeletal complaints between patients and providers during the COVID-19 pandemic. An anonymous survey was distributed to patients who visited the authors' orthopedic clinics in January and February 2020 and practicing orthopedic surgeons. The surveys were administered in May 2020 after COVID-19 was officially labeled a pandemic and included questions regarding demographic information and perceptions of orthopedic urgency. A total of 1491 patients and 128 physicians completed the surveys. A significantly higher percentage of physicians considered the following diagnoses an appropriate indication for an urgent visit compared with patients: fracture (P<.001), acute dislocation (P<.001), infection (P<.001), neurologic compromise (P<.001), tumor (P<.001), acute tendon injury (P<.001), weakness (P<.001), inability to bear weight (P<.001), post-surgical problem (P<.001), and painful joint effusion (P<.001). There were no significant differences in the perception of urgency for the following conditions: bursitis/tendonitis (P=1.00), joint/extremity deformity without pain (P=.113), and loss of range of motion of a joint (P=.467). Younger patients and those with higher levels of education were significantly more likely to consider their conditions urgent. Patients may require additional education to prevent delay in treatment of urgent conditions-especially time-sensitive conditions such as neurologic compromise, tumors, and infections-when access to physicians is limited. [Orthopedics. 2021;44(4):e534-e538.].

Patient Perception of Physician Attire in the Outpatient Setting During the COVID-19 Pandemic.

INTRODUCTION: In response to the SARS-CoV-2 pandemic, physician attire has evolved to incorporate personal protective equipment (PPE). Although PPE is mandated for all healthcare workers, variability exists in choice and availability. The purpose of this study was to determine patient perception of physician attire during the COVID-19 pandemic in an outpatient setting. METHODS: Three hundred sixty-eight patients who presented to our outpatient orthopaedic clinics completed an anonymous survey. In addition to demographic characteristics, patient preferences for attire, PPE, and social distancing were obtained. RESULTS: Scrubs (81%, 298/368) were found to be the most acceptable physician attire. Eye protection (34.2%, 126/368) and gloves (32.6%, 120/368), however, were deemed much less acceptable; 93.5% (344/368) of patients reported that no mask was unacceptable, with 41.0% (151/368) preferring a surgical mask. Predilection for a surgical mask and N95 rose with increasing patient education level. Interestingly, 55.2% (203/368) responded that physicians should stop wearing PPE only when the Center for Disease Control recommends. CONCLUSION: During the COVID-19 pandemic, most of the patients found scrubs to be the most acceptable attire in an office-based outpatient setting. Patients also found physician mask-wearing to be important but are less accepting of providers wearing eye and hand protection.

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates).

After multiple drugs were removed from the market secondary to drug-induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical-industry perspective making the case that "double-negative" nonclinical data (negative in vitro hERG and in vivo heart-rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double-negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double-negative nonclinical data could be used to reduce the number of "Thorough QT" (TQT) studies and reach a low-risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a "stage 2" of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc-prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double-negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

Correlation of Early Outcomes and Intradiscal Interleukin-6 Expression in Lumbar Fusion Patients.

OBJECTIVE: To determine if there is correlation between intradiscal levels of interleukin-6 (IL-6) and early outcome measures in patients undergoing lumbar fusion for painful disc degeneration. METHODS: Intervertebral disc tissue was separated into annulus fibrosus/nucleus pulposus and cultured separately in vitro in serum-free medium (Opti-MEM). Conditioned media was collected after 48 hours. The concentration of IL-6 was quantified using enzyme-linked immunosorbent assay. Pearson correlation coefficients quantified relationships between IL-6 levels and pre- and postoperative visual analogue scale (VAS) back pain and Oswestry Disability Index (ODI), as well as change in VAS/ODI. RESULTS: Sixteen discs were harvested from 9 patients undergoing anterior lumbar interbody fusion (mean age, 47.4 years; range, 21-70 years). Mean preoperative and 6-month postoperative VAS were 8.1 and 3.7, respectively. Mean preoperative and postoperative ODI were 56.2 and 25.6, respectively. There were significant positive correlations between IL-6 expression and postoperative VAS (ρ = 0.38, p = 0.048) and ODI (ρ = 0.44, p = 0.02). No significant correlations were found between intradiscal IL-6 expression and preoperative VAS (ρ = -0.12, p = 0.54). Trends were seen associating IL-6 expression and change in VAS/ODI (ρ = -0.35 p = 0.067; ρ = -0.34, p = 0.08, respectively). A trend associated IL-6 and preoperative ODI (ρ = 0.36, p = 0.063). CONCLUSION: The direct association between IL-6 expression and VAS/ODI suggests patients with elevated intradiscal cytokine expression may have worse early outcomes than those with lower expression of IL-6 after surgery for symptomatic disc degeneration.

Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Drug-Induced Inotropic Effects in Early Drug Development. Part 2: Designing and Fabricating Microsystems for Assaying Cardiac Contractility With Physiological Relevance Using Human iPSC-Cardiomyocytes.

Contractility of the myocardium engines the pumping function of the heart and is enabled by the collective contractile activity of its muscle cells: cardiomyocytes. The effects of drugs on the contractility of human cardiomyocytes in vitro can provide mechanistic insight that can support the prediction of clinical cardiac drug effects early in drug development. Cardiomyocytes differentiated from human-induced pluripotent stem cells have high potential for overcoming the current limitations of contractility assays because they attach easily to extracellular materials and last long in culture, while having human- and patient-specific properties. Under these conditions, contractility measurements can be non-destructive and minimally invasive, which allow assaying sub-chronic effects of drugs. For this purpose, the function of cardiomyocytes in vitro must reflect physiological settings, which is not observed in cultured cardiomyocytes derived from induced pluripotent stem cells because of the fetal-like properties of their contractile machinery. Primary cardiomyocytes or tissues of human origin fully represent physiological cellular properties, but are not easily available, do not last long in culture, and do not attach easily to force sensors or mechanical actuators. Microengineered cellular systems with a more mature contractile function have been developed in the last 5 years to overcome this limitation of stem cell-derived cardiomyocytes, while simultaneously measuring contractile endpoints with integrated force sensors/actuators and image-based techniques. Known effects of engineered microenvironments on the maturity of cardiomyocyte contractility have also been discovered in the development of these systems. Based on these discoveries, we review here design criteria of microengineered platforms of cardiomyocytes derived from pluripotent stem cells for measuring contractility with higher physiological relevance. These criteria involve the use of electromechanical, chemical and morphological cues, co-culture of different cell types, and three-dimensional cellular microenvironments. We further discuss the use and the current challenges for developing and improving these novel technologies for predicting clinical effects of drugs based on contractility measurements with cardiomyocytes differentiated from induced pluripotent stem cells. Future research should establish contexts of use in drug development for novel contractility assays with stem cell-derived cardiomyocytes.

Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Adverse Drug-Induced Inotropic Effects in Early Drug Development. Part 1: General Considerations for Development of Novel Testing Platforms.

Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dtmax) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, in vitro test systems would be a valuable addition to our strategies for identifying the best possible drug development candidates. Thus, testing platforms with reasonably high throughput, and affordable costs would be helpful for early screening purposes. There may also be utility for testing platforms that provide mechanistic information about how a given drug affects cardiac contractility. Finally, there could be in vitro testing platforms that could ultimately contribute to the regulatory safety package of a new drug. The characteristics needed for a successful cell or tissue-based testing platform for cardiac contractility will be dictated by its intended use. In this article, general considerations are presented with the intent of guiding the development of new testing platforms that will find utility in drug research and development. In the following article (part 2), specific aspects of using human-induced stem cell-derived cardiomyocytes for this purpose are addressed.

Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) Science and the CBRNE Science Medical Operations Science Support Expert (CMOSSE).

A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.

Does Riluzole Influence Bone Formation?: An In Vitro Study of Human Mesenchymal Stromal Cells and Osteoblast.

STUDY DESIGN: A post-test design biological experiment. OBJECTIVE: The aim of this study was to evaluate the osteogenic effects of riluzole on human mesenchymal stromal cells and osteoblasts. SUMMARY OF BACKGROUND DATA: Riluzole may benefit patients with spinal cord injury (SCI) from a neurologic perspective, but little is known about riluzole's effect on bone formation, fracture healing, or osteogenesis. METHODS: Human mesenchymal stromal cells (hMSCs) and human osteoblasts (hOB) were obtained and isolated from healthy donors and cultured. The cells were treated with riluzole of different concentrations (50, 150, 450 ng/mL) for 1, 2, 3, and 4 weeks. Cytotoxicity was evaluated as was the induction of osteogenic differentiation of hMSCs. Differentiation was evaluated by measuring alkaline phosphatase (ALP) activity and with Alizarin red staining. Osteogenic gene expression of type I collagen (Col1), ALP, osteocalcin (Ocn), Runx2, Sox9, Runx2/Sox9 ratio were measured by qRT-PCR. RESULTS: No cytotoxicity or increased proliferation was observed in bone marrow derived hMSCs and primary hOBs cultured with riluzole over 7 days. ALP activity was slightly increased in hMSCs after treatment for 2 weeks with riluzole 150 ng/mL and slightly upregulated by 150% (150 ng/mL) and 90% (450 ng/mL) in hMSCs at 3 weeks. In hOBs, ALP activity almost doubled after 2 weeks of culture with riluzole 150 ng/mL (P < 0.05). More pronounced 2.6-fold upregulation was noticed after 3 weeks of culture with riluzole at both 150 ng/mL (P = 0.05) and 450 ng/mL (P = 0.05). No significant influence of riluzole on the mRNA expression of osteocalcin (OCN) was observed. CONCLUSION: The effect of riluzole on bone formation is mixed; low-dose riluzole has no effect on the viability or function of either hMSCs or hOBs. The activity of ALP in both cell types is upregulated by high-dose riluzole, which may indicate that high-dose riluzole can increase osteogenic metabolism and subsequently accelerate bone healing process. However, at high concentrations, riluzole leads to a decrease in osteogenic gene expression, including Runx2 and type 1 collagen. LEVEL OF EVIDENCE: N/A.

A Proof-of-Concept Evaluation of JTPc and Tp-Tec as Proarrhythmia Biomarkers in Preclinical Species: A Retrospective Analysis by an HESI-Sponsored Consortium.

INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.